The Hindu Explains | Is SARS-CoV-2 a latent virus which can recur?

Is there a possibility of a 'second' COVID-19 infection? Or are there flaws in the testing system?

The story so far: Ever since cases of 'reinfection' — people who had tested negative for COVID-19 testing positive again after a while — emerged in early January, the question of latency of the SARS-CoV-2 virus is being hotly debated. The first such cases emerged in the east (China, South Korea) where scientists were puzzled over why or how individuals who had tested negative twice for the virus, had, after a few weeks or months, tested positive, the second time around albeit with milder symptoms. A latent infection is when the virus in the body is dormant and does not replicate within the host. It however possesses the capacity to be reactivated at some point, causing a flare-up of the disease much later.

What is a latent viral infection?

A latent viral infection is an infection that is inactive or dormant, authors Sergey Sheleg and Alexey Vasilevsky write in an article in the Global Journal of Infectious Diseases and Clinical Research. "As opposed to active infections, where a virus is actively replicating and potentially causing symptoms, latent (or persistent; but not chronic) infections are essentially static which last the life of the host and occur when the primary infection is not cleared by the adaptive immune response," they explain. Examples are Herpes simplex viruses type 1 and 2, varicella-zoster virus, HIV, Epstein-Barr virus (human herpesvirus 4), and cytomegalovirus. They are known to cause typical latent infections in humans, Sheleg and Vasilevsky add.

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They go on to explain that "latent viral infections can be reactivated into a lytic form (the replication of a viral genome). The ability to move back and forth from latent to lytic infections helps the virus spread from infected individuals to uninfected individuals".

Ryan McNamara, a research associate at the Department of Microbiology and Immunology, University of North Carolina, in a long tweet thread sought to explain the difference between the types of viral infections. Tweeting from @Ryan_Mac_Phd, he says: Viruses fall into two broad categories: chronic and acute; while a chronic virus will infect its host for extended periods of time, often through the lifetime of the host. An acute infecting virus, such as influenza and rotavirus, is cleared from the body after a few days or weeks.

"A chronic virus can go into latency. This is when a virus is present within a cell, but not actively producing more infectious virus particles. For example, when a herpes virus infects a cell, its genome can remain in that cell as long as that cell is alive," Dr. McNamara says.

The reactivation to the lytic state, when the production of new virus particles occurs, he calls an 'intentional strategy by the virus to promote its survival'. A perfect example of this would be chickenpox, caused by the human herpesvirus 3 — after infection, "the body responds and the virus goes into latency. Decades later, it can re-activate, resulting in shingles". What causes reactivation is not very clear in this case. According to him, HIV can also go into latency after infection. It integrates itself into the host chromatin (a substance within the chromosome), and can reactivate upon stimulation such as inflammation induced by co-infecting pathogens. This can lead to uncontrolled HIV replication and clinical AIDS.

Also read | Scientists break down three stages of infection, suggest individualised treatment for patients

Does SARS-CoV-2 go into latency? What causes second infections?

Sheleg and Vasilevsky have recorded South Korean officials reporting that nearly 100 people thought to be cured of the novel coronavirus have tested positive for COVID-19 again. According to Jeong Eun-Kyeong, director of the Korea Centers for Disease Control and Prevention, the COVID-19 virus may have "reactivated" in the patients rather than them becoming re-infected.

In Chennai too, last week, the civic body recorded a couple of cases of patients who had recovered from COVID-19 testing positive again after a span of time.

Also read | Tamil Nadu reports second COVID-19 case

Prof. T. Jacob John, an eminent Vellore-based virologist, says: "None of the observations conclusively proves a second infection. In each one of these cases, there is sufficient reason to suspect that it is one infection, with negative results in between. While the RT- PCR [reverse transcription/polymerase chain reaction] tests are considered to be the gold standard for testing, all tests are not 100% accurate. False positives and false negative results are expected to occur. Patients are known to test negative, then positive, and negative again, in subsequent tests performed even within days."

Dr. McNamara explains the concept of "limit of detection" of a virus, here. This is the threshold where a virus can be detected. A negative SARS-CoV-2 test does not mean zero infection; it means no detectable infection."

Prof. John clarifies that another issue is that many viruses can survive at the mucosal level in spite of immunity. "A classical example is the polio virus, which, like SARS-CoV-2, is also a positive sense, single strand RNA (ribonucleic acid). While immunity kicks in two weeks after infection, viral shedding can continue for up to 10 weeks, in spite of very high antibody levels. Why this happens has not been explained by anybody, so far. And, in polio, if a stool test came back negative in between and then tested positive, we don't take it as a second infection, it is a continuous infection." He further found with lab tests that the host harbours an "antibody-bound virus that is non-infective".

Also read | Recovered patient tests positive again in Himachal

He goes on to add: "If second infections were sufficiently common we would have picked it up by now. But it is possible that some people have specific problems with immunity against this virus. In that case, it must be investigated further."

Dr. McNamara explains: "It's entirely possible to have detectable, then non-detectable, and then detectable SARS-CoV-2 virus because of the limit of detection of our current testing. Also, a SARS-CoV-2 test doesn't necessarily mean there is infectious virus. Testing for SARS-CoV-2 RNA on surfaces can yield a positive result, but that simply means that there is some SARS-CoV-2 RNA present, it doesn't necessarily mean the RNA is intact, or that the RNA is inside an infectious particle. So, fragmented RNA can actually yield a positive result."

Korea Biomedical Review (koreabiomed.com) reported in April that the country's Central Clinical Committee for Emerging Disease Control had said the reason 263 Koreans tested positive after recovery from the new coronavirus seemed to have been not because they contracted the virus again; rather, remaining virus fragments were detected in them.

Also read | No hard scientific evidence showing there are less virulent strains, says virologist Malik Peiris

Does testing criteria make a difference?

Globally, it is now accepted that clinical signs are sufficient to commence treatment for COVID-19, even before an RT-PCR test is done. Also, cessation of symptoms is said to signal that a person has recovered. Unless someone has been critically ill, it is no longer necessary for the patient to test negative twice for COVID-19 to be declared cured, or sent home.

"We do know that finding cases is now largely determined by testing in India. But the experience of other nations has shown that we could do the same with clinical diagnosis too, they did not suffer the consequences of that," Prof. John adds.

While 100% protection is not possible, he insists that ultimately, the use of masks and physical distance is going to be the only deterrence for transmission.

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