Coronavirus: Evolving epidemic

Even as the World Health Organisation has declared the coronavirus outbreak in China a public health emergency, there are many unanswered questions about the virus, its pathogenicity, its modes of transmission and the disease characteristics.

Medical workers with a 2019-nCoV patient in the isolation ward at a hospital in Wuhan in central China on February 6.

ON February 8, as this article goes to print, the rapidly escalating number of infections caused by a previously unknown virus, but which belongs to a well-known large family of viruses called coronaviruses (CoVs), since its detection in mid December stands at 34,400 confirmed cases and over 700 deaths. It has spread to over 24 countries besides China (including three confirmed cases in India), with its epicentre in the city of Wuhan in central China. This number includes 61 people identified on a cruise ship currently in Japanese territorial waters.

Soon after the first cluster of 41 cases presented themselves at Jinyintan Hospital in Wuhan with severe pneumonia-like symptoms, the causative virus was quickly identified from the throat swabs of three of these patients and has been provisionally named 2019-novel coronavirus (2019-nCoV).

Given the emerging scenario of the growing epidemic that was spreading across several countries, on January 30, the World Health Organisation (WHO) declared the epidemic a Public Health Emergency of International Concern (PHEIC), on the basis of the consideration of the possible impact the outbreak could have in countries with weak health infrastructure. This is the sixth time that a PHEIC has been declared (the first was in 2009 during the H1N1 pandemic).

With increased awareness among people about the disease, and the consequent large numbers of people presenting themselves at hospitals and clinics even with mild symptoms, the detection rate has risen sharply in recent days, with as many as 3,500 cases being added every day. Of the total number of confirmed cases, 31,211 (98 per cent) are from within China, of which 22,112 (69.4 per cent) are from the Hubei province alone, whose capital is Wuhan.

Of the 3,205 new cases added in the last 24 hours, 3,151 are from China. The disease has spread to all 34 administrative divisions of the country and all deaths, except for one in the Philippines, have occurred within China. Risk assessment for 2019-nCoV by the WHO for China is “very high” while it is “high” at both the regional and global levels.

Coronaviruses are so called because when seen through an electron microscope the halo of protein spikes on the round virus envelope resembles a crown or solar corona. They are a large family of single-stranded RNA viruses that can be divided into four genera, namely, alpha, beta, gamma and delta. Of these, alpha and beta are known to infect humans. Until the turn of the century, only four human CoVs (229E, NL63, OC43 and HKU1) were known, and these are globally endemic (continuously circulating), accounting for nearly one-third of mild upper respiratory tract infections among adults, such as the common cold.

SARS & MERS

But the long-held belief that human CoVs were mild and harmless pathogens causing nothing more serious than the common cold was badly shaken when two highly pathogenic CoVs emerged in the 21st century: SARS-CoV, which caused the severe acute respiratory syndrome (SARS) outbreak in 2002-03 (it emerged from Guangzhou, China), and MERS-CoV, which caused the Middle East respiratory syndrome (MERS) outbreak in 2012 (it emerged in Saudi Arabia). Both resulted in widespread epidemics—global in the case of SARS and regional in the case of MERS—with a large number of cases and deaths. And now there is the 2019-nCoV, which, too, is a highly pathogenic variety of human CoV.

Coronaviruses infect a large number of animals and humans. They are zoonotic in origin; that is, they are the result of a “spillover” from animal reservoirs when a genetic mutation in the virus enables it to jump from an animal and attach to human cells and infect them. Both SARS-CoV and MERS-CoV are known to have jumped from horseshoe bats belonging to the genus Rhinolophus . But this jump is believed to have occurred not directly into humans but via an intermediary animal host: palm civets and raccoon dogs in the case of SARS-CoV and dromedary camels in the case of MERS-CoV. The 2019-nCoV falls into the category of SARS-like coronaviruses. Its genome is 80-85 per cent identical to SARS-CoV and about 96 per cent identical to the bat coronavirus genome isolated from R. affinis bats.

However, it is not yet quite clear how the new virus originated. Given that humans do not come into close contact with live bats, the unanswered question is the identification of the intermediate animal host in which the reassortment of genes and mutations occurred and from where it spilled over to humans. Epidemiologically, most of the early cases detected in Wuhan were found to be linked to the big wet Huanan Seafood Wholesale market that has over 1,000 stalls selling all kinds of processed meat and live animals, including reptiles. The immediate suspicion was that the animal host could be one of the animals sold in the market.

On January 22, a study by Chinese scientists that was published in Journal of Medical Virology claimed that the source animal host could be snakes. The team had analysed the codons used by 2019-nCoV to make viral proteins after they invade human cells. Codons are triplet sequences of DNA or RNA nucleotides that specify how amino acids stack up during protein synthesis. In the case of pathogens, the codons between them and the animal they infect tend to be similar. The researchers compared 2019-nCoV codons with those of the potential animal reservoirs, including humans, chicken, bats, hedgehogs, pangolins and two snake species.

From this, they concluded that “snake is the most probable [intermediary] wildlife animal reservoir for the 2019-nCoV”. The scientists also suggested that a virus from the many-banded krait ( Bungarus multicinctus ) or the Chinese cobra ( Naja atra ) may have combined with a bat virus and led to the new outbreak. Many scientists feel that while not impossible this seems highly improbable because CoVs tend to be found only in mammals. As corroborative evidence, viruses from the animals that were sold in the market (which apparently included snakes) should be investigated. However, with the market having been shut down as of January 1, this seems a difficult proposition. Also, snakes are what are known to be poikilothermic (animals, mostly vertebrates, whose internal body temperature is not stable and varies considerably). So, how can a virus establish itself both in warm-blooded and cold-blooded animals? This argument, too, seems to rule out the possibility of snakes having been the source of the new virus. But identifying this source is important for protective measures in the future.

SARS resulted in 8,098 cases with 774 deaths (a mortality rate 9.6 per cent) before global public health measures that were evolved in the wake of the outbreak, and were put in place quickly, brought the pandemic to an end. On the other hand, MERS, though confined to West Asia, has continued to simmer, with sporadic transmissions resulting in clusters of infections, and until date has caused 2,494 cases and 858 deaths (mortality rate 34.4 per cent). The two outbreaks, however, differed significantly: while in the former, human-to-human transmission was efficient, resulting in the wide geographical spread of the disease, in the latter most of the cases have resulted from direct zoonotic transmission.

In comparison, however, the mortality rate for 2019-nCoV (2 per cent) is significantly less, and hence the disease appears to be much less severe. The number of cases within a month and a half of the discovery of the disease (and its causative virus) far exceeds the number of SARS cases over eight months of the epidemic. Clearly, it is much more contagious, and the human-to-human transmission in this case appears to be even more efficient. Even this mortality rate will be an overestimate because in an evolving epidemic such as this, there would be a clear bias towards detecting serious cases in the initial phase of case identification and as improved surveillance measures begin to pick up mild and even asymptomatic cases (through contact tracing), the denominator of the total number of confirmed cases will only increase to bring the mortality rate down. So there are still a lot of unknowns and questions about the virus, its pathogenicity, its modes of transmission and the spectrum of the disease characteristics.

Of course, detecting a large number of cases within a short span could also be in part due to the rapid exchange of information among scientists about the genetic structure of the virus resulting in quick development of diagnostic kits in different laboratories across the world, a highly evolved methodology and guidelines for case identification, surveillance measures and contact tracing that have been put in place across the world, and far improved health infrastructure in the post-SARS scenario. After the first isolation of the virus, Chinese scientists quickly characterised the genome of the virus as well and made it public by January 7. This has certainly helped in the rapid identification of cases across the world and will also speed up the research work towards development of therapeutics and vaccines against the disease.

Symptoms

The early symptoms of 2019-nCoV, too, are much like SARS and MERS, with high fever, cough and shortness of breath, indicating a lower respiratory tract disease. Unlike the other human CoVs that cause influenza-like illness or the common cold by attacking the cells in the upper airway, these severe illness-causing CoVs invade the epithelial cells of the lower airway much closer to the lungs, resulting in severe pulmonary and pneumonia-like conditions, including acute respiratory distress syndrome. However, unlike the other two, 2019-nCoV seems to have affected the gastrointestinal tract in very few cases.

The incubation period for a viral infection, the severity of the disease and the transmissibility of the virus—which determines the sustainability of the infection in the human population—depend crucially on where the virus establishes itself in the body of the human host after invading it. Currently, scientists are not fully clear about where the virus tends to enter the body, where it is eventually likely to lodge itself and how it manages to evade the immune system. Both SARS-CoV and MERS-CoV were very effective in evading the immune system. They infected intrapulmonary epithelial cells more than the cells of the upper airways. As a result, the incubation periods for these were long—up to seven days on the average compared with an upper respiratory tract infection like flu that has an incubation period of only one to four days.

On the basis of the results of several research investigations on 2019-nCoV cases, the WHO has given the incubation period as up to 14 days, with a mean of 5.5 days, which is long and suggestive of the new virus, too, establishing itself in the cells of the lower rather than upper airway. Consequently, transmission is expected to occur primarily from patients with recognised illness and not from asymptomatic or mildly diseased patients. So human-to-human transmission is more likely through large respiratory droplets from patients with lower respiratory infections—up to distances of about two metres—and not farther than that as in flu, which is spread by aerosols from upper airway sneezes.

As in the case of SARS-CoV, here, too, studies have implicated hACE2 (human angiotensin-converting enzyme 2) as the receptor protein to which the spiky glycoprotein on the virus envelope latches on to. hACE2 is found primarily in the lower airway and is responsible for regulating cardiac functions. So transmission is expected only after signs of lower respiratory tract disease—pulmonary morbidity such as shortness of breath or dyspnoea and pneumonia-like symptoms—develop. The case of MERS-CoV was somewhat different. Although it shared many features of SARS-CoV, significantly, the majority of MERS patients had prominent gastrointestinal systems and acute kidney failure. This was because the binding protein in this case was not hACE2 but DPP4 (dipeptidyl peptidase 4), which is present both in the lower airway and in the gastrointestinal tract and kidneys.

However, there is a conundrum with regard to the virus’ transmissibility. Investigations by researchers with the first confirmed case in the United States detected the new virus in specimens from the upper airway (with low threshold values in the detection assay with polymerase chain reaction), which is suggestive of high viral loads and easy transmissibility. The team had also detected the virus in the loose stool specimen from the patient, which would suggest transmission by the faeco-oral route as well. Also, researchers had reported in The New England Medical Journal of a cluster of cases in Germany after a businesswoman from Shanghai visited the group during January 20-21. Although this claim has been challenged since the researchers had not spoken to the Chinese woman but presumed her to be asymptomatic from appearance, she seems to have had mild symptoms at best and not severe respiratory illness.

So does asymptomatic transmission occur or not? This is not yet a settled question. If yes, it would only make the surveillance measures difficult and more complicated. Anthony Fauci, the well-known virologist and the chief of the U.S. National Institutes of Health, believes that it does. He has been quoted by sciencemag.org as saying that he has subsequently confirmed from a reputed Chinese infectious diseases scientist that asymptomatic people were transmitting the infection. In fact, in the early stages of the outbreak, Chinese health officials, too, had claimed that there was evidence of transmission from asymptomatic patients. The question whether there was transmission from asymptomatic SARS cases that was not detected is moot but clearly cannot be answered as there is no way of knowing. However, in the case of 2019-nCoV, the question becomes pertinent, especially in other countries when screening procedures and quarantine measures for citizens returning from disease-affected regions in China are in place, which involves looking for high fever or shortness of breath or cough. The guidelines for these will have to be suitably revised.

The disease, like SARS, has no treatment. However, several antiviral drugs that were found to be reasonably effective against SARS and MERS, and also against HIV, are being tried, and clinical trials with them have been initiated in different parts of the world. Chinese researchers have recently reported that a combination of the broad-spectrum antiviral drug remdesivir (made by Gilead) and the antimalarial chloroquine was found to show efficacy against 2019-nCoV. The medication regimen being followed to treat the three confirmed Indian cases from Kerala (who had been brought to India from Wuhan) is not known. Also, there was a curious case of two suspected cases in Kerala who had been advised house quarantine for two weeks having violated the quarantine and travelled to Saudi Arabia. To avoid wider spread of the disease within the country, stricter quarantine measures should be imposed for people who have recently travelled to the affected regions in China.

The development of a vaccine against 2019-nCoV is well under way in several laboratories, in coordination with the WHO, using both the new messenger-RNA platform technology and DNA-platform technology. According to Fauci, given the rapid exchange of information about the virus genome and about the identification of its receptor protein and target cells in the host, a vaccine should be ready within three months, which is half the time it took to develop a vaccine against Ebola.

The current estimate based on available data from different affected regions for the reproductivity rate (R0) for 2019-nCoV, which is the number of people a confirmed case is likely to transmit the infection to, is between two and four. That is, one infected person can potentially infect two to four healthy people. An outbreak can be contained and stopped only if the R0 can be brought down to less than one with control measures, including medication. While the confirmed cases are no doubt mounting exponentially, ongoing multiple efforts towards finding suitable therapeutic agents and vaccines should also yield results soon. Hopefully, despite the huge case numbers and their wide geographical spread that seem forbidding, the experience gained from the control of SARS could turn the trend around before the virus becomes entrenched in the human population and the disease becomes endemic in different parts of the world.