Spreading stealthily?

Asymptomatic carrier transmission of COVID-19 throws up a formidable challenge as the world confronts a novel virus

Spreading stealthily?

Fears of a global COVID-19 pandemic have become real as the new virus spreads across continents, with a rising number of new infections and fatality reported every day. 

As of the end of February, 99% of confirmed cases of the virus infection have been restricted to China. However, the soaring number of cases in South Korea, an eruption of hundreds of cases in Italy, a spike in the number of deaths in Iran and a big uptick in the number of infections in North America have heightened concerns that the deadly disease will soon start spreading to the people in countries ill-equipped to handle such massive outbreaks.

The WHO, while declaring COVID-19 outbreak a “public-health emergency of international concern” in January, highlighted the potential of the infection reaching countries with weaker health systems as one of the biggest worries. 

As fears of the outbreak curtail travel; tourist destinations, hotels and shopping malls have shut down in Asia all the way from Japan to Thailand, as well as in many other regions.

Even as the coronavirus outbreak cripples China, disruptions to the Asian dragon’s production lines have had a ripple effect on airlines, automakers, tech companies and other sectors.

Tech giants like Apple have lowered their financial forecast. USFDA fears shortages of critical medical products and devices in the country. India is concerned that a dearth of Chinese raw materials would deplete its essential medicines stockpile, while Japan is anxious that the 2020 Olympics in Tokyo could be rescheduled.

Stock markets around the world continue to be jittery, even as China keeps postponing the reopening of its industrial hubs which have been locked down in the aftermath of the outbreak. 

Novel virus; novel challenges 

The detection of COVID-19, which is currently wreaking havoc in the world, was somewhat accidental. It followed an outbreak of pneumonia without a clear cause in the Chinese city of Wuhan. Further investigations led to a novel strain of coronavirus in December 2019. 

COVID-19 is now leaping far and wide, infecting and killing more and more people across countries.

First identified in the mid-1960s, coronaviruses belong to a family of enveloped, non-segmented positive-sense RNA viruses. They have a zoonotic origin and are known to infect humans and a variety of animals and birds.

Given the high rates of occurrence of coronaviruses, their large genetic variety, recurrent recombination of their genomes and increasing human-animal interface undertakings, new coronaviruses are likely to emerge sporadically in humans owing to periodic spill-over events and common cross-species infections, researchers say.

“There are many more coronaviruses circulating in animals that have not yet spilled over to humans,” says Foster Kofi Ayittey, research scholar at Curtin Malaysia Research Institute, Curtin University, Malaysia.

Ayittey, who is the author of two recent publications on COVID-19 in Journal of Medical Virology, adds that keeping in mind popular cases of SARS-CoV spilling over to humans via civet cats, MERS-CoV spilling over to humans via dromedary camels, and COVID-19, whose intermediate host is not yet certain, the possibility of spill-over events in other regions of the world is high. 

There are currently four known genera for coronaviruses, all of which have zoonotic origins and can originate from bat, avian or pig gene pools. This implies that wherever these animals are in close human contact, there is a probability of a spill-over event. 

Once in humans, the virus is likely to spread from human to human, mainly causing respiratory diseases.

Severe Acute Respiratory Syndrome (SARS-CoV) originated in southern China in 2003, and Middle East Respiratory Syndrome (MERS-CoV) was identified in Saudi Arabia in 2012. Together, they took a toll of 1,600 lives.

Pangolins—The missing link?

Crucial details about the emergent virus and its exact transmission dynamics are yet to be clear. The similarity in the genetic sequence of COVID-19 virus and those of other known coronaviruses supports the bat-origin theory. 

However, there should be an intermediate host – another animal – that probably transmitted the virus to humans as in the case of SARS and MERS.

The identity of the animal source of the coronavirus has been one of the key questions that researchers have been racing to answer.

Initially, scientists in Beijing claimed that snakes were the source of the virus. But this theory was later debunked.

COVID-19 is thought to have leapt to humans at a seafood and wild-animal market in Wuhan, where many of the first people to become infected worked.

In February, some researchers in Guangzhou, China, identified pangolins as the potential animal source of the coronavirus outbreak. Pangolins are long-snouted, ant-eating mammals often used in traditional Chinese medicine.

A genetic comparison of coronaviruses taken from pangolins and from infected humans found that the sequences are 99% similar, the researchers reported. This observation looks plausible as emerging data suggests that pangolins carry viruses that are closely related to the new coronavirus.

The scientists, however, did not reveal where in pangolins they found the virus. 

Parts of pangolins are controversially used in traditional Chinese medicine to treat various skin diseases, arthritis, menstrual problems etc.

Pangolins are protected animals and were not listed in the inventory of animals sold in the market.

As the current outbreak is suspected to have originated in wild-animal markets, China may soon clamp down on trading wild animals, reports say. 

Consumption of the meat of wild animals is considered to be behind the Ebola outbreak in Africa.

A total ban, however, is unlikely in China as wildlife trade is a significant part of people’s livelihoods in the country.

Asymptomatic “super” spreaders  

The mode of transmission as well as the incubation period of the emergent virus continues to remain complex.

Transmission is believed to be via cough or respiratory droplets, contact with bodily fluids and from contaminated surfaces. 

Since there are no conclusive findings on the intermediate host, it is important that unprotected contact with any wild animal is avoided, while scientists struggle to come out with exact etiological findings for COVID-19 to prevent any more infections from the reservoir and intermediate hosts of this virus, warns Ayittey.

Even as concerns about the transmissibility of the virus remain, a small observational study in Wuhan found no evidence that COVID-19 can be passed on to the child while in the womb. Infection during pregnancy was also not associated with higher rates of maternal and neonatal complications, unlike in case of SARS. The long-term effect of the disease on the mother’s and child’s health is yet to be evaluated. The findings, however, are disputed. 

What baffles researchers is that a large number of people infected with the virus do not show any symptoms, and can still transmit the infection to others.

According to Ayittey, the incubation period for COVID-19 keeps changing based on information from current research articles.

Currently, the quarantine guideline for COVID-19 is for 14 days. Researchers have found that it could take up to 24 days for symptoms to manifest. That notwithstanding, findings reveal that asymptomatic patients can spread viral disease with high efficiency.

Some preliminary estimates show that two-thirds of the coronavirus infections in Wuhan, before the travel ban came into force on January 23, was transmitted by people who were not documented as infected.

New England Journal of Medicine reports that infectiousness reaches its peak shortly after people start to feel sick. NEJM also described the case of a Munich patient with a non-specific illness who has transmitted the infection during the incubation period.

There is also the story about a British “super-spreader” who infected 11 people before finally showing symptoms. JAMA too chronicles a similar case of a 20-year-old Wuhan woman without any outward symptoms, who infected five relatives.

This unique feature sets the new virus apart from SARS, which usually spreads only once people are ill enough to need hospital care. SARS was contained once outbreaks in hospitals were brought under control, and currently, there is no evidence that the virus is still circulating in humans, say experts.

Scientists are also worried about the high sputum viral loads in convalescent patients, indicating prolonged shedding of the virus after recovery. The asymptomatic spread of the virus can mean that it would be difficult to rein in the pathogen. So, it is more likely to become endemic.

According to Prof Bassetti, if the current findings on asymptomatic transmission are replicated and confirmed, this may contribute to hampering infection-control measures. However, the mechanism and the rate of such presumed asymptomatic transmissions require further investigation.

“Pre-symptomatic transmission of COVID-19 is certainly one of its most striking features, but to say it is the most striking feature is not possible now,” comments Ayittey.

The fatal disease has features attacking other organs of the body apart from the lungs; unlike its close cousin SARS-CoV, which only targets the lungs. 

Similarly, whereas SARS-CoV is thought of to be a lower respiratory infection only, the current COVID-19 is found replicating even in the upper respiratory tract, he explains. 

Deadly for the old; milder for young?

Though the infection rate is very high and rapid, the case fatality rate of COVID-19 infection looks comparatively lower to the other coronaviruses.

A mortality analysis revealed that the infection runs a severe course in older people with co-morbid conditions, leading to deaths, while youngsters usually see a milder form of the disease.

“In a recent study report published in JAMA on 138 hospitalised patients with COVID-19 infection, the proportion of ICU-admitted patients were higher in older people and in people with baseline comorbidities. So, this seems to indicate that the disease could be more severe in these populations,” says Dr Matteo Bassetti, Professor of Infectious Diseases, Department of Health Science, University of Genoa, Italy.   

According to initial, published reports, although COVID-19 is able to cause severe acute respiratory syndrome with fever, dry cough and dyspnoea as the characteristic features, there are some important differences compared to SARS-CoV and MERS-CoV, adds Prof Bassetti, lead author of the article: “The novel Chinese coronavirus (2019-nCoV) infections: Challenges for fighting the storm”, in the January issue of European Journal of Clinical Investigation.

First of all, the overall case fatality rate of COVID-19 infection seems lower than those of SARS-CoV and MERS-CoV infections. But this does not mean that the lung disease is not severe, but that the proportion of severe cases could be lower than in SARS-CoV and MERS-CoV infections.

Secondly, some of the initial reports suggest a possible lower frequency of diarrhoea compared to SARS-CoV and MERS-CoV infections, but this has to be confirmed. 

Very importantly, Prof Bassetti asserts, it should be reminded that the other four coronaviruses known to infect humans (229E, NL63, OC43 and HKU1) are unable to cause severe disease in the lower respiratory tract and are responsible for mild upper respiratory tract diseases.

ICU patients with COVID-19 infection showed higher amounts of pro-inflammatory cytokines, well in line with SARS and MERS. Tests revealed a large amount of anti-inflammatory markers as well in some of these patients (unlike SARS or MERS). 

The possible inference, according to Prof Bassetti, who is also the Chairperson of the European Society of Clinical Microbiology and Infectious Diseases in Critically Ill Patients (ESGCIP), is that this could be one of the reasons for the possible reduced severity compared to SARS and MERS. 

However, this interpretation should be made very cautiously, since this evidence arises from a very small sample of patients. Consequently, further assessments of both the reproducibility of this laboratory finding and of its possible correlation with disease severity is warranted before supporting this claim.

A WHO expert says that COVID-19 can turn severe in a fifth of the infections, and has a fatality rate of around 2%. This is significantly lower than SARS, which killed around 10% of the people it infected. Virologists say that the known death rate for the new coronavirus is likely to decrease as mild and asymptomatic cases are identified.

2% is still quite high for an infectious disease. The 1918 influenza outbreak, known as the Spanish flu, which started in 1918, infected around half a billion people and killed 50 million at the infectious rate of 2.5%. 

COVID-19 has killed more than SARS-CoV and MERS-CoV combined, according to Ayittey. But the fatality rate of a disease is a ratio of fatalities to the total number of infected people. SARS-CoV infected approximately 8,098 people and killed at least 774, resulting in a fatality rate of 9.6%. Out of the 2,494 people infected by MERS-CoV as of November 2019, 858 of them died, equating to a fatality rate of 34.4%. 

Since records of new cases and deaths are constantly being updated, it is difficult to calculate the fatality rate for a virus in the middle of an outbreak.

But the current scenario could change, fear some researchers. As the virus spreads to more people, it can mutate to become more virulent and cause disease in young people. Others maintain that such mutations are uncommon in outbreak pathogens even though viruses constantly mutate as part of their life cycle. Most mutations are detrimental to the virus and some of them could even reduce their virulence.

Tepid initial response; high frontline casualty

The global research community is also upset that the initial response to the Wuhan outbreak has been rather slow. There has been a lot of misinformation and mishandling despite clear signals, they rue.

Health authorities started acting only when the situation started deteriorating. Urgency was felt when things really got out of hand. This is in stark contrast with similar outbreaks in recent times.

“Looking critically at how the global community has responded in attempts to curb the fatal disease, I will not say the response has been unprecedented,” says Ayittey. 

When the new H1N1 virus emerged in the US in April 2009, WHO declared a PHEIC within 10 days of the emergence of the virus, by which time the virus had only infected 4 people in the US. 

The US Centre for Disease Control and Prevention (CDC) began investigating candidate vaccines on April 21, 6 days after the first case was detected. 

On the contrary, WHO took approximately one month to declare COVID-19 as PHEIC, and vaccine investigations began almost a month after the emergence of the disease. 

News reports also indicate that Chinese authorities did not report the outbreak to WHO early enough. 

“Considering all the lessons learnt from the SARS-CoV outbreak, MERS-CoV outbreak, and the response mechanisms implemented by the CDC in 2009 during the second H1N1 outbreak, I believe stakeholders could
have acted faster in a more effective way to avert some of the aftermaths of the 2019 novel coronavirus outbreak,” opines Ayittey.

China reported a peak in infections among healthcare workers in the 3rd or 4th week of January. More than 3,000 health-care workers have been infected, according to Chinese public health authorities.

The WHO is currently leading a joint investigation with Chinese experts on how, where and when the health workers infected so far contracted the new virus in Wuhan.

Even though frontline infections were not unusual in outbreaks, it was very important to understand if it happened in the emergency ward or if it has happened when they were treating patients or somewhere else within the hospital facility, WHO authorities said.

Aftermath of China lockdown

The Chinese government has initiated some extraordinary and draconian efforts to combat the epidemic and bring back the situation to normal. The central and local governments have built an aggressive, all-round and multi-level prevention and control system focusing on Wuhan city and Hubei province. 

Since late January, the Chinese government has put at least 760 million people — more than half of its population — under residential lockdowns by sealing off cities, shutting down businesses and schools and ordering people to remain indoors, according to a New York Times analysis of government announcements in the provinces and major cities.

China’s bold approach has changed the course of the outbreak, which was rapidly escalating, say experts. The WHO has praised China’s aggressive efforts that led to a steady drop in new infections. Meanwhile, others frown at the official numbers provided, as China keeps changing its criteria to diagnose the disease.

More than 50 countries including India have so far reported confirmed cases as coronavirus is seeding to newer countries.  

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