AS MUCH as the gloves and N95 masks, âs constant companion early last February was a sense of gnawing anxiety. As a physician at the Oregon Health Sciences University, he braced himself for a tidal wave of covid-19 cases. A few weeks later, it arrived. Like doctors around the world, Kansagara found himself having to care for patients with a deadly disease he knew very little about. âEveryone was grasping at straws,â he says.
Ideas flooded in from all corners, ranging from the medically plausible to the utterly crackpot. Various clinical insights began to emerge from cities hit early by the outbreak such as Wuhan in China and Milan in Italy. Doctors and researchers had to decide in real time which strategies to pursue and what warranted further testing.
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It all happened at a blistering pace. Doctors swapped advice over WhatsApp, Facebook and Twitter, changing clinical practice in hours instead of years. Scientists launched clinical trials, enrolled participants, analysed data and rapidly disseminated results.
Some pinned their hopes on new, life-saving medicines. Yet while thousands of drugs are being tested or are in development, few have yet proven to make much difference (see âWhere are the medicines?â).
In spite of this, we have made tremendous progress since those early days. Although outcomes vary by location, and new variants pose new challenges, people hospitalised with covid-19 now are much more likely to survive than they would have been at the start of the pandemic. This is largely thanks to three major changes.
The vast majority of people infected with SARS-CoV-2, the virus that causes covid-19, wonât need hospital care, says , a respiratory physician at the National Heart and Lung Institute at Imperial College London. But about 3.5 per cent will need to be looked after in hospital, according to data from the and the .
A wide array of measures, from better protective gear and greater test availability, to improved understanding of transmission and the first roll-out of vaccines, have affected care for those who go to hospital. But there has been a major change in how doctors deliver oxygen. One of the big dangers that covid-19 poses is lung damage, which prevents enough oxygen from reaching the rest of the body. Most healthy people should have an oxygen saturation in their blood of between 95 and 100 per cent. In some people with covid-19, it can dip .
That is why official policies from around the world say that people who show signs of significant hypoxia â which include shortness of breath, headache, fast heartbeat and a bluish tint to the skin â should go to hospital.
âPeople hospitalised with covid-19 now are far more likely to survive than at the start of the pandemicâ
Early in the pandemic, the staggeringly low oxygen levels seen in covid-19 patients sent doctors into panic, especially as they noticed that some people could crash into critical illness within minutes to hours, says , a critical care physician at the University of Pennsylvania. So putting patients on mechanical ventilators early in their hospital stay seemed like the best option.
âWe believed that we were doing exactly the right thing,â says Kaplan. âIf you got really sick and were about to die, we would have to rescue youâand we would rather treat than rescue.â
With experience, they began to discover that even people with worryingly low oxygen levels . Early on, â often very soon after admission. Now it is about half that. Making the shift required many doctors to defy what they knew.
Research suggests that using less-invasive oxygen delivery methods, such as nasal cannulas and continuous positive airway pressure masks, helped doctors to . But perhaps most crucially, it reserved mechanical ventilators for the very sickest patients, who have no other option (see âThe view from intensive careâ).
A second major change was born of desperation. Intensive care specialists had long known that placing sedated, ventilated people face down in the prone position makes it easier for oxygen to reach more of the lungs. Early in the pandemic, in places like Milan there simply werenât enough ventilators to go around. With no other options, doctors had people lie on their stomachs. This âawake proningâ hadnât really been done before, and certainly not as a matter of routine.
Buying time
A similar scenario played out at hospitals around the world. At the height of New Yorkâs surge in early April, doctors at Columbia University had eight patients who needed mechanical ventilators simultaneously, but only enough staff to do one patient at a time. To buy precious minutes, they placed three patients in the prone position. An hour later, all three saw their breathing improve so much they no longer needed ventilators. Within days, the doctors , and other universities followed suit. Studies showed that prone positioning helped keep hospitalised patients on non-invasive ventilation from getting sicker and needing to be admitted into intensive care. It isnât just drugs that have saved lives, says Simonds.
That said, one drug has been a game changer. The third major alteration to care for people hospitalised with covid-19 came last summer in the form of a cheap, readily available steroid first used for rheumatoid arthritis: dexamethasone.
It quickly became clear that what often killed patients wasnât the virus itself, but the bodyâs own immune system trying to fight off the infection. For some people with the coronavirus, an out-of-control immune response could cause deadly collateral damage to the lungs, heart, blood vessels, kidneys and brain. Much of the search for drugs has focused on compounds that might help tamp down this overblown response.
Early on, doctors tried medicines already approved to treat autoimmune disorders. Disappointingly, early clinical trials showed no benefit. Then in July 2020, the RECOVERY Trial at the University of Oxford posted results for the anti-inflammatory dexamethasone. Many immune modulators are precise, switching off specific parts of the immune response. Dexamethasone is a much blunter weapon â more a sledgehammer than a chisel, says Kaplan. But the study found that hospitalised covid-19 patients needing supplementary oxygen or invasive ventilation who also received low-dose dexamethasone were one-third less likely to die.
âWe announced the results at lunchtime, it was policy by teatime, and it was saving lives by the weekendâ
âIt really did completely change everything,â says , an epidemiologist at the University of Oxford and co-director of the RECOVERY Trial. âWe announced the results at lunchtime, it was NHS policy by teatime, and it was saving lives by the weekend.â
The drug is also cheap and readily available, meaning that nearly every hospitalised covid-19 patient who needs help breathing in .
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To a casual observer, it might seem that not much of significance has changed in the way hospitals treat covid-19 patients. Far from it, says Simonds. Over time, the cumulative effects of these three changes â and a variety of other small, subtle shifts in patient care â have helped . And many of these improvements are within reach for much of the global community. A course of dexamethasone is cheap and widely available, as are nasal cannulas. Prone positioning is free.
Now the goal is to help these standards continue to evolve as we learn more, says Janet Diaz at the World Health Organization. The sheer volume of clinical trials that emerged in the wake of covid-19 have made it challenging at times to sift the high-quality data from the rest. That makes it really difficult to make many definitive statements, says at the US National Institute of Allergy and Infectious Disease. For now, physicians still rely on clinical judgement and educated guesses far more than he would like.
Where are the medicines?
There have been , but so far regulatory agencies have approved only three: the antivirals remdesivir and favipiravir, and the widely used anti-inflammatory dexamethasone (see main story).
Making sure new compounds are safe and effective medicines takes a long time, and the broad strategy has been to focus on three main kinds. This is the progress so far.
IMMUNE MODULATORS should work by reining in the bodyâs potentially dangerous overactive immune response to covid-19, as is the case with dexamethasone. Tocilizumab and sarilumab, already approved for use in autoimmune conditions in the UK and US, have been investigated as treatments for covid-induced pneumonia in 13 countries in people over the age of 50 as part of the . In January, it was announced that the two drugs together reduced the need for ventilators and intensive care treatment by a quarter.
The University of Oxfordâs began in September 2020 to test adalimumab, which is used to treat inflammatory bowel disease and arthritis. The study was prompted by observations that people with covid-19 in care homes who were already taking adalimumab were less likely to need hospital care. That trial is still under way.
ANTIBODIES are the bodyâs defenders. When we are infected with a pathogen, our immune system produces these proteins, which bind to the invader. This alerts the rest of the immune system to a pathogenâs presence and prevents it from multiplying.
It had been hoped that injecting antibodies from people who have recovered from covid-19 might protect those who are newly infected, but trials of this convalescent blood plasma have had mixed results. The UKâs RECOVERY Trial to test convalescent plasma after preliminary data showed it wasnât beneficial.
Single antibodies have also been synthesised in the lab. These monoclonal antibodies act like the proteins produced by the immune system and are being investigated both for their ability to treat infected people and to prevent infection (see âCovid-19 prophylacticsâ).
The US Food and Drug Administration has granted emergency use authorisations for monoclonal antibodies from pharmaceutical firms Eli Lily and Regeneron â and two studies show that these drugs can cut hospitalisations and deaths. As yet, however, both the US National Institutes of Health (NIH) and the Infectious Diseases Society of America say there isnât enough evidence for their routine use.
A synthesised by biotech firm Brii Biosciences kicked off in January to see if they can prevent hospitalisation and death at 28 days of infection. More than a dozen other studies of monoclonal antibodies are under way globally.
ANTIVIRALS work by stopping a virus from replicating. Many early hopes for a quick end to the pandemic were pinned on remdesivir, developed by Gilead Sciences to combat Ebola. Tests had shown it was safe but not effective against Ebola, but maybe would work against covid-19.
In May 2020, early results of a trial, including more than 1000 people hospitalised with covid-19, showed that . In the US, UK and EU, the drug has been approved for hospital patients with severe disease and its use has become fairly routine. However, other trials, such as , including 11,000 adults in 30 countries, showed no benefit to survival. The WHO doesnât recommend the drug for any patient.
âWeâre trying to resolve some of these differences in data on the NIH COVID-19 guidelines panel,â says Clifford Lane at the US National Institute of Allergy and Infectious Diseases.
Antiviral drugs developed for other diseases are also being investigated. Influenza drug favipiravir has been approved to treat covid-19 in China, Italy, India and Russia. HIV drug lopinavir-ritonavir unfortunately hasnât proven successful in clinical trials.
Still, broad-spectrum antivirals remain a goal. In August 2020, the Corona Accelerated R&D in Europe (CARE) consortium launched to develop monoclonal antibodies and broad-spectrum antivirals over the next five years. Even if is doesnât find anything to help in this pandemic, it will help the world be prepared for the next emerging infectious disease, says Kumar Saikatendu at biopharmaceutical firm Takeda, a CARE participant.
âThe expectation ultimately will be to create not only an effective medicine, but an affordable medicine that can be globally distributed, even to remote places of Africa and Asia,â he says.
The view from intensive care
Fears about ventilators are costing people their lives, Alison Pittard tells Tiffany OâCallaghan
Alison Pittard is dean of the Faculty of Intensive Care Medicine in the UK
As an anaesthetist and intensive care specialist, has been on the front lines of the covid-19 pandemic, which she says has forced her profession to rapidly adapt how they develop new practices. As well as concern about burnout and moral injury among her colleagues, she worries that misconceptions about intensive care are driving people to turn down life-saving treatment.
Tiffany OâCallaghan: How do you decide if someone needs a ventilator?
Alison Pittard: We take each patient as an individual, look at their blood oxygen levels, their respiratory rate, how tired they are, whether itâs becoming difficult for them to breathe, how distressed they are.
We have several non-invasive modes of ventilation, including kinds that help to support breathing by providing a little bit of pressure to help keep the lungs open, rather than just supplemental oxygen, so you donât have to work quite as hard to get that big breath.
If these are not enough or if the patient is becoming really distressed, then we would sedate them and insert a tube down into their windpipe and use a ventilator.
Are you able to talk patients through this?
I think people often get the impression that in intensive care everything is rushed and there are emergencies going on all the time. And it can be like that. But certainly for these types of patients, weâre watching them very, very carefully and closely and can start to see when they are getting tired, that theyâre heading towards needing to be ventilated.
We are speaking to patients all the time, so we can say to them, âThis is what weâre planning on doing. It doesnât look like youâre managing very well.â They can often see that theyâre struggling, theyâre getting tired. Itâs very frightening for them. But you can have that conversation and explain what weâre going to need to do.
Usually, we can see a steady deterioration and it becomes fairly obvious to us that the only option available is to sedate the patient and put them on a ventilator, because without it they would die.
How difficult are those conversations?
One thing weâre finding in intensive care is that people are really scared of being sedated and ventilated because they think that it kills people. Thatâs not the case. The disease kills you.
Itâs really difficult for staff when you can see a patient in front of you who desperately needs to be sedated and ventilated, but they refuse. They would rather just try and avoid it and they are adamant. And we know that if we canât do that then theyâre going to die.
My plea is for people to put their trust in us. Allow us to share our knowledge and experience. Take our advice. We donât want to see people die unnecessarily, and if we know that sedating and ventilating somebody gives them a chance of survival, that has to be better than no chance. We only ever want to make people better.
Covid-19 prophylactics
Vaccines are the best option to prevent covid-19 infections, but they still arenât widely available throughout most of the world. Even once they have been widely rolled out, there will be people who canât be vaccinated. So we need other ways to protect people from infection.
Early findings on monoclonal antibodies called casirivimab and imdevimab from pharmaceutical firm Regeneron have shown that . Eli Lillyâs monoclonal antibody called bamlanivimab showed similar benefits to nursing home residents.
A currently in trials was less encouraging. It primarily included existing medicines, rather than new compounds being developed specifically for covid-19, but joined the chorus of research concluding that the anti-malarial drug hydroxychloroquine makes no difference to recovery from covid-19, and that there isnât enough evidence for other drugs.
Areas in Africa where the anti-parasitic drug ivermectin is widely used , which has inspired hopes that it could be an effective prophylactic. This is now under investigation.
