A fascinating (and scary) article here
Coronavirus: now for the next challenge — what don’t we know about Covid-19?
Scientists are rushing to get the measure of the virus, but their efforts are likely to be hampered by factors we don’t yet understand
JULIAN OSBALDSTONE
Tony Allen-Mills and
Andrew Gregory
Sunday May 03 2020, 12.01am, The Sunday Times
As the new coronavirus was spreading disease across America in late February, Donald Trump appeared at one of his news briefings with an annotated map of the world. It showed, in his words, that America was “rated No 1 for being prepared” to deal with a pandemic.
The map was based on the GHS Index, a global ranking of national health capabilities. Trump did not mention that the UK, in second place, was the country judged next best-equipped to prevent, detect and respond to a global health threat. In one category of the survey, the UK finished first of the 195 nations studied. That category was “emergency preparedness and response planning”.
The coronavirus has sprung many surprises on the global scientific community, which has been worrying and warning for years about pandemic threats. Not the least of these has been the shattering of assumptions about the world’s vulnerability to pandemic disease.
“One observation that has struck me, and for which I don’t honestly have a good explanation, is the disparity in how Covid-19 is affecting industrialised rich countries versus lower- and middle-income countries,” said Professor Babak Javid, a consultant in infectious diseases at Cambridge University Hospitals and a principal investigator at Tsinghua University’s medical school in Beijing.
“In most pandemic preparedness scenarios, it was always assumed resource-poor settings would be the hardest hit, by orders of magnitude,” added Javid. Yet four months into the new pandemic, bodies are piling up in New York, not Delhi, and in London, not Lagos.
The deadly pattern of a rapid rise of cases experienced from the outset by many industrialised countries has not yet materialised on the Indian sub-continent or in sub-Saharan Africa, where there may be limited testing but there have also been fewer reports of unexplained pneumonia-related deaths.
Is this simply because other countries are “just behind on the trajectory curve”, Javid wondered? Or is there something going on we just have not figured out yet? Something, he suggested, that “may yield clues to genuine differences in disease dynamics that may then be applied elsewhere”.
Donald Rumsfeld, the prickly US secretary of defence at the time of the September 11 attacks, once caused a stir when he summed up the challenge of dealing with invisible threats that cannot be immediately identified or neutralised.
In a 2002 briefing about the elusive weapons of mass destruction supposedly developed by Saddam Hussein of Iraq, Rumsfeld referred to the “known knowns” — the things we know that we know. There are also the “known unknowns” — the things we know we do not know. The toughest category, he concluded, was the “unknown unknowns” — the ones we do not even know exist.
Last week some of Britain’s leading specialists in infectious disease discussed some of the knowns and unknowns of the pandemic, and the threat that unknown unknowns may yet derail what Lawrence Young, professor of molecular oncology at Warwick University, described as a “stupendous” worldwide research effort to understand Covid-19.
How is the virus surprising us?
An improbable new phrase has begun to pop up in medical descriptions of hospitalised patients. Doctors are talking about “happy hypoxia”, an unsettling conjunction of a cheery adjective and a dangerous breathing condition. Hypoxia is the result of oxygen deprivation, a cause of altitude sickness in climbers and a threat to divers who hold their breath too long. The “happy” part refers to a phenomenon observed in coronavirus patients whose oxygen levels plummet without them showing signs of distress.
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By now it is well known that Covid-19 attacks the lungs, and shortness of breath has been regarded as a key symptom of the disease from the start. Hospital staff monitor the levels of oxygen in the bloodstream: in many people, a healthy pair of lungs will produce an oxygen saturation reading of at least 92%.
Anything much below that is a danger sign, as a drop in oxygen supply will threaten the heart, brain and other vital organs. That is why the availability of ventilators and other forms of oxygen delivery became such an urgent issue in treatment of virus patients.
Yet two things have happened in recent weeks. First, evidence is mounting that most patients who decline to the point they need to be put on ventilators suffer grim outcomes. In a new UK study of almost 17,000 patients published last week, only 20% of those requiring mechanical ventilation were discharged; 53% of them died and 27% were still in hospital in mid-April. Those ventilators obviously help some, but seem to trigger fatal organ inflammations in others. How can we tell whether they will help or hurt?
Second, doctors began to notice some patients seemed to be functioning normally with oxygen levels that would typically indicate imminent collapse. One New York medic posted a picture on Twitter of his patient checking her phone while her monitor showed an oxygen saturation reading of 54%, a prime example of happy hypoxia. Should the doctor place such a patient on a ventilator immediately, even if they are not in distress? Or are other, less intrusive forms of oxygen supply a better bet at this stage?
“We don’t know what the most effective respiratory option is,” said Bronwen Connolly, a critical care specialist at Queen’s University Belfast. She told a specialist webinar last week: “There is a real inconsistency in recommendations for non-invasive respiratory support and a real need for high-quality evidence generated from the Covid-19 population.”
Ventilators help some patients but seem to trigger fatal organ inflammations in others
Ventilators help some patients but seem to trigger fatal organ inflammations in others
STUART FRANKLIN
What else don’t we know about the disease?
The answer, in Rumsfeldian terms, is that there are many known unknowns, and very probably some unknown unknowns — but these are still early days. “I have been an HIV researcher for the past 30 years and there are still many things we don’t know about HIV,” noted Professor Sarah Rowland-Jones, an immunologist at Oxford University.
Not the least of the problems confronting scientists is that the virus is described as a respiratory syndrome, but it does not restrict its attacks to the lungs. It has been widely associated with heart, liver and kidney problems, neurological complications and lethal blood-clotting. A US doctor whose otherwise healthy 47-year-old son overcame the virus after a near-fatal visit to intensive care told the Stat news website: “This virus is a combination of Alien, The Day the Earth Stood Still, The Andromeda Strain and Apocalypse Now.”
The NHS recently warned about shortages of dialysis supplies for coronavirus patients who need kidney support. Chinese reports indicated early on that the virus was attacking the heart muscle, causing myocarditis, a condition that can lead to heart attacks or strokes. Some US researchers suspect that Covid-19 affects blood vessels, creating clots or hordes of microclots that cause problems elsewhere. Doctors are still juggling drug combinations to find solutions that help one organ without damaging another.
If that sounds bleakly apocalyptic, the most bewildering unknown of all may be that many people are infected with the virus without suffering so much as a sneeze. Children also mostly seem to shrug off Covid-19 as if it were no worse than hiccups.
Why does it wreak havoc on some people but not others?
One possible answer was proposed last week by Professor Alison Sinclair, a molecular virologist at Sussex University. “I have a burning question,” she said. “Do people who are more severely ill have a variation in their genome [genetic material] that causes an underlying susceptibility? There are examples of other diseases caused by viruses where a small variation in people’s genomes predisposes them to a more severe disease when they are infected.”
By comparing the DNA of patients with severe disease to the DNA of people who were infected but showed no symptoms, “it could identify whether a genetic predisposition for severe Covid-19 exists”, said Sinclair. Protective measures might then be developed.
What is happening to our immune systems?
Another discordant medical phrase that armchair virologists have lately been puzzling over is “cytokine storms”. Cytokines are a group of proteins crucial to the functioning of the immune system. The first responders to viral invasion, they are the body’s equivalent of First World War carrier pigeons, dispatched from the source of infection to warn other parts of the body that the germs — as opposed to the Germans — are coming. The problem detected in numerous severe cases of the coronavirus is that instead of swivelling its defences to confront the invading virus, the immune system blows itself up.
The cytokines appear to provoke a storm of overreactions, causing raging fevers and organ inflammation. Some doctors have found that steroids calm the storms, but steroids have another effect: they can suppress immune responses, leaving virus patients defenceless.
The most urgent of our known unknowns, many scientists agree, is the extent to which exposure to the virus offers a degree of immunity, and how long that immunity might last. The World Health Organisation has warned that no evidence of immunity has yet been found for Covid-19. “I would argue that the key issue is not to discover something new about the virus but to understand the immune response it stimulates,” argued Jonathan Stoye, a virus expert at the Francis Crick Institute in London.
Professor Will Irving, a virologist at Nottingham University, added: “Understanding what constitutes a protective immune response is the most important missing piece of the jigsaw at the moment.”
Sars-CoV-2: a ‘stupendous’ worldwide research effort to understand it is under way
Sars-CoV-2: a ‘stupendous’ worldwide research effort to understand it is under way
NATIONAL INSTITUTES OF HEALTH/AFP/GETTY
Oxford’s Rowland-Jones concurred: “The really crucial question is whether or not infection leads to protective immunity. All our current effective vaccines operate on a principle that if you don’t succumb to the infection in the first instance, you develop long-term immunity to that pathogen. Measles is a good example.” She concluded: “This is essential knowledge for both vaccine strategies and also control strategies for the coronavirus.”
The early promise shown by British and other vaccine developers, offering hope of a life-saving jab within months, may quickly turn to dust if evidence does not emerge of the immune system’s ability to resist the virus. “There are some who even question whether long-term protective immunity against Sars-CoV-2 is possible,” said Warwick professor Young.
“One particular component of the immune response which is essential to study is the response that occurs on our mucous membranes and that we need to induce to protect from a virus which spreads by infecting cells in our noses and throats.”
He added: “We need a vaccine that will induce this response but we currently know next to nothing about it in the context of Sars-CoV-2.”
Do we know why more men are infected than women?
The gender imbalance first detected in China was attributed to a variety of causes, from men smoking more than women — supposedly leaving them with more fragile lungs — to men congregating in larger groups than women. But the pattern has repeated itself around the globe, most notably in the latest UK research, which found that 60% of the hospitalised patients it studied were men.
“The discrepancy between men and women is still present in countries where the smoking rates are similar between the sexes, so that can’t be the explanation,” said Rowland-Jones. “There hasn’t been such a major sex difference in outcomes for any previous infection as there is for Covid-19.”
Some experts question whether long-term protective immunity against Sars-CoV-2 is possible
Some experts question whether long-term protective immunity against Sars-CoV-2 is possible
ISABEL INFANTES
Possible biological explanations include stronger innate immune responses recorded in women, and differing distribution of the substance ACE2 — angiotensin-converting enzyme 2 — which is found in noses, lungs and other organs. Normally, the enzyme performs tasks such as helping to keep blood pressure stable, but it has also been identified as the doorway through which the virus infiltrates cells and begins to replicate itself, spreading through the body. Time and research may provide answers, but “it’s difficult to do research into the basic biology and immunology of the virus when confronted with the clinical problems [of patients] that need immediate management”, noted Young.
Similar restraints apply to studies of children, with unknown factors including why they appear to suffer mainly mild symptoms. This may be related to the distribution of ACE2 receptors in younger humans, but equally important is to what extent they are infectious. “We need to know if younger people . . . can pass the virus to others to predict what the impact will be of [reopening] crowded environments, including nurseries and schools,” said Sussex University’s Sinclair.
As for Rumsfeld’s unknown unknowns, their number and importance is, of course, unknown. But science has plenty to be getting on with in the pursuit of the knowledge we need. “Is it reasonable to expect a solution to Sars-CoV-2 in four months?” asked Stoye. “As various people are supposed to have said: ‘The difficult we do immediately. The impossible takes a little longer.’”
