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By Roger Highfield on

Up close with coronavirus

Roger Highfield, Science Director, talks to Ajit Lalvani, who recently recovered from a serious COVID-19 infection and is now undertaking a major pandemic study

Professor Ajit Lalvani is Chair of Infectious Diseases at Imperial College London, a Trustee of the Science Museum Group and Director of the National Institute for Health Research’s Health Protection Research Unit in Respiratory Infections.

Prof Lalvani’s edited answers are in italic to distinguish them from my commentary. He also recommends the UK Research and Innovation (UKRI) coronavirus science website, to which he contributed.

How did your covid-19 first manifest itself?

My illness came on suddenly. My temperature rose to 39.5 deg C and stayed there for five days. I am in my mid-fifties, the same age as the Prime Minister, and felt more ill than I have ever done before.

Fevers are caused by the release in the body of chemicals called pyrogens (such as interleukins and interferons).

When these pyrogens bind to a structure in the brain called the hypothalamus, the body temperature rises and this reduces the ability of some viruses and bacteria to replicate.

For this reason, there is scientific debate about whether, within reason, it is a good idea to use drugs to bring down a fever.

When did this happen?

My symptoms developed on 12 March. By day six or seven, I felt better. On day eight I relapsed. The fever returned. Next, I coughed up blood (this is not a typical development in a COVID-19 infection, I should stress). I was very unwell.

That was also a significant day for the pandemic in the UK.

The Prime Minister announced that people would no longer be tested for the virus in their homes (so that they and their contacts could be traced and contained) and the Government would instead pursue a delay strategy, through social distancing, lockdown and so on.

Was covid-19 like a bad cold or influenza?

No. It lasted two whole weeks, which is very unusual for a viral infection: a common cold lasts a couple of days, while flu consists of a fever for four or so days.

With COVID-19, I was totally exhausted. I would wake up, brush my teeth and have to sit in an armchair after just 10 minutes of activity.

Was your experience of covid-19 typical?

Everyone reacts differently but profound exhaustion is common. Two general patterns of more severe COVID-19 infection seem to be emerging.

Some people decline very quickly. Usually, these are people who are over 70 years of age or have underlying conditions but not always.

Others have a biphasic illness, as I did. By days seven to ten in the latter severe cases you reach a fork in the road, and get worse or better.

At first, I got worse, as did the Prime Minister. I developed pneumonia, when the inflammation is severe.

Earlier, for 60 other consultants from Imperial, I organised a masterclass from colleagues in China that said that a severe case was when blood oxygen dropped below 94 per cent.

My levels were at 93 per cent for two days. That was not a good place to be.

I was in twice daily contact with my colleagues in Rome, London and Beijing who were dealing with COVID-19.

In retrospect, I probably should have gone to hospital, but managed my way through at home with expert advice. If the inflammation tips over to produce fluid in the lungs, you get very short of breath and then you need a ventilator.

Normal amounts of blood oxygen — called oxygen saturation rates — range between 95% and 100%, whereas at 93% there is a risk of further rapid decline.

If simpler measures such as providing oxygen through a mask don’t help then patients may need mechanical support to help them breathe.

When the patient is sedated, a tube is introduced into the airway and the ventilator takes over breathing.

Unless air sacs in the lungs are filled with fluid, ventilation may not be necessary. We also know from people who survive severe pneumonia with the help of a ventilator may be at greater risk of long-term complications.

We don’t know for sure why people respond so differently to the COVID-19 virus but, aside from how much virus they were exposed to in the first place, the answer may also lie in differences in the way the body responds to the invading virus.

Cardboard and plastic model of an adenovirus, part of the Science Museum Group Collection.

The virus is a bundle of genetic code, wrapped in protein and fat. It measures around one thousandth of a human hair diameter.

It has only one objective, which is to reproduce by turning human cells in the nose, throat and lungs into virus factories.

When the body encounters an invading virus, the immune system ramps up the production of white blood cells. These include B lymphocytes, which produce antibodies that bind to the virus and stop the infection from spreading between cells, and T lymphocytes, which kill infected cells.

Details of this battle between virus and immune defences are revealed by a detailed study of nine patients with mild to moderate disease in Munich published in the journal Nature.

Protective antibodies take up to ten day to appear and other factors are important, such as the creation of specific killer T lymphocytes and the body’s first line of defence, the innate system, a range of physical, chemical and cellular tools that are designed to hold off any potential invaders in the first few days.

The study also showed that individuals with COVID-19 are most infectious early on.

Other studies show that people are often infectious before they develop symptoms, which is why placing contacts of COVID-19 cases in quarantine is so important to stem the spread of the virus.

This is one factor fuelling the debate about face masks. They could help stop these symptom-free people passing on infection, though there are other factors to consider.

For instance would recommending the public wear face masks make it even harder to supply masks to doctors, nurses and other front-line workers?

What do you make of claims that the virus can reactivate?

There is very little published on this so it’s hard to know if re-infection or relapse (ie reactivation) of an existing infection are actually happening or not. If either phenomenon is occurring, we don’t know how common that is.

If these early reports of either reinfection or reactivation are confirmed, this would have worrying implications for the effectiveness and durability of immunity to SARS-Cov-2 – and would make development of an effective long-lasting vaccine more challenging.

We need more data.

What happens in serious covid-19 cases?

You can tank or recover. I was fortunate that I did recover.

When you deteriorate more there is really severe inflammation, the lungs begin to seep fluid making it harder to breathe.

That is when you need support. At first oxygen and then, if that is not enough, a ventilator.

Breathing problems arise from the ‘collateral damage’ when the body fights the COVID-19 infection with white blood cells.

These and other cells produce immune signalling chemicals called cytokines. If produced in excess, this can cause a cytokine ‘storm’, inflammation which in extreme cases can cause the shutdown of vital organs including the lungs, heart and kidneys.

I actually feel fortunate to have had the opportunity to become so intimately acquainted with the virus and recovered unscathed.

I am now working 12 hours a day, having re-focussed my entire research team of immunologists, epidemiologists, respiratory infection specialists and nurses on trying to find scientific solutions to enable a definitive exit strategy.

How did you get the infection?

I didn’t knowingly come into contact with a known case of COVID-19.

I think there was sufficient, but under-recognised, transmission of virus in the community by early March so that one could pick it up quite easily in London.

Coronaviruses are generally transmitted by droplets scattered when an infected person sneezes, coughs or talks, which then quickly fall onto surfaces which, when touched, can pass on infection.

However, evidence is beginning to emerge that the droplets may be so small – aerosols – that they can travel over greater distances than originally thought.

This is called airborne transmission and would mean that the current call to ensure a two metre separation from other people is not enough.

One estimate puts the distance the virus can travel at 8 metres.

There was an important study out a few days ago in Nature Medicine about the transmission of seasonal human coronavirusesinfluenza viruses and rhinoviruses in exhaled breath and coughs of children and adults with acute respiratory illness.

Professor Gabriel Leung and colleagues at the World Health Organisation’s Collaborating Centre for Infectious Disease Epidemiology and Control in Hong Kong found coronavirus genetic material was present in aerosols. 

Almost half of coronavirus patients had the virus in exhaled breath which stays airborne, though they showed you could drastically cut this by wearing a mask.

If this finding also applies to the novel coronavirus, airborne transmission via aerosols may be happening, which would make interruption of transmission more challenging and underlines the importance of patients and their carers wearing suitable face masks.

Aerosol transmission may also help to explain the current estimates that up to 80 per cent of infections could be arising from people before they develop symptoms, or from those who are infected but show no symptoms.

Model of influenza virus magnified 5 million times. Part of the Science Museum Group Collection.

Tell me about your covid-19 study and why you think it will be transformative?

I am deeply fascinated by three questions.

First, what is the proportion of infections that are symptom-free (this is fundamental to understanding the pandemic and spread of disease, since they are infectious)?

Second, what are the risk factors that promote or impede transmission of COVID-19 within households and healthcare facilities?

Third, I want to identify which early immune responses predict whether a given recently-exposed person (contact) will have a symptom-free infection or instead develop symptomatic or severe illness.

To answer these questions, we are launching the Integrated Network for Surveillance, Trials and Investigations into COVID-19 Transmission (INSTINCT) study of newly-diagnosed cases and their contacts both at home and in primary care settings, such as GPs’ surgeries.

Working with the Royal College of General Practitioners Research Surveillance Centre at Oxford University and Public Health England we aim to recruit 300 COVID-19 cases and 600 contacts.

What makes this study important?

Answering the first two questions will provide much-needed data to inform strategies to limit the spread of infection in the community.

Answering the third question will reveal which immune responses allow people to successfully contain the virus and thereby experience minimal or no symptoms.

Such pivotal responses, known as correlates of protective immunity, will guide rational design and evaluation of novel vaccines as well as the development of new treatments that could enhance beneficial immune responses in patients with symptoms to hasten recovery. 

We will also look at the genetic sequence, DNA, of the contacts and patients themselves to see if there are features of their genetic code that determine the type of immune response they develop and make them more or less susceptible to developing serious symptoms.

If we find how the early immune response links to clinical outcomes, we will also see if that response is genetically determined in their genes.

Why are you so confident this study will give us new insights?

At the time of the 2009 swine flu pandemic, I asked the same questions that we now want answered about COVID-19 through a rapid in-pandemic research study.

Our results revealed which initial immune responses to the swine flu went on to predict whether people would experience only mild or no symptoms.

We tracked this protection down to a class of white blood cells, called CD8 killer T lymphocytes which went into action when the body encountered swine flu.

Since swine flu was a wholly new virus, no-one had been previously exposed to it and therefore we all lacked protective antibodies, similar to the current situation with the novel coronavirus.

However, having the right type of killer T lymphocyte enabled many people to successfully control their swine flu infection and experience only mild or no symptoms.

We suspect a similar mechanism of protection may be operative in COVID-19 infection and our INSTINCT study will confirm or refute this hypothesis. 

Where are we with treatments?

This coronavirus consists of around 30 genes – the instructions to make proteins – and a hunt is on for established drugs that can interfere with this viral protein machinery.

A decades-old malaria drug, hydroxychloroquine is of interest.

Prof Chris Butler of the University of Oxford, who is testing the drug in people aged over 50 will confirm whether the early evidence of the antiviral effects of the drug in the laboratory translates into a clinical benefit for patients treated soon after symptoms begin.

The virus has a corona (crown) of protein spikes that it uses to invade human cells and it is thought this old malaria drug may block the virus from fusing with the membrane of human cells, the first step in the process of infection.

However, Profs Butler and Lalvani, like many scientists, do not share the optimism of President Trump that this drug is ‘one of the biggest game changers’ in the history of medicine.

They are more cautious, remembering how countries stockpiled the drug Tamiflu for pandemic influenza before a study showed the drug was no more effective than paracetamol.

It would be a mistake to provide hydroxychloroquine on a large scale without better evidence of its efficacy, side effects and the risk-benefit balance between them.

The World Health Organization has announced a global trial, SOLIDARITY, on what it says are the four most promising therapies:

  • the malaria medication hydroxychloroquine and chloroquine
  • an experimental antiviral compound originally developed to treat Ebola virus, remdesivir, which targets the polymerase protein
  • a combination of two HIV drugs, lopinavir and ritonavir, which block viral replication
  • a combination of lopinavir and ritonavir plus interferon-beta, an immune system messenger that can help disable viruses

Other candidates have been unearthed by a worldwide effort.

A clinical trial is already underway of camostat mesylate, a drug originally used to treat pancreatitis. At UCL, a team is screening existing compounds and drugs for ones that can be repurposed for the COVID-19 fight using the biggest supercomputers on the planet.

There is also an old-fashioned and effective treatment in which a seriously ill COVID-19 patient is given convalescent blood plasma collected from a recovered patient.

There is already evidence that debilitated patients can rally after a dose of survivors’ blood and the United States has launched a national effort to roll these blood-based therapies out as soon as possible.

Identifying the specific antibodies within convalescent plasma that can neutralise the virus, and synthesising them to scale, is the 21st century equivalent of these old blood-based treatments.

Would these drugs be relatively cheap?

The good news is that many of the drugs being tested can be made for $1 a day per patient or less. A coordinated international effort will be needed to ensure they are affordable for people worldwide.

Can drugs be used to counter a cytokine storm?

Yes. There are some antibodies that we know can shut down a deadly cytokine storm, such as one that interferes with the receptor – docking point, if you like – in a cyotokine called interleukin 6.

However, though an overactive immune system plays a role in the death of coronavirus patients, care has to be taken not to undermine the body’s ability to fight the infection.

How important are antibody tests?

Even if we get home antibody tests, the information they will provide is really not straightforward.

It can take up to 10 days for the antibody response the tests are designed to detect to build up in an infected person. However they will prove really useful to survey the population to see who has had a past infection.

Sir John Bell of the University of Oxford, who is a Government advisor on life sciences, commented on 5 April that no home antibody tests have performed well to date.

How else can we get the big picture of covid-19 in the uk?

More than two million people have downloaded an app – the COVID Symptom Tracker app – in what may be the UK’s biggest ever citizen science project.

The app has already revealed that the rate of new symptoms being reported nationally has slowed significantly in the past few days as a result of the lockdown.

Figures released last week (6-12 April) suggest that 1.4 million people in the UK aged 20-69 have symptomatic COVID-19, a fall from 1.9 million on the 1 April.

Tim Spector and his colleagues at King’s College London say the most predictive individual symptoms, in order of importance, are: lack of taste and smell, fatigue, shortness of breath, fever and persistent cough.

What is the overall state of the pandemic?

You can get the latest news on how far this pandemic has spread worldwide from the Johns Hopkins Coronavirus Resource Center, compare the state of the pandemic in Europe using these data and forecasts from Imperial College London, see the UK hotspots identified by the symptom tracker app and check the number of UK COVID-19 cases by consulting Public Health England data. There is a wealth of information in my earlier blogs, from the UKRI, on this COVID-19 portal and Our World in Data.

Sylvia Richardson, director, Medical Research Council Biostatistics Unit and Sir David Spiegelhalter, chairman, Winton Centre for Risk and Evidence Communication, have explained how to make sense of COVID-19 statistics.

This is the fourth in a series of blog posts from our Science Director, Dr Roger Highfield, which explores the science behind the coronavirus.

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