Covid-19 and Viral Persistence

All those with Long Covid will at some point consider “if my symptoms are carrying on months after my initial infection, and act as if I have the acute infection all over again, could I still have the Covid-19 virus inside my body?”

I mean obviously after the initial panic of a potential reinfection. What we are describing is known as “Viral Persistence” - how long SARS-CoV-2 can stay alive inside our bodies.

I was especially concerned as I had fevers to 38 degrees on a daily basis up until eight months. The doctor in me kept thinking " I have a fever therefore I must be still fighting off the virus" . However the patient in me felt that this was different - I just somehow didn’t "feel" infectious.

I put my Mum at risk and let her into the house after Lockdown 1.0 to help with the housework and the children as I was asleep most of the day. After weeks she didn’t become ill, thank god, so this calmed my paranoia about still being infectious.

I now know it’s a lot more complicated than that and my fevers continued to throw up questions of autoimmunity and dysautonomia but what about the potential of viral persistence?

Ongoing positive tests:

The PCR test takes a sample from the oro-nasal pharynx. It looks for the virus’s genetic material, which consists of RNA, using a method called a polymerase chain reaction hence PCR. Initially studies had not been able to grow any infectious virus from samples of people with Covid-19 more than nine days after their diagnosis. This prompted the decision to recommend to those infected with Covid-19 isolate for 10 days. If the patient “feels well” after 10 days following symptom onset they can just leave self quarantine rather than retested.

one doctor in San Francisco reported to have had multiple positive coronavirus tests for at least 90 days after her initial diagnosis. Was she still infectious? Numerous reports like this initially suggested to scientists that the viral genetic material found in people after that time window is just the coronavirus fragments, which have no ability to replicate and be contagious.

However hints of the lasting presence of the coronavirus arose in the strangest of places. In the autopsy of George Floyd, conducted on May 26th, a day after he was killed by Minneapolis police, possible viral persistence was found. The autopsy noted that a nasal swab was positive for SARS-CoV-2. Before he was killed, Floyd had tested positive on April 3. Was this reinfection or viral persistence?

Dr Randall, a virologist at the University of St. Andrews in the United Kingdom feels that public health officials need to research how long the coronavirus lasts in the body. Although “it may be that 99.9% of people completely clear the virus within a few months it’s not an impossibility that there might be a very tiny proportion of people who shed infectious virus for six months or a year”

"Those people may act as seeds or reservoirs for the virus and potentially could be the source of a local outbreak. I’m not saying that happens with Covid-19 because the data’s not there. But that happening would not be surprising.”

Anthony Fauci, MD, director of the U.S. National Institute of Allergy and Infectious Diseases, agrees with this need to ascertain whether people with ongoing positive Covid-19 tests are still infectious. PCR tests for the virus work by trying to amplify signals of its genetic code over multiple machine replication cycles, and in a podcast interview in July he said that if it takes 35 or more cycles for the test to be positive the chances of a person being infectious are “minuscule.” Fauci added that knowing exactly how to interpret test results that hover around this threshold is complicated. Infectious disease doctors note there is no approved test that reports the number of PCR replication cycles needed to get a positive signal. The testing machines simply report whether the signal was detected before the 40th replication cycle. So our PCR tests are likely to be missing positive cases - an added complicating factor.

I digress - onto viral persistence. Scientists always look to past established research when studying new diseases. There are many examples of viruses persisting inside the human body.

Known infections which demonstrate Viral Persistence:

  • “In late March 1969, 14 men and five husky dogs hunkered down to spend the remainder of the year at a British survey base in the Antarctic until aircrafts were scheduled to return in mid-December to resume survey expeditions on the continent. They lived in complete isolation. The group ate from packets and cans and took vitamin supplements, and the dogs, which were used for small expeditions, were fed meat from a pile of dead seals near the base. The men were between the ages of 21 and 35, and in good health until July rolled around. But that month began with 12 days of blowing and drifting snow, so they stayed in the safety of the central hut, in close quarters. On July 14 the first man showed signs of a viral upper respiratory tract infection. A “cold”. Over the next two weeks, eight more of the men there showed signs of respiratory illness. When scientists learned about this later they were curious — how could an illness like this come out of nowhere? Many months later, researchers analyzed the handkerchiefs the men had blown their noses with, and looked for signs of certain pathogens, including influenza and one of the common coronaviruses that only causes mild to moderate colds. They even exposed volunteers to nasal secretions collected by the men during the outbreak to see if the volunteers would get sick. Ultimately, the research proved inconclusive. But it fueled a growing curiosity among scientists that viruses might last longer in the body than previously thought.The occurrence of a common cold during isolation, when the chances of introduction of new infection from the outside are virtually nil, implies that in some way virus persisted, either in the environment or in the men the scientists concluded”

  • “Certain viruses remain in the body for life after the initial infection. The varicella-zoster virus, which causes chicken pox, is one of these and can cause shingles later in life. Other examples include the Epstein-Barr virus, which causes mono, and retroviruses like HIV that integrate into a person’s DNA”

  • "Measles is one example where the scientific thinking might be changing. Doctors have known since at least the 1970s that there is a rare neurological complication called subacute sclerosing panencephalitis, which affects the brain and causes death usually in one to three years after symptoms such as seizures appear. The complication usually arises seven to 10 years after someone is infected with measles as a child, and vaccination to avoid getting sick measles is the only known way to avoid it. It was thought to be rare for measles to hang around in the body. But autopsies conducted in 1995 on 51 healthy people in Japan who died from events such as accidents or heart attacks found that around half of them had measles virus in their body. The average age of the individuals was 54 years, and since measles is generally a childhood disease, it suggested that the virus could linger at detectable levels for decades” . Dr Griffin, a virologist at the Johns Hopkins Bloomberg School of Public Health, has spent years trying to understand how long measles persists in the body. “If you look for the viral RNA, it’s present for a very long period of time. Those people with lingering measles virus are not transmitting the disease to new people. But they’re PCR positive for months.” Dr Griffin says that one theory is that the virus may persist in the body to keep the immune system vigilant against the pathogen. There might be cells in the lymph nodes that retain viruses or their fragments. The persistent virus in the body might stimulate some sort of immune system protection.

  • Scientists were surprised to find that the Zika virus infiltrated the testes. The testes are protected to some degree from the body’s immune system, so it could effectively evade detection. A study published last year in the New England Journal of Medicine found that in a rare instance, one man’s semen tested positive for Zika 281 days after the initial illness

  • The Ebola virus has been documented to remain in men’s semen up to 565 days after recovery.

Examples of viral persistence in severe acute Covid- 19:

  • In a small study semen from six out of 38 hospitalized patients tested positive for SARS-CoV-2. However another study that looked at semen samples from recovering patients 8 to 75 days after diagnosis found no evidence of the virus.

  • In May a small study from researchers in China found PCR positive test results for severe cases up to around 49 days for nasal swabs and faecal samples. The average time for throat swabs to stop testing positive was around 16 days. Governments still cite that patients with a mild to moderate Covid-19 illness remain infectious no longer than 10 days after symptom onset

  • A preprint study from the Netherlands, analyzed samples from severely ill Covid-19 patients, some of whom were immunocompromised, and found that one patient who was moderately immunocompromised had the infectious virus for 20 days.

  • Bussani et al published “Persistance of viral RNA, pneumocyte syncytial and thrombosis are hallmarks of advanced COVID-19 pathology” They cite “our study combined with existing evidence indicates that Covid-19 represents a unique pathology, distinct from other causes of Acute Respiratory Distress Syndrome. The long-term persistence of infected cells and the major structural changes detectable in the lungs after several weeks from first diagnosis could represent the anatomical substrate for long-term complications in infected patients who survive the acute phase. Thus, our findings provide a reference for future studies investigating the long-term consequences of SARS-CoV-2 infection.

  • Dr De Chang and his research team have worked tirelessly into viral persistence and have produced several research papers. “Persistent Viral Presence Determines the Clinical Course of the Disease in COVID-19” in the Journel of Allergy and Clinical Immunology Practice concludes that persistent viral presence (>16 days) has more severe disease outcomes including extensive lung involvement and requirement of respiratory support and therefore therapies that may impair the viral clearance may impair the host recovery from COVID-19.

  • In “Host tolerance contributes to persistent viral shedding in COVID-19” in The Lancet Dr De Chang et al show clinical characteristics of three patients with persistent viral presence for at least 50 days. “Surprisingly, all three patients had underlying comorbidities, including hypertension and diabetes, both of which have been a well-established risk factor for disease severity and death due to COVID-19. Despite these underlying morbidities, these patients had minimal to no symptoms but had a persistent viral presence for prolonged periods.

  • In the American Journal of Respiratory and Critical Care Medicine the paper “Time Kinetics of Viral Clearance and Resolution of Symptoms in Novel Coronavirus Infection”. The ability to spread may arise from the ability of the virus to transmit from subclinical patients. Cases have been reported in which patients infected their close contacts even after “apparent recovery” from the infection. This warrants investigation of the “shedding window” after the clinical recovery of the patient. In this study, we report that half of the patients continued to be virus positive even after the resolution of symptoms up to 8 days.

Viral Persistence in Long Covid:

As with all things Long Covid research is slowly starting to emerge.

  • In Dr Chang et al paper “Host tolerance contributes to persistent viral shedding in COVID-19” they cite: "This evidence suggests the presence of host tolerance mechanisms that can explain both mild disease and prolonged presence of the virus in the host. We propose that due to high tolerance to the virus, these patients mounted limited host antiviral and anti-inflammatory response that led to minimal or no symptoms. At the same time, limited host antiviral and anti-inflammatory response allowed the virus to persist for prolonged periods. Previous studies have shown that viral shedding continues even after symptom resolution in milder infections.”

  • Zuo et al recently published in the British Medical Journal - “Depicting SARS-CoV-2 faecal viral activity in association with gut microbiota composition in patients with COVID-19” - “This pilot study provides evidence for active and prolonged ‘quiescent’ GI infection even in the absence of GI manifestations and after recovery from respiratory infection of SARS-CoV-2. Gut microbiota of patients with active SARS-CoV-2 GI infection was characterised by enrichment of opportunistic pathogens, loss of salutary bacteria and increased functional capacity for nucleotide and amino acid biosynthesis and carbohydrate metabolism”

In other words much as Dr Chang’s work after recovering from the acute infection active virus has been found in the gut. Unfortunately this was only undertaken on infected patients whilst in hospital. However in a pre print paper “Evolution of Antibody Immunity to SARS-CoV-2" by Gaebler et al this work was taken further.

They found that in a small study of 14 asymptomatic Covid-19 patients 50 % of them had viral persistence on intestinal biopsies at 3 months.

This was proved to be intact virus though it was not described as replicating ie manufacturing new virus.

This viral persistence has been confirmed by Dr Bruce Patterson who detected viral RNA in a patent 87 days after the initial infection. He went onto look at CD8 counts in Long Covid sufferers and found levels to be low in 25% which hints that there is persistent virus within some but again it is not replicating. He found the SARS-CoV-2 inside the monocytes - white blood cells which are first responders and eat up the virus.

Is this viral persitence enough to keep stimulating the immune system and therefore responsible for our multitude of relapsing and remitting symptoms? A low CD8 count could also mean that we could reactivate CMV, EBV and HSV infections lying dormant - or struggle to fight them off. It would also mean we would find it difficult to clear the SARS- CoV- 2 virus from our bodies.

Dr Mary Kearney a HIV drug resistance researcher says it is tricky as scientists don’t know how viral persistence might vary by individual or even organ by organ. If there is long term persistence there may be long term consequences. This is seen with other RNA viruses such as Hepatitis C. A persistent infection of this can lead to liver cirrhosis or cancer decades after the original infection.

In Dr Chang's most recent paper "ASYMPTOMATIC AND SYMPTOMATIC PERSISTENT INFECTION BY SARS COV-2" he says faced with Persistent Symptoms, it is appropriate to rule out the presence of persistent viral infection.

"The existence of asymptomatic persistent Infections (latent, sub-clinical or silent), which can affect different organs, such as the heart, intestines, endothelium, brain, skin and kidneys, among others, should also be taken into account. In the case of the heart, its involvement is more clinically relevant, since it can be the cause of an acute clinical episode with severe disease or sudden death" " Finally, it should be known that the available molecular tests are not useful for diagnosing persistent infections that affect the heart and other extrapulmonary organs, so that to date it is not possible to make an adequate etiological diagnosis of a persistent SARS Cov-2 infection"

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