We know a lot about what we dont know

Five months in, and the shape of the Covid-19 pandemic remains elusive, with the lack of clarity extending to what the disease looks like, who has it, who is infectious, who is immune, and what the future holds.

The initial case definition included fever, a dry cough, and myalgia, but recent reports suggest that other symptoms diarrhea in some cases and loss of the sense of smell in others were also indicative of the disease, according to Jeanne Marrazzo, MD, of the University of Alabama at Birmingham.

We were treating it and viewing it very much like a classic respiratory viral infection, Marrazzo told reporters in a briefing organized by the Infectious Diseases Society of America. A lot of people were refused testing because they didnt fit the diagnostic criteria.

A lack of available test kits required some sort of triage, she noted, but as understanding of the disease has increased, it has become clear that the scope of infection is much wider, with the SARS-CoV-2 virus affecting a lot of body systems not just the respiratory system, although thats how people die.

How Many Covid-19 Cases Are Being Missed?

I wonder how much of [the pandemic] was missed because we werent recognizing a wide range of symptoms, she said. Knowing about the rarer symptoms, Marrazzo added, should lead clinicians to have a lower index of suspicion [for Covid-19] and a much lower threshold for diagnostic testing.

But, of course, diagnostic testing aimed at people with symptoms will miss anyone who is either asymptomatic or pre-symptomatic, according to Carlos del Rio, MD, of Emory University School of Medicine in Atlanta.

During the IDSA briefing, Del Rio noted that it now appears that 6%-12% of people infected with the virus will be infectious during a pre-symptomatic phase that can last from 24 to 48 hours.

One report, from Singapore, found seven Covid-19 clusters with likely pre-symptomatic transmission. At the time, the country had found 157 locally acquired cases; 10 of them, or 6.4%, were thought to arise from contact with a person who had not yet developed symptoms.

Where a date of exposure could be fixed, the investigators reported, the transmission occurred between one and three days before the index patient developed symptoms.

Del Rio said its not clear that anyone with the infection is truly asymptomatic; instead, he said its likely most will eventually develop symptoms.

An analysis of the literature, from Great Britains Centre for Evidence-Based Medicine, found that children and young adults can be asymptomatic. But there is not a single reliable study to determine the number of asymptomatic patients, the investigators wrote.

It is likely we will only learn the true extent once population-based antibody testing is undertaken, the agency reported.

Also, it has been recognized from the beginning of the outbreak that most people some 80% is the usual estimate will have symptoms mild enough that they wont need or even seek medical care before recovering.

Those people too will remain essentially unknown until widespread antibody testing looking for the immunological consequences of infection is rolled out.

The diagnostic tests, aimed at viral RNA, cant distinguish between people who have had the disease and recovered and those who have never been infected. In both cases, the test will usually be negative.

Will Antibody Testing Show Who Is Immune?

Blood tests looking for antibodies are now being rolled out, looking for immunoglobulin M (IgM), which is the first sign of a humoral immune response, and immunoglobulin G (IgG), which appears later.

People talk about antibody detection as though its simple, Marrazzo said, but it has not initially been clear what antibodies to look for. The FDA has approved one antibody test under an Emergency Use Authorization and others are expected.

Marrazzo said she hasnt had enough clinical experience with the new test to know how well it performs it was only approved April 1 but she is confident that a very good, reliable test will be widely rolled out within a month.

Then we can screen to see whos immune, she said findings that will help guide decisions on how to deploy exposed health care providers, as well as how to use non-pharmaceutical interventions such as social distancing.

But its important to remember, Del Rio cautioned, that antibodies arent the whole story of immunity. In HIV, for instance, IgG and IgM antibodies occur alongside a chronic and incurable infection, while in chronic hepatitis B and C, antibody responses exist but are not sufficient to clear the virus.

Having antibodies doesnt mean immunity, Del Rio said. We still need to identify the correlates of immunity. That would include both the adaptive antibody response and the innate cell-mediated response.

Researchers might get some guidance from earlier work on immunity to the original SARS coronavirus and its cousin MERS (Middle East Respiratory Syndrome).

For instance, an analysis of innate and adaptive immune responses of 40 patients with SARS, published in 2007, suggested that the early disease response included high levels of interferons, interferon-stimulated chemokines, and interferon-stimulated gene expression.

Most patients resolved the interferon crisis and expressed adaptive immune genes, the researchers reported, but those with poor outcomes did not, implying that unregulated interferon might have led to a malfunction of the switch from innate immunity to adaptive immunity.

A later animal experiment by the same authors suggested that immunity, either from infection or vaccination, prevented the interferon response.

Theres no evidence that SARS-CoV-2 establishes a reservoir, as HIV does, that could complicate patient management, commented Rajesh Gandhi, MD, of Massachusetts General Hospital in Boston.

This looks like an infection like others in its class of viruses, Gandhi told BreakingMED during a separate IDSA briefing. I think people will recover and not have recurrences.

What About Those Who Test Positive After Infection?

He noted that some patients might be clinically well but temporarily test positive for the virus after recovery. Exactly how long the virus lasts in a person is still being worked out, Gandhi said.

There have been anecdotal reports of both recurrence and reinfection, with the suggestion that leftover virus might still be active; diagnostic tests only report the presence or absence of viral proteins, not whether the complete virus is present and active.

But an animal study by investigators from China (still not peer-reviewed) suggests reinfection is unlikely. The researchers tracked what happened in macaques that had recovered from an experimental SARS-CoV-2 infection.

They challenged half of the recovered animals with the virus and saw no viral replication in any body compartment and no recurrence of symptoms, suggesting that reports of reinfection and/or recurrence in humans might be the result of testing errors.

Importantly, a large fraction of people infected with Covid-19 will recover or already have recovered, and if recovery leads to immunity, how long might that last?

Its too early to tell in the middle of this outbreak, but a 2007 study of 176 Chinese SARS patients suggests a couple of years of protection is possible.

The investigators had serum samples from patients taken initially during March through Aug. 2003, with follow-up samples taken at six months, 12 months, and three years after the onset of symptoms.

Analysis showed that seven days after the start of symptoms, 11.8% of patients were positive for SARS IgG, and that proportion reached 100% at 90 days, remaining largely unchanged up to 200 days. Immune responses were maintained in more than 90% of patients for two years, the researchers found, but then the percentage declined to about 50%.

Similarly, the percentage of patients who were IgM positive within the first seven days was 21.4%, peaked at 76.2% after 21 to 30 days, and then was mostly absent after 60 days.

A smaller study, in 2016, looked at the longevity of antibody responses among nine health care workers who had MERS and found that those who had the most severe disease (pneumonia requiring intubation) had the most long-lived antibody response, with a positive test up to 18 months after recovery.

Patients with milder pneumonia were antibody-positive for only three months, while those who had upper respiratory disease, or no symptoms, had no detectable antibodies.

A 2005 report on 80 Singapore hospital staff exposed to SARS patients without contact precautions during the first days of the 2002-2003 found that 56% were positive by a serology test.

Of those, 82% had radiologic changes characteristic of pneumonia, 4% had subclinical disease, and 13% were asymptomatic. The figures suggest that in that outbreak, exposure led to disease in a majority of cases and subclinical cases were rare, but even so, some people never developed symptoms.

A study in Hong Kong, which was one of the hard-hit regions in the first SARS outbreak, found in 2005 that 386 healthcare workers had acquired SARS, accounting for 22% of the total local patient population, but another 688 did not.

A survey, combined with serological tests of those 688 workers, found that only one nurse was positive for SARS antibodies, again suggesting a very low rate of subclinical disease, the researchers said.

Unprotected exposures such as torn gloves or inappropriate personal protective equipment were commonly reported by study participants. Despite that, disease transmission was low, suggesting that direct exposure to a heavy viral load was required for SARS pathogenesis, they argued.

Its not clear, given the large proportion of mild and asymptomatic cases, if heavy viral load is needed for SARS-CoV-2 pathogenesis, but it might be important for severe disease.

Will Covid-19 Be Seasonal?

A big question is whether the pandemic will take on a seasonal aspect, as did the H1N1 influenza pandemic of 2009-2010, and here the SARS and MERS outbreaks give little guidance.

SARS was essentially contained through aggressive public health measures and disappeared before it could demonstrate whether or not it had a seasonal aspect. And MERS, an epidemic that is still ticking over, shows occasional spikes in incidence but no marked seasonality.

These are all great questions: Is this virus going to go away, how long will the epidemic last, is it going to keep coming cyclically like influenza during the winter months? commented Adarsh Bhimraj, MD, chair of the IDSA Covid-19 Rapid Guidelines Expert Panel and a staff physician at the Cleveland Clinic.

These are all questions we dont have answers for, he concluded. Right now, we should focus on getting over this pandemic.

This is the third and final part of a special BreakingMED series examining the state of the science regarding SARS-CoV-2 and Covid-19.

Take Aways:

Five months into the Covid-19 pandemic there are still more questions than answers What is the shape of the disease, who has it, who is infectious, what does the future hold?

From accurate diagnostic tests to developing antibody testing, gathering all the elements to see the full picture is ongoing.

Michael Smith, Contributing Writer, BreakingMED

del Rio serves as a consultant and on the advisory board of the Infectious Diseases Society of America, he also has relevant relationships with NIH/National Institute of Allergy and Infectious Diseases, NIH/National Institute on Drug Abuse, and serves on the editorial board of the Clinical Infectious Diseases; JAIDS:Journal of Acquired Immune Deficiency Syndromes and on the boards of Directors of the INternational Antiviral Sociaety-USA and the American Conference for the treatment of HIV.

Marrazzo disclosed relevant relationships with BD Diagnostics and Gilead.

Cat ID: 125

Topic ID: 79,125,730,933,125,190,520,926,192,927,151,928

Infectious Diseases Society of America Infectious disease specialists offer their insights on a range of Covid-19-related issues April 10, 2020 briefing.

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