Beginning from December 2019, the present COVID-19 has ravaged the world for almost two years. While it appears to have peaked in many countries, it is still not under control in other areas. Worse still, new mutations of the virus continue to drive new waves of infection which manage to break through natural and human measures of defence.

Beginning from December 2019, the present COVID-19 has ravaged the world for almost two years. While it appears to have peaked in many countries, it is still not under control in other areas. Worse still, new mutations of the virus continue to drive new waves of infection which manage to break through natural and human measures of defence. In the following brief review, we shall attempt to analyse the problems confronting this pandemic from the historical, social-psychological, geopolitical, biological, and medical perspective.

Idemics date back to the beginning of human history and often shaped the course of history [1]. The term epidemics appeared in ancient Egyptian, Indian and Chinese languages over 4,000 years ago. In ancient Greece, it sealed the fate of the Athenians in their war with the Spartans in 430 B.C.

It was probably one of the factors that halted the conquest of Alexander the Great, who seemed to die prematurely in 323 B.C. of an infection caught in one of his campaigns. It ravaged China during the beginning of the first century eliminating a quarter of the population and again in the third century eliminating a third of the population. Around the same time similar epidemics broke out in the Roman Empire in the West, raising speculations that this was probably a pandemic. The situation was repeated during the 13th century when an epidemic coincided with the Mongolian conquest sweeping over most of Asia and half of Europe. Evidence was not strong as the “Black Death” did not appear to afflict Mongolia itself. In modern times, we have seen many epidemics come and gone, including small pox, cholera, typhoid fever, scarlet fever, poliomyelitis. Other infections have kept resurfacing, defying various temporarily successful measures. These include influenza, malaria, tuberculosis, syphilis etc. Still others we seem to be gaining control as typified by HIV and the viral hepatitis B and C. So, in this fight against the coronavirus SARS-CoV2 why is victory so elusive? We shall approach the problems according to the conventional factors in an epidemic.

Zootic Reservoir

One of the early hints that infections could be perpetuated in animals and jump species to affect humans was documented in ancient China when in 476 A.D. silk worms were first found to die in large numbers, followed by cattle and finally humans, with the epidemic sweeping down the course of the Yellow River from West to East [1]. In the 19th century [1], Patrick Mansion, researching in Hong Kong and Southern China, discovered the transmission of filaria by the mosquito. He finally convinced Ronald Ross that mosquitoes could transmit the pathogen and solved the mystery of malaria, which has a reservoir in forest animals including monkeys, an intermediate host in mosquitoes, which ultimately pass the infection to humans [2]. The notorious pandemic in 1919 originated in U.S.A., extended to Europe, where it was misnamed the “Spanish Flu”, and swept over the world causing the most massive and lethal disaster of the 20th century [3]. With the advancement of molecular science, the causative influenza virus H1N1 was found to have considerable resemblance to the swine influenza virus and probably originated from a pig reservoir. More recently, the first SARS epidemic in 2002-2003 was traced to coronavirus perpetuated in animal hosts like bats and civet cats and passed further on to humans. Similarly, subsequent repeated outbreaks of coronavirus infections, the MERS, arose from the Middle East and was traced to reservoirs in the bats with the camels as intermediate hosts.

The early stage of the pandemic and its control – lock-down and isolation

The present pandemic has been traced to zootic reservoirs in bats with the pangolin as one of the known intermediate hosts. The causative virus, SARS-COV2, bears strong resemblance to the first SARS pandemic but also important differences which are reflected in the transmission trajectory, the clinical course and the problems of control and treatment. Evidence exists which suggests sporadic infections in various places within or outside China [4]. Some infections passed as “influenza” due to lack of recognition, while others failed to develop into epidemics and simply died out [5]. The fact remains that the first confirmed infection appears in December 2019 in Wuhan, China. There was some delay in the recognition of the gravity of the infection. Most health workers believed that it was like another “bird flu”, serious if not lethal, but mainly an infection passed from the pangolin to human, with little risk of human-to-human transmission. There was no cover-up of the infection as subsequently alleged by various other countries, but a definite failure to recognize the full nature and gravity of the infection. This is understandable since it was due to an entirely new virus unknown to mankind. 

By mid-January 2020, the true nature of the epidemic was recognized. The action of the Chinese leadership was swift, resolute and painful. The methodology of lock-down and isolation to control an epidemic is long established based on centuries of past experience [1]. As early as the year 2 A.D., a Chinese Emperor ordered to fight an epidemic in Eastern China by, “Empty out some premises and put (isolate) the sick people there, yet make sure they are looked after by physicians and well-supplied with medicine.” Remarkably, the Emperor was only nine years old and had to handle the crisis all alone, as his maternal uncle and prime minister was too busy lobbying for popular support for his own plan to usurp the throne, and he couldn’t be bothered with any distraction by the epidemic. Another Emperor of the Han Dynasty, (himself an ardent musician and played the flute), in facing another epidemic ordered, “Dissolve the imperial orchestra, close the imperial stable and dispose of the stallions; cut the imperial banquets; let all my subjects do likewise, and divert the resources to fight the epidemic.” Traditionally, in the face of an epidemic the top priority of a Chinese leader has always been health over wealth. A lock-down was slapped on Wuhan,6 the greatest industrial centre in China. It was the eve of the traditional Chinese New Year and hundreds of thousands of travellers were stranded on their homeward journey to celebrate the annual family reunion. It was also a great blow to the booming Chinese economy which was not on the way to catch up with U.S.A. as viewed by the West but only trying to shrug off poverty in reality. (The West only look at the sum-total GDP figures, but if you divide it by the huge population, the per capita income for many Chinese people is still barely trying to get over the poverty line.) And so, with a huge setback in economy and an immensely unpopular lockdown decision, China achieved early control of the pandemic [6].

A similar and even more remarkable example of infection control is seen in Macau [7]. The small peninsula with a population of half a million, flanked by two small adjacent islands on the Southern Coast of China. It was occupied by the Portuguese for four centuries but returned to China in 1999. In late January 2020, Macau enforced a strict lock-down immediately following Mainland China and closed all its casinos and tourism as well as putting on hold all its manufacturing industry (which depends heavily on factories and labour force in Mainland China). The territory sacrificed all its major source of revenue in putting health as top priority. Today, as one of the smallest and most densely populated cities in the world, Macau stands out as the only one with a minimal number of infection (77 cases in 18 months), no mortality and zero new indigenous COVID-19 cases for over a whole year.  But this policy may not be easily generalized to other territories who are not based on the casino industry. As soon as the pandemic is under control tourist gamblers are expected to rapidly return and a rapid economic recovery is anticipated. The same may not be expected of most other industries.  This is the first and most important problem confronting the world today, the question of priority which boils down to the choice between health and wealth. 

Masks, face shields, hand hygiene, quarantine

Lock-down is to break the transmission of virus at the level of society. Transmission should also be blocked at the personal level. The most obvious and important tool is the face mask. Originally used by 19th century European surgeons to reduce wound contamination during operations, surgical masks were refined by the Chinese epidemiologist Wu Lien-teh in fighting the plague epidemic in Northern China in 1910 [8]. Dr. Wu was able to prove scientifically that the bacteria spread from the lymph node (bubonic plague) to the blood stream (septicaemic plague) and from the blood to the lungs (pneumonic plague). Once the lungs were infected the infection spread rapidly among humans via sputum, droplets and aerosol trajectories. Wu followed his common-sense logics and redesigned the surgical mask to break the transmission chain of the plague. In 1910, China was withering in a sub-colonial status. All major public services were headed by Europeans including the health service. His European superior remained entrenched in the old concept of bubonic plague and was biased against this “Chinaman’s new unorthodox idea” of pneumonic plague as well as the use of the facial mask. Dr. Wu was laid off and the plague raged on. But very soon this senior European doctor caught the infection himself and died within days. Dr. Wu could now carry out his anti-epidemic measures without hindrance, and the mask was instrumental in bringing the highly lethal pneumonic plague under control. The mask has since established its critically important role in subsequent air-borne and droplet-borne epidemics. Sadly, in 2002 the health system in Hong Kong was caught off-guard by the first SARS pandemic, all equipments were in short supply. Administrators were slow to apply remedial measures, and frontline health workers were forced to reuse disposable masks and gowns resulting in substantial tolls. Such tragic experience was repeated in 2020 in some health management organizations in Western countries, with the administrators covering their ineptitude by high-handedly suppressing the complaints of front-line health workers. This is the second major problem confronting our fight against any epidemic including the present pandemic, the biased refusal to accept the crucial importance of the facial masks and other simple and common-sense measures and the administrators putting other considerations above the safety of frontline workers. 

Another common problem with masking is objection from the lay people. In spite of ample scientific evidence on the efficacy of masking and its common usage in East Asia, there were strong objections from certain sectors in the West based on individual interpretation or misinterpretation of personal freedom and human rights. There were also objections to social and physical distancing. Some churches refused to close congregations of worship. Some choirs continued to hold singing sessions. Some men and women continued to seek pleasure among various partners and spread the virus. Some people continued to travel and the airplane cabin and tourist cruises provided many opportunities of contact and spread of the virus. Offices, schools and shopping centres continued to open or started to reopen before the disease was under control. 

It has been shown that, after shedding from the patient, the coronavirus could remain viable with infection potential for up to 48 hours. So, cleaning of fomites and hand hygiene is important. A less common portal of entry for the virus is through the eyes and it is shown that wearing eyeglasses (but not contact lens) confers some protection. For those not wearing glasses, a transparent face shield should be a good, if not better, substitute [9].

Caps, gowns, masks, face shields, hand-scrubs, gloves are all inexpensive items. The problem is they are used on a disposable basis and daily costs do add up to significant figures and impact on the budget. Once again, administrative interference may come into play. If administrators put profit as top priority, the safety of health workers will be compromised.

Characteristics peculiar to COVID-19

The next problem is asymptomatic transmission. COVID-19 could easily boast as being one of the most incomprehensible and intangible infections [10]. The clinical features present problems at almost every step and every corner [6]. To begin with, it is almost impossible to calculate the incubation period which varies from one or two days to a few weeks. For asymptomatic patients, we shall never be able to find out. In certain communities like the antenatal clinics a population-wide study showed up to 40% asymptomatic carriers. But this may not apply to the general population.

More importantly, the timing of virus shredding determines the infectivity of the patient and the risk of the contacts. It also indirectly determines the fate of the pandemic and the human race under its ravage. For the first SARS pandemic virus shedding began from the first two days of symptoms rising to a peak around day 5 and then declined. That was why it tended to infect health workers more than other contacts because by day 5 the patient was usually seeking medical help or hospitalized. So, once the disease was well-recognized it would have been isolated in hospital and the infection chain broken. Thus, the pandemic rapidly faded off after the first few months [11].

Not so with the new COVID-19, virus shedding starts within one to two days after virus entry and peaks one to two days before symptoms appear. The disease spreads freely and unknowingly at the pre-symptomatic or asymptomatic stage, evading conventional methods of screening such as taking temperature, checking clinical history and contact history and even blood tests and chest X-ray films. The only way to sort out such asymptomatic and pre-symptomatic carriers is to do complete virus screening for the whole population at the first hint of a new wave of infection. This in fact, has been the practice in Macau and undoubtedly contributed to their success.

Once again, the problem of personal freedom and human rights comes into play. The individual may argue that since she/he has no symptoms, the screening tests are unnecessary and infringes on his personal liberty and human rights. There could also be a subconscious bias against something like the anti-infection mask and the stringent lock-down measures, developed in a country historically well known for its poverty and backward status. 

Problem of Hospital Beds

COVID-19 may hit a community with widely waxing and waning severity. At its height the number of patients may overwhelm any apparently well-equipped and well-staffed medical establishment [12]. China, based on previous experience with SARS has devised methods to build instant hospitals and large number of hospital beds by conversion of indoor stadiums and exhibition halls into make-shift hospitals. When the pandemic subsided, these facilities are returned to their original purpose. Again, such conversions may not be palatable or acceptable in other countries.

Problem of Medications (see Table 1)

A number of medications have evolved since the appearance of COVID19, some have since been delisted as useless or even deleterious (see Table 1). A few have shown marginal benefits. None has come to any high efficacy for cure. Even if a new drug were to succeed, it would probably come at a price beyond the budget of the average low or middle-low income country. Our best hope may lie with the repurpose of established old drugs (see Table 1).

Table 1: A list of agents used or misused on COVID-19 patients

AATD, alfa-1-antitrypsin deficiency

DM, diabetes mellitus

Esp., especially

Fr., from

Hosp., hospital, hospitalization

HR, hazard ratio

OR, odds ratio

PIKfyve, phosphatidylinositol-3-phosphatase five kinase

Rec.hu, recombinant human

Rx, treatment

The problem of thrombosis

A well-known complication of COVID-19 is the risk of deep vein thrombosis and pulmonary embolism (PE) [13, 14]. In COVID-19, the blood marker D-dimer has 100 sensitivity but only 9 specificity for PE. Due to virus-induced endothelial inflammation the D-dimer will be always raised. Raising the threshold of D-dimer will improve specificity for PE but sacrifice its sensitivity. Thus, the test may not be helpful in COVID-19. Although a low value of D-dimer may exclude deep vein thrombosis and pulmonary embolism, it is rare to come by because the pathology of the infection itself would raise the value, while a high value might be due to other factors than deep vein thrombosis and pulmonary embolism. Other in-depth investigations such as ultrasound doppler, and pulmonary CT angiogram may be necessary.

The treatment of thrombosis is also problematic as heparin might induce PF4-related thrombotic thrombocytopenia and alternative anticoagulants might be necessary and it would be a delicate balance between the risk of bleeding and the risk of thrombosis.

The problem of hypoxia

To begin with, severe hypoxia may develop deceptively with very little symptoms. Often diagnosis dependents on vigilance and liberal use of oximeter and blood gas analysis. Certain refinements on non-pharmacological intervention have developed since the first SARS pandemic. We are more experienced in applying the prone position in lung ventilation, in administering high flow oxygenation and non-invasive biphasic respiratory support. We have developed sophisticated enclosed methods of tracheal intubation and tracheostomy. Yet, we shall always have problems with the hospital administration whose first worry is about the safety of the staff and other patients from cross infection, and this goes with all positive pressure ventilation and aerosol generating manipulations. Advancing the ECMO (extra-corporal membrane oxygenator) from the third line to second line rescue of oxygen desaturation may be a solution. The problem is it will be against the guidelines which relegate the use of this advanced technology to a late and moribund stage of the disease [15]. 

Problems in convalescence

While most patients will recover at the end of two to three weeks, some will have lingering symptom and/or continue to shed the virus. Others might be virus negative for two or three tests and then become positive again. Such “Long COVID” patients often, but not invariably, come from the elderly or debilitated group and warrant prolonged monitoring and follow up.16

A more serious problem is “Multi-system Inflammatory Syndrome” (MIS), more common in children (MIS-C) [17] than adults (MSI-A) [18]. The disorder is most likely related to cytokine release and its pathogenesis and treatment is still evolving.

Vaccine and vaccine related problems (see Table 2)

A variety of COVID-19 have been produced at record speed. Some are based on conventional methods of production such as using inactivated virus or recombinant viral proteins. More important is the major technological breakthrough of using messenger RNA to direct the recipient’s own cells to produce the viral protein for eliciting antibodies from the recipients. This reduces the cost, time and labour of vaccine production as most of the work of production is passed from the manufacturer to the recipient’s own cells. The problem is the technology has no substantial past human experience to back up its safety. Even experimental animal study is scanty. Effects on the elderly, the very young, the pregnant mother and the unborn child are all unknown.

Table 2: A List of COVID-19 vaccines

Ab, antibody

Ad/AdV, adenovirus

CVST, cerebral venous sinus thrombosis

d, day

GBS, Guillain-Barre syndrome

GMT, geometric mean titre

MAE, major adverse event

NDV, New Castle disease virus

NVX, Novavax

RBD, receptor binding domain

Rec/recomb, recombinant

S, spike protein

VITT, vaccine-induced thrombotic thrombocytopenia

The next problem with COVID-19 vaccines is over-inflated expectation, so that the public is misled to believe vaccines would solve all problems of the pandemic.  Anti-viral vaccines principally work by eliciting neutralizing antibodies that bind to specific sites (epitopes) on the Spike protein of the virus and stop its gaining attachment to receptors (ACE-2) on the human cells. There are 3 scenarios where this neutralization might fail. First, the level of antibodies might be inadequate due to its waning with time or inadequate original response of the recipient’s immune system from old age, debilitation or immune suppression from disease and/ or disease treatment. Second, the exposure of the individual is so severe that the number of virus overwhelms the level of antibodies. Third, the virus has mutated so that the antibodies could no longer effectively neutralize the invader. Vaccines should work along with other measures like masking, and reduction of exposure by social distancing and not replace them altogether. The time to relax our vigilance is when the disease is eliminated, not when the population is 70, 80 or 90 vaccinated.

By relaxing on lock-down measures, masking and social distancing, and relying exclusively on the vaccines we are creating a paradox in the infection trajectory. The vaccine will effectively protect the recipients from high mortality and morbidity but not entirely from asymptomatic infection. Instead of ensuring a clear interruption of virus transmission, our vaccines are creating an ever-increasing number of asymptomatic carriers, silently spreading the infection undetected and unhindered in our society.

Improving vaccine efficacy

The current method to improve vaccine efficacy is to add another booster dose. Already, a third dose has been applied on the elderly and those immunologically compromised in developed countries. In Israel they are going on to a fourth booster dose. For the ChAdOx vaccine it has been demonstrated that a higher antibody response could be elicited if the second dose of vaccine is given 4 weeks after the first dose instead of the officially recommended 3 weeks. However, such a delay would also expose the recipient to the risk of delay in achieving full protection. Choice of vaccine also may make a difference. E.g. BNT-162b2 is found to elicit a level of antibodies nine times that of SinoVac [11]. 

Intradermal versus intramuscular vaccine injection

The skin has been the route of administering vaccine for many years, being the site for small pox vaccine and the BCG against tuberculosis. The skin is endowed with a rich supply of dendritic cells to process the antigens [11]. Locked in a small intradermal blister, for the first 15 to 30 minutes, the vaccine has more time to interact with skin tissues, with no chance of accidentally entering a blood vessel or a nerve, both would result in grave consequences. In the case of HBV vaccine, intradermal vaccine has been shown to need only 1/10 of the standard dose to elicit a protection level higher than the intramuscular injection. Booster doses would put extra demand on vaccine supply and expenses. Changing to intradermal injection at reduced dosage would effectively expand the vaccine supply at no extra cost. Moreover, dose reduction implies risk reduction and might even change the attitude of some vaccine skeptics.

Here the problem is the rigidity of guidelines which stipulate that the vaccines have to be given by the intramuscular route and any change would have go through elaborate trials before official approval.

The problem of virus mutations (see Table 3)

The virus SARS-CoV-2 that causes this pandemic is a positive-sense single-stranded RNA virus. Because of this, its genome ranks among the most unstable among virus, surpassed only by the influenza virus which has the additional advantage of having its genome divided into eight segments and capable of reshuffling (like in a pack of cards). Nonetheless, the coronavirus CoV-2 already possesses great propensity to mutate. Such mutations have led to frequent emergence of new variants, some of which might give the new variants advantages in transmission, evasion from host immunity, resistance to treatment and, worst of all, increased pathogenicity. Certain virus variants are capable of overcoming immunity conferred by vaccines or previous infections. And the virus can mutate much faster than the development of new vaccines by humans.

Table 3: A list of some of the more important mutations in the SARS-CoV-2 virus

Ab, antibody

Assoc., associate or associated

fr., from

mut, mutation(s)

NAb, neutralizing antibody

nsp, non-structural protein

pt., pts, patient, patients

w/, with

Can virus mutation help mankind to solve the COVID-19 problem?

Not all virus mutations are deleterious to mankind. Many are also deleterious to the virus itself.

Singapore has reported on the deletion of 382 nucleotides in a SARS-CoV-2 variant causing truncation at ORF 7b and elimination of ORF8 transcription [19]. This resulted in a milder form of infection with lower virus replication, less inflammatory cytokine production and reduced morbidity and mortality with none of the 29 infected patients requiring any oxygen supplement compared with oxygen requirement in 30 of patients infected with wild type virus. 

Japan’s fifth wave of the pandemic following the summer Olympic Games was considerably milder than expected. Ituro Inoue recently offered a plausible explanation [20]. The virus non-structural protein nsp-14, under pressure of host APOBEC enzyme activity has gone through mutations that initially leads to much faster replication, but also to loss of capability to suppress host IL1-led anti-viral defence, and ultimately accumulation of a heavy load of mutations incompatible with the virus’ own survival. If substantiated, this mechanism would add a silver lining to the dark cloud hanging over the pandemic. 

And it brings out a stark basic problem in this pandemic. While even the virus itself may be helping us with mutations that favour its own control, we humans continue to put other priorities above consideration of health. As late as the 20th century the US and the Soviet Union joined hands, put the Cold War aside, and developed vaccines that led to control of the polio pandemic. Today, all that cooperative spirit is buried under the obsession of a desire to stay on top of the world in terms of wealth and power.

This is the greatest problem confronting the present, the bias and lack of mutual trust and conjoint effort to fight the virus. What does it profit a nation if it gains the status as the “greatest” in the world but suffers the loss of the health of its own people?