Viral Pneumonia

In this session, we're going to look at some aspects of viral respiratory tract infections

What Viruses affect the Respiratory Tract?

Many viruses affect the respiratory tract, and they are a common cause of infection worldwide, which all
of us suffer from on a regular basis. Looking at the left hand side of this table, we have some of the more
common viruses.

The top ones of these the adenoviruses, metapneumovirus, rhinoviruses and parainfluenza viruses
predominantly cause mild disease, usually upper respiratory tract disease that may increase your risk of
developing secondary bacterial infections and may trigger exacerbations of underlying airway disease,
particularly asthma and chronic obstructive pulmonary disease COPD. But they will rarely cause severe
disease in otherwise healthy individuals. They are occasional causes of severe disease in the
immunocompromised host particularly, for example, in the transplantation setting and have on occasion
led to hospital-based outbreaks in such groups. I'm not going to discuss these viruses any further today.

Respiratory syncytial virus is also a global world wide virus, causing many diseases every year. And most
of the time it does cause mild disease, but it causes severe disease in some specific circumstances. In very
young infants, it causes inflammation of the very small airways, the bronchioles. And in these infants,
that induces significant narrowing of these airways, obstruction and respiratory distress. It tends to cause
autumn or winter outbreaks and therefore,
neonatal intensive care units and paediatric departments will experience surges in outbreaks of this virus.
In older children and adults it predominantly causes upper respiratory tract infections may again on
occasion cause exacerbations of asthma or COPD.

But in the elderly or immunocompromised, it may cause more severe pneumonia. Work is ongoing on a
vaccine for respiratory syncytial virus and I'm sure this will be covered further elsewhere in your course.
Measles virus has a predilection for the respiratory tract and some of its more severe complications occur
in relation to respiratory infection, particularly measles pneumonia, which may be severe.
Coronaviruses and influenza viruses are the viruses which are most unlikely to cause outbreaks of severe
disease affecting health care. And these are the viruses I would focus on mainly through this talk. Some
viruses will cause respiratory disease in specific circumstances.

Cytomegalovirus involves the lung in severe cell mediated immune deficiency states and is a major cause
of morbidity and mortality in transplantation medicine. Varicella Zoster Virus, the virus, which causes
chickenpox, transmits predominantly through the respiratory route. Pneumonia is uncommon, but when it
occurs, it is severe and that is more likely to happen in adults, adults who smoke, pregnant women and the
immunocompromised host.

Respiratory viral infection can cause pandemics

Virus infections can lead to pandemics. An endemic infection is an infection which regularly occurs
amongst particular people or in a certain area. Endemic infection may be worldwide, as it is with most
respiratory virus infections, or it may be localised to a region. For example, with malaria where malaria is
localised to the parts of the tropics which are able to sustain year-round mosquito activity.
Endemic infections often show seasonal variation in outbreaks relating to environmental factors and in
relation to respiratory infections.

We have more people crowded indoors with a greater opportunity for transmission of infection during the
winter. And respiratory viruses will most commonly, but not always cause winter outbreaks.
Epidemics are where we have an outbreak of a disease that spreads quickly and affects many individuals
at the same time, that may be localised or regional, but an epidemic becomes a pandemic when the
infection has spread across a large region such as multiple continents or worldwide, affecting a substantial
number of individuals. Therefore, there's no biological difference between epidemics and pandemics. It's
a difference of scale.
What Viruses are known to have caused epidemic/pandemics

Let's go back to our table on respiratory viruses. So we have viruses with which are endemic with
seasonal outbreaks. And this includes all of the respiratory viruses that we mentioned before, the
adenovirus, corona, influenza, measles, metapneumovirus, rhinoviruses, parainfluenza and respiratory
syncytial virus.

But those which are able to cause epidemics and pandemics are much more limited. Thats influenza
viruses, coronaviruses and measles. Some of you may be surprised to see measles there. So why do we
get epidemics and pandemics?

Why do we get epidemics/pandemics

The fundamental principle here is that a virus, it may not be a virus obviously it can be other organisms,
but for this talk we are talking about viruses.

A virus enters a nonimmune population with rapid transmission and significant disease. This can occur
really through three types of situations. Firstly, we may be dealing with a regular endemic virus where the
genome changes are sufficient antigenic change to avoid adaptive immune responses generated by
previous infection and vaccination. And we discussed this in quite a lot of detail in previous talks, the
processes of genetic drift, where we have a small number of mutations building up over time or genetic
shift when we have sudden change can lead to pandemics from influenza.

We may have a virus which is endemic in one area, but now moves into another area with a new
geographical range and therefore allows it to enter a population which has no underlying herd immunity.
And the best example of this is probably the measles virus. Measles was predominantly a European
continent virus. And as Europeans entered into other continents, they took viruses with them, including
measles. And measles was responsible for major epidemic outbreaks associated with very high rates of
morbidity and mortality in the Americas, in the African continent and in parts of Asia and the Far East.

And finally, we have the situation of a virus emerges, which is new to humans. So the humans have not
seen that virus before and therefore nonimmune. And most commonly the virus has crossed from the
animal species to humans. This has been demonstrated for respiratory viruses with the novel
coronaviruses, but also occurs with some novel influenza strains due to recombination of influenza
between human strains and animal strains within animals, and then crossing back to humans. Other
examples of this, this would include the HIV pandemic, where we had simian viruses spreading across
into humans, adapting in humans to then spread human to human, and then leading to a very large and
persistent pandemic.
Influenza Viruses

Let's move now to look at influenza and coronavirus in more detail. We'll take influenza first. Influenza A
is the most important influenza type. It affects a range of animals, most particularly birds and mammals,
including pigs and humans. And because humans have close contact with birds and pigs in the production
of food, we have that potential for the viruses to mix and exchange between birds and humans, pigs and
birds and pigs and humans.

We get seasonal outbreaks; we can get epidemics and we can get pandemics. Influenza A is characterised
by surface antigens, haemagglutinin and neuraminidase. These are particularly important because they are
virulence factors they are the targets for immunity, but they're also how we refer to different influenza
types of strains. The H1N1 strain of influenza, which was responsible for the 2009 pandemic strain. And
a strain of concern is the H5N1 strain, which is the current dominant bird flu strain, which has caused
havoc in bird populations around the world for the last decade or so.

Other influenzas are important, but not to the same extent as influenza A. Influenza B is human. It has
modest seasonal disease that A but some people can get very ill, predominantly with a secondary bacterial
pneumonia. Influenza C is human with mild, endemic and seasonal flu. For completeness, influenza D so
far has not infected humans, but is found in cattle and pigs.
Global infection due to Influenza A

Global infection due to influenza A we have a number of scenarios here. I just picked a few. So typical
seasonal flu is caused by a mix of strains. So we will have a mix of strains circulating.
It is usually going to come from humans the R value, so its propensity to spread on average is around
about 1.2 So that means that more cases will occur over time. It is very infectious through the droplet and
close contact route and so we will get significant transmission.

And in an average flu season, somewhere around about 5 to 15% of the world's population will suffer
from influenza. Not all of those will be very symptomatic from that point of view. But some people will
get very ill, predominately those with underlying significant diseases with somewhere between a quarter
of a million and 650,000 deaths every year. So, mortality rate of around 0.1%. And as I mentioned,
predominantly the mortality is going to occur in the elderly and people with underlying significant illness,
mainly cardio-respiratory disease.

Pandemics, however, bring in new strains of flu, and we see different things occurring. The 1918
pandemic is the biggest recorded pandemic, sometimes called the Spanish Flu. That also was an H1N1
strain. And we know from later studies that this was recombination between avian and human strains at a
relatively high R value with significant transmission. But because of the non-immune nature of the of the
human population and rapid global transmission, we ended up with 30 to 50% of the world population
infected, around about 50 to 100 million deaths. So much higher case fatality. And that case fatality was
seen very often in young, otherwise fit individuals showing what can happen when a new strain enters a
non-immune population.

We've had subsequent pandemics 1957 H2N2, 1968- H3N2. But the 2009 pandemic of H1N1 was
recombination between avian and swine, and human strains emerged in Mexico, spread very quickly
around the world, estimated between 10 and 20% of the global population infected, but fortunately didn't
have a very high death rate. And therefore we only had somewhere between 150 and 570,000 deaths,
which although a large number and is still not much more than you would see, or still around about the
same that you would see in a typical flu season. What was interesting about this strain, however, was a
particular predilection for causing severe disease in pregnant women. And in 2009-10 influenza was the
leading cause of maternal mortality in pregnant women in Europe.
Bird flu, I mentioned before as a flu of concern, and it has been on the World Health Organisation watch
list since the early 2000s, when it emerged. Transmission so far has only been from direct bird contact,
usually through butchering freshly killed birds, which gives that ability to get the virus coming directly
across the skin. It therefore has an R value of zero because it does not spread human to human. There
have only been 865 cases, but those cases have an extremely high case fatality of at least 50%, with 450
or so human deaths. Obviously millions of birds have died and the World Health Organisation is
obviously concerned that mutations in this strain could allow it to transmit human to human. And it may
be the next pandemic flu, but fortunately so far this has not occurred.

Transmission of Influenza A

Transmission of influenza A, is by aerosols or droplets that contaminate environment and it can live in the
environment for quite a long time up to 48 hours. It has a short incubation period of 1 to 3 days, and the
virus is excreted 24 hours before symptoms. It may be secreted for 9 days or so after the symptoms have
ended, but various studies have shown that there's really only a significant infection risk when people are
symptomatic. So it is when people are symptomatic that they're actively shedding influenza virus into the
environment.

It's highly infected. The value may be up to three in certain circumstances. And the 2009 pandemic R
value, was around about 1.6. But there's also risk of transmission in health care setting. And influenza is
one of those viruses which may temporarily close parts of hospitals and have significant impacts on
health care delivery.
How does Influenza A infect cells

A little bit on pathogenesis of influenza A, and this is important in relation to how it is protected against
and treated. Influenza A has these two surface molecules of importance. Haemagglutinin and
neuraminidase. Viral entry into host cells is mediated by the haemagglutinin binding to cell surface sialic
acid molecules, and the neuroaminidase actually cleaves those sialic acid residues off the surface of the
cells, and that's to allow the newly produced virus to escape from the dying cell, which has been infected
by the influenza virus. If the influenza virus doesn't do this, then much less virus will escape the cell, and
therefore that will cause less severe disease. And the neuraminidase has been the major target for anti
influenza drugs.
Clinical Presentation

Clinical presentation relatively straightforward.

We have a classic influenza like illness with a high fever, a cough beginning in the last ten days. It can
cause a variety of systemic symptoms headache, fever, muscular pains, joint pains, sometimes quite
significant gastrointestinal involvement and upper respiratory tract symptoms. This is not specific for
influenza and needs to be interpreted in the context of epidemiological evidence of what viruses are
circulating in the community.
And this is a role of public health health systems, both locally and globally. And these systems will send
alerts out that will say we now have influenza virus circulating in your area. And, of course, we know,
you know, also used for things such as coronaviruses. There's also the concept here of a severe acute
respiratory infection.

This is where we have an influenza like illness plus pulmonary infiltrates and the patient sick enough for
admission to hospital. And it was a recognition of patients with a severe acute respiratory infection being
admitted to hospitals in China with no organism identified. That led to the alert that there might be a new
virus causing severe acute respiratory illness. And that then led to the identification of COVID 19.
Pneumonia due to influenza is common in a primary pneumonia. We have viral infection causing
sufficient pulmonary damage lead to consolidation. This is usually a diffuse infection. It may be on one
side or both sides of the lung, and it tends to cause this rather ground glass type of appearance, which we
can see on this chest x ray here.

This is a chest x ray from a 26 year old woman I looked after during the 2009 pandemic who was 18
weeks pregnant. You can see that she had severe pneumonia. Pneumonia was severe because this line
going down here is an endotracheal tube and she required intubation and ventilation. Fortunately, she
survived.

This is caused by direct cell damage from influenza and the indirect damage from severe inflammatory
responses. More common are secondary bacterial infections, such as pneumococcal infections and
staphylococcus aureus infections.

And this is important because if there is a significant influenza outbreak, community acquired pneumonia
empirical antibiotic guidelines will change to make sure that we are covering Staphylococcus aureus as
because if we do not have influenza circulating, then Staphylococcus aureus is a very uncommon cause of
community acquired pneumonia in an otherwise healthy individual.
Influenza Vaccination

The mainstay of controlling influenza is vaccination. The vaccine is an inactivated vaccine given
intramuscularly in most cases, and it induces neutralising antibodies against haemagglutinin and
neuraminidase. It is proven to reduce mortality, but also to reduce transmission.

But the vaccine is a mixture against different strains. It changes on a regular basis to cover a range of
subtypes for influenza A, it also has activity against influenza B and the strains that it covers are chosen
by a group involving the World Health Organisation regularly. And because of this, the efficacy does tend
to vary between 30 and 80%, but because of course what they are doing is they are trying to estimate what
are the strains which are most likely to be circulating.

There is also a live attenuated virus available, which is administered through a nasal spray.

Vaccines, use virus cultures in eggs, and therefore there's quite a lead time to making virus. But you need
a lot of eggs to make a lot of virus. But it also means that there is a risk of this vaccine to individuals with
egg allergies. And you must check about egg allergy before administering the influenza virus. And this
can be mitigated by using vaccine which has very low of ovalbumin.

Pandemic strains need a new vaccine, and that's why a pandemic can really cause a lot of trouble before a
vaccine comes on board. But because we know how to make influenza vaccine, one can be developed
relatively quickly.

Current UK annual influenza vaccine does a number of different things. First of all, we vaccinate the
vulnerable people over the age of 50, pregnant women, long term medical conditions and people in long
term stay residential care.

Secondly, we recommend vaccination of the close contacts of the vulnerable in order to help to protect
them. So this will be the very vulnerable. These will be immunocompromised individuals, so family or
household members, but also health and social care workers. And I would absolutely implore you always
to have you have a new influenza vaccine.
This is not about protecting you. It is about protecting others. You do not want to be responsible for
transmitting influenza. And also we vaccinate children between the ages of two and 17. This is done with
the nasal spray vaccine, and this is about limiting the burden of disease in your country because it's
recognised that children are the spreaders of influenza, they catch it at school, they bring it home and they
spread it to their families and then vaccine deployment to the wider population is always going to be
considered in pandemic scenarios.

Management of Influenza

Management,diagnosis is based on the clinical symptoms and the epidemiology. So it's the symptoms
when we know influenza is circulating. Nucleic acid amplification PCR can be done on nasopharyngeal
swabs or other respiratory samples and is now quite routine in people being admitted with respiratory
infections.
Serology is not useful in clinical management but may be used in epidemiological studies. In terms of
how we treat the patient, it is predominantly high quality supportive care. That's what's going to save
most patients. Antiviral agents probably have a role but that role is limited. Antibiotics should be
considered if secondary bacterial pneumonia is likely, and that decision is based on the clinical features,
the radiology and the laboratory tests.
The available antiviral therapy is predominately based on neuraminidase inhibitors and these inhibit the
neuroamindase of influenza A and B. There are two licenced preparations, oseltamivir, which is an oral
only drug, and some resistance has begun to emerge within immunocompromised patients.

Zanamavir is available only via a nasal inhalation spray. And there is an unlicensed intravenous
preparation available. A number of other agents are under investigation.

Some older drugs were used for influenza, amantadine and rimantadine, which inhibit the M2 proton
channel, which prevents release of viral genetic material into the cytoplasm. And there was some early
evidence of efficacy for these, particularly in prophylaxis, for example, in a care home setting when there
was an outbreak of pneumonia.

But currently at least 45% of Influenza A strains are resistant and therefore there is limited use for these
agents. Current UK guidance based on NICE, Oseltamavir or Zanamavir are recommended if the national
surveillance schemes indicate that influenza virus A or B is circulating. So like many countries, we have a
national surveillance scheme of community physicians, general practitioners who, when they have people
presenting with influenza like illnesses, takes swabs which are sent off for analysis. If the person is in an
at risk group (an influenza illness), they can start treat within 48 hours. If they are presenting more than
48 hours after the onset of symptoms. There is no evidence of benefit of these drugs. Zanamivir is
preferred for children and immunocompromised adults.
Coronaviruses

That's the end of the section on influenza we'll turn to coronaviruses. We've covered quite a bit about
coronaviruses in relation to pathogenesis in previous talks, and so we will just focus on a few aspects of
the coronavirus here.

As you know, it's a single stranded enveloped RNA virus with these spikes on the surface from this
particularly important spike glycoprotein, which is the target for the immunological responses. They
commonly causes infections in mammals and birds. It's endemic in humans, causing mild upper
respiratory tract infections. But as new strains, completely new viruses have emerged. These were the
ones which cause, significant morbidity and mortality.
Severe Acute Respiratory Syndrome Coronavirus - 1

The first one which emerged was in 2002 Sars-Cov-1. This spread from southern China and Hong Kong,
with secondary outbreaks in Singapore, Canada and a number of other countries. Very small case
numbers in other parts of the world, only 4 in the UK. It was contained really just by good public health
measures by July 2003, with the last case occurring in January 2004 and in total there were only 8000
cases about a 10% case fatality, about 800 deaths. Very similar to SARS-CoV-2 to COVID 19 the case
fatality, very low in young individuals, and much higher in older individuals. It was tracked down
eventually that it came from Chinese horseshoe bats. It's a bat virus and it probably spread to humans
from other animals. So the bat transmitted to other animals and then coming from those other animals to
humans again probably through those animals being butchered in preparation for cooking. So I think if
you look at this epidemic curve, it's a sharp contrast to the COVID curves, which go on and on and on,
and that's because it managed to be contained. And I think what this shows is if you can recognise these
viruses early and get good containment in early, they can be contained. It is probably more luck than
really good efficacy that we didn't have a pandemic from this SARS strain.
Middle Eastern Respiratory Syndrome Associated Coronavirus

MERS - The Middle Eastern Respiratory Syndrome associated coronavirus is still with us. The first case
was in 2012 with an initial outbreak in Saudi Arabia. You can see here on the graph, this is the first
outbreak in Saudi Arabia and the disease remains endemic.

And therefore, we need to consider MERS anyone coming from Saudi Arabia and closely geographically
associated countries who come into your country, who have got some acute febrile respiratory illness.
And those patients need to be isolated until MERS has been excluded.

And that is shown really clearly by this outbreak that occurred in 2015 in South Korea. A single infected
person returned from the Middle East. They weren't diagnosed or they weren't even considered to be
infected until around nine days after presentation. And that led both in the community but also within the
hospital to an outbreak with a total of 186 cases and 38 deaths occurring in South Korea.

MERS in terms of hospitalised patients has a high case fatality. Around a third of people hospitalised will
die from MERS. So far it's had a relatively low R-value, relatively low risk of transmission transmitted by
the same routes as all of the other coronaviruses. And because of that, we have not had a pandemic from
MERS, but active surveillance needs to occur to prevent this from happening.

Again, similar story it is a bat virus, but it seems to spread to humans through camels. And then you can
get human to human spread from there.
Severe Acute Respiratory Syndrome Coronavirus - 2

Finally, we'll turn to Sars-Cov2, more commonly referred to as COVID 19.

First identified in Wuhan in late 2019. Public Health Emergency Declared in 2020. With the pandemic
just a couple of months later, in March 2020, transmission to many countries and mutations leading to the
emergence of new variants which are more easily transmitted.

And I think the reason why COVID 19 has caused a tremendous global pandemic rather than the original
SARS is through two factors. One is these rapid emergence of the new variants, the mutation strains. And
secondly, was the global transmission network or transport network.

So,very large number of people had already become infected worldwide by the time it
was recognised that this was emerging and coming through. The European first phase of the pandemic,
was really triggered by transmission from China to Italy. And subsequent evaluation has shown that strain
emerging in Italy was more transmissible, than the parent strain in China. And then the part of Italy that
was infected is a ski resort area and lots of countries in Europe
went there. They had their people from those countries going to that ski area during the half term holiday
in the early part of March 2020, so by the time we realised there was a problem, the virus was already
seeded across all the European countries.

This continues to occur with successive waves of COVID 19 going through and I'm just currently actually
infected with COVID 19, my second infection.

I've been infected in the first wave. I've now caught it more recently. So far we are up to around about
630 million cases, with 6 million deaths reported worldwide. So a lower case fatality than SARS or
MERS, but a higher global case number.
 Coronavirus Symptoms

Symptoms, I'm not going to go through this in detail. We all know about them.

But I think really the continuous cough, the loss or change to sense of smell, I think are the two things
which really set apart COVID 19 from the other respiratory viruses.

Some of the later strains seem to cause a change to sense and smell much less than the early strains.
Shortness of breath, exhaustion, aching body, myalgia, headache, sore throat all
of these are common. And don't forget, some patients may present with a predominately gastrointestinal
presentation, particularly young individuals and children with diarrhoea, nausea and vomiting.

Comorbidities and fatality in hospitalised COVID-19

Again, this is from the early days, this from the Italian outbreak in the first wave. But just to remind
ourselves of the huge impact of co-morbidities as well as age in relation to the case fatality of COVID 19.
Overall a global case fatality reported cases of about 1%, very low in people under the age of 25, rising
sharply in people over the age of 65. But also this is hospitalised individuals in Italy.

Look at the effects of hypertension, type two diabetes, ischaemic heart disease, chronic renal failure and
interestingly obesity. In the Italian cohort this was a relatively low effect. In American cohorts, much,
higher probably because of the higher prevalence of obesity in America. This has not been fully
explained. It might simply be because significantly obese people have more difficulty in ventilating their
lungs.

But it is a curious fact this obesity link is not seen in many other infections. Interestingly, some forms of
immunosuppression, such as HIV, quite a low comorbidity impact, which I think reflects the fact that
most people with HIV in Europe nowadays are on therapy and actually generally pretty well. As the
number of co-morbidities increase, the mortality goes right up.

Coronavirus disease – multisystem inflammatory illness

Coronavirus mustn't be considered to be simply a pulmonary disease. In the pulmonary track that causes
acute respiratory failure, respiratory distress syndrome, which, as you know, is caused by that
inflammatory response which we discussed before, that can lead to pulmonary fibrosis and pulmonary
hypertension, secondary infections bacterial and fungal and this big increase in thromboembolic disease.

But it also affects, many other organs, renal failure and myocarditis. And the myocarditis can lead to heart
failure. This has also been seen with the MRNA based vaccines, but I think it's quite reassuring that data
coming in now, more than six months after this was identified and more than six months follow up of
patients who were identified with this has shown that this vaccine associated myocarditis is firstly quite
uncommon in less than five per 100,000 vaccinated cases and also has generally quite mild.
Haematological cases, an increased risk of thromboembolic events, and that is really still being seen and
we need to think of this in people presenting with unexplained thromboemboli.
Thromboembolism again linked to the AstraZeneca vaccine through an unusual mechanism.
And that is a condition that you need to be aware of vaccine associated immune thrombosis and
thrombocytopenia, which does seem to be limited just to that vaccine. On the neurological side we have
obviously got anosmia, we may get the thromboembolic things such as stroke and venous sinus
thrombosis.

And we may get the effects of any acute virus infection such as delirium or encephalitis, And we may see
sort of post infection, inflammatory conditions such as Guillain-Barre syndrome. There has been a
substantial psychiatric morbidity. Mental health morbidity from COVID.

Some of that is just from the disruption that COVID has caused to people's day to day lives,
anxiety, depression, post-traumatic stress for people who've been particularly affected. But also there has
been an increase in psychotic episodes sometimes in people who've got no history of psychosis. And
whether that's a direct effect of COVID 19 on the brain remains to be seen.

We have, of course, long COVID and which remains poorly understood but is still affecting a lot of
people. And finally, this unusual syndrome in children of a multisystem inflammatory syndrome like
Kawasaki syndrome, which fortunately is quite rare.

Anti Coronavirus Treatment

Where are we with treatment for the coronavirus? Antiviral agents do show improvement in some but not
all clinical studies. The outcome benefit is modest and it varies relating to the timing of use.

And I think it has been impeded to date by the fact that the agent most commonly used remdesivir has
only been available through intravenous use. They inhibit viral RNA polymerases: remdesivir and
Molnupiravir and there is a new combination Nirmatrelvir which is combined with a protease inhibitor,
Ritonavir. Ritonavir was one of the first protease inhibitors that was used for the treatment of HI
Antibody therapy has had some success, so post-infection plasma.
So passive immune therapy giving the plasma purified from individuals who've recovered from COVID.
That's been beneficial in some studies, but it's difficult. We need a steady supply of donors. There's
always a potential risk of human products, and so we need to work out how to do that. And therefore,
there has been a lot of interest in the development of monoclonal antibodies. There's a couple of listed
there and there does seem to be quite good evidence of early use in infection reduces hospitalisation and
mortality and also some evidence of efficacy when used as prophylaxis for high and very high risk
individuals for COVID.

The antibodies are strain specific and therefore cross-reactive mixtures of antibodies providing multiple
strain cover are still being developed.

Anti inflammatory therapies

Other treatments which are having a particular benefit I think on mortality are anti-inflammatory. So we
have corticosteroids, they are used systemic corticosteroids.

Dexamethasone is the best studied. A meta analysis of randomised study showed significant reductions in
mortality with an Odds ratio of death of around 0.5. That benefit is greatest in patients with more severe
illness requiring supplemental oxygen and there is insufficient data to recommend the use of
corticosteroids for patients with milder disease, to recommend the use of inhaled corticosteroids or to use
corticosteroids as prophylaxis.

Don't forget that corticosteroids have a significant adverse effects. Quite a lot of our patients with COVID
also had diabetes. You give dexamethasone to somebody with diabetes, you certainly have problems
controlling their diabetes for a few days.

Then we have the biological anti-inflammatory therapies, the best studied so far, the anti-interleukin six
inhibitors and the JAK kinase inhibitors. And they seem to benefit hospitalised patients with evidence of
inflammatory illness so that a clear evidence of inflammation within the lung and increasing and
worsening oxygen requirements. So a little bit more severe than that dexamethasone alone group. There is
an increased risk of secondary infections from the use of these agents.
You don't need to look at this in detail, but just to show you how the guidelines evolve over time, this is a
National Institutes of Health guideline from August. And as you can see, they say we'll stratify this down
by disease severity so: hospitalised but not requiring additional oxygen; hospitalised requiring oxygen;
hospitalisation requiring oxygen through a high flow device; and then hospitalised requiring mechanical
ventilation or ECMO.

Looking at the severity here and then you have the recommendations for antiviral and immunomodulator
therapy. And so in the first group without supplemental oxygen, they recommend against the use of
steroids.

So it's really important that guidelines tell you what not to do as well as what to do. Hospitalised with
oxygenation, antiviral and dexamethasone. And if the oxygenation is really worsening then you could use
your secondary immunomodulator units. Hospitalised with high flow oxygen, again, steroids, remdesivir
and our immunomodulators. And again, the same in your mechanical ventilation group.
Coronavirus prevention

Prevention simply in reducing exposure. Social distancing, isolation, face masks and hand hygiene. So in
terms of isolation, recognising that people have got COVID when they come into hospital remains a
major plank in trying to prevent hospital based transmission.

Vaccination- a range of vaccines have proved effective subunit vaccines, mRNA vaccines, etc. and the
optimal type of vaccine. The booster schedules will emerge over time.

That takes us to the end of this talk.

Further reading on the epidemiology of viral pneumonia, immunopathology of COVID 19.

And an interesting article on the CDC websites looking at past pandemics.
Summary

So in summary, a wide range of viruses affect the respiratory tract most are mild, self-limiting seasonal
viruses and repeat infections maintain levels of herd immunity. Epidemics and pandemics result from
highly transmissible and virulent respiratory viruses. And although antiviral therapies have been
developed, vaccination remains the most effective tool both for influenza and coronavirus and hopefully
in the future, in the near future for respiratory syncytial virus as well. So as always, thank you very much
for your attention and I look forward to our next session.