Dr.

Sujeet 0:00

Hello, I'm Sujeet Rajan consultant Pulmonologist at the Bombay Hospital Institute of Medical Sciences in
Bhatia Hospital in Mumbai. And I welcome you all to the fourth episode of Healthcare Superstars. As you
know, in Episode three, we focused on the early detection of COPD. Difficult subject, and very well
discussed with two of our faculty which were Dr. Richard Russell and Dr. Mona Bafadhel.

Dr. Sujeet 0:31

I would encourage you all to view that if you haven't yet seen that episode. Today, we will be addressing
a much more debated topic, and especially when it comes to pharmacology and that is management of
severe COPD with three interactive cases. Before I move forward to invite our speakers, I'd like to first
thank our collaborators, which are The Sri Lankan College of Pulmonology, The Myanmar Thoracic
Society, AAA and AOSR from Algeria, APPM and AFMAPATH from Morocco, (ASONEUMOCITO) and
ACME from Colombia, the Iranian Society of Pulmonology, SDNCT and Newman North from the
Dominican Republic, The Panama pneumology Association, and the Yemeni
Association for Respiratory Care. I'd like to introduce our first faculty. And that's Professor Dave Singh.
Dave is a dear friend and an outstanding person in respiratory medicine, particularly COPD, not a
stranger in that space at all. He specialized in clinical pharmacology and respiratory medicine, and his
research interest has been the development of new drugs for both asthma and COPD. He's a member of
the Gold Guidelines Science Committee and chairs the ERS Airway Pharmacology Group. He's also the
former editor of the BJCP and the current editor at the ERJ. He's acted as the principal investigator in
over 300 clinical trials and has over 250 publications. So welcome, Dave.

Dr. Sujeet 2:22

We also have Dr. Mark Miravittles, from Barcelona in Spain. Mark is a consultant and a senior
researcher. He's also been the former guidelines director and chair of the Respiratory Infections Group
of the ERS, and is an editorial board member of 15 journals in COPD. He's participated in preparing nine
international guidelines on COPD exacerbations and has been invited for over 1370 lectures on COPD
itself. He has over 450 publications related to COPD till date. So, thank you, Mark, for coming. So, Dave,
over to you a rare combination of clinical pharmacology and respiratory medicine. We have two cases
that you're going to present. And I'd request you to start off with the first case that we can discuss.

Dr. Dave 3:22

Okay, so I have two case histories. And they're focused around inhaled corticosteroids. And I think
there's been a huge change in the way we think about appropriate use of these inhaled medicines in
COPD and the way that we're using them in clinical practice. And this is all being driven by a number of
large randomized clinical trials with combination inhalers. I think we're all used to seeing the evidence.
The question is, how does this play out in clinical practice? On an individual basis, what should we do
when faced with patients who ultimately are all slightly different when we look at the RCTs? That gives
us group data. But of course, in the clinic, we're faced with N equals one. And that's really what me and
Mark will be discussing today. What do we do with every single N equals one, and they're all completely
different to each other? So just briefly, before we get into the meet of the cases, there's my disclosures
of interest.

Dr. Dave 4:32

So, Case number one, and actually this lady I saw back in 2005. She's a memorable COPD patient, and
I'm going to jump slightly to the end. She's memorable because when I describe to you the stage she
was in when I first saw her, I don't think as a as a doctor, you would then project forward to 2021 and
think she would still be alive, but she is. So, here's what's happened to her. When I saw her, she was
being looked after by another respiratory consultant in a different hospital, who had managed her for a
few years with great difficulty. She had a long smoking history, but she had stopped. And in the other
hospital she had suffered with multiple exacerbations. She had been ventilated twice. She had
numerous new admissions for pneumonia episodes. So, when I first saw her one of her big problems
was these recurrent infections, she had chronic sputum production between infections. She was on
triple therapy, and at that time, we had no single inhaler triple therapy, so she was using two inhalers
and inhaled corticosteroid long-acting beta agonist combination is one and a long-acting muscarinic
antagonist is another. So, investigations supplied to me and repeated in my lab that showed an FEV 1of
about 35% predicted so severe COPD. A high-resolution CT scan showed widespread emphysema. No
evidence of bronchiectasis. So, looking back through her notes, she often grew various bacteria. And one
of the most common both in the stable state and during exacerbations was Haemophilus influenzae, the
Nontypeable Haemophilus influenzae NTHi. There had actually also been episodic positive cultures for
other bacteria, including once Pseudomonas. But the thing that that was a regular pattern was this NTHi,
she seems to be colonized, it seems to be present during episodes of exacerbations. So I'm going to just
show you a little bit about NTHi from some papers, and here's one we did. And there's other data like
this as well. There are, there is considerable antibiotic resistance for this bacteria. And here are a
number of patients in the UK, I must stress that some of this is regional. But you see here that some of
the common antibiotics that we use, so Macrolides, Penicillins. You find that a number of the strains are
resistant to NTHi. Now, interestingly, in this sample set, if you were to use something like Ciprofloxacin
and we had 100% sensitivity. Tetracycline, so obviously Doxycycline would fit as well, you've got over
90% sensitivity.

Dr. Dave 7:49

So here one of the things that we need to look at with this extremely common colonizer is careful use of
antibiotics, looking carefully at antibiotic sensitivity. And I just like you to just remember what you see
on this slide about Macrolides. In this sample set of over 50 patients, you see that about half the strains,
maybe 30 to 50% of the strains are actually resistant to different Macrolide antibiotics. Now another
point to bring out about Haemophilus is, I've mentioned that it was present in the stable state and
during exacerbations. I think one of the questions that commonly arises from clinicians about bacterial
colonization is what's its relevance. So you have patients who present you with dirty green sputum.
They're in their usual state. So, they say yes, I usually cough up some phlegm. They say yes, my
symptoms are normally like this. So, you might think, right, that's normal for them. You take a sputum
culture, and you grow a bacteria. Is that relevant? What should you do about that bacteria? And I've
heard two schools of thoughts. Some people would say, Yes, we should treat it and other people would
say, well, the patient's not ill at this point in time, maybe that bacteria is there in a small amount, even
though we've grown it. Maybe I should leave it because if I treat it, we're increasing the chances of
antibiotic resistance. I'm not saying I agree with that, I've just heard people articulate that view. So, I
found this study by Tom Wilkinson, who's in the UK based in South Hampton, I found this very
interesting. He conducted this very careful study where he sequentially sampled patients, their upper
airways sputum, for the presence of bacteria and viruses. And there seem to be this interaction between
Nontypeable Haemophilus influenzae NTHi, and the common cold virus HRV Human Rhino virus. So, if
you have a look at this data, if you had both of these present in your airways, and I've circled them, you
were far more likely to exacerbate compared to just having the bacteria alone. So have a look at the top.
That's NTHi is present. So that's, but there's an absence of human rhinovirus. Your odds ratio of
exacerbation is 1.69. Now, NTHi is present with HRV, with the virus, a fivefold increase. Now, that's also
represented a bit lower down when you've got an 18-fold increase. And all this is there's two ways
round one is where something's a colonizer, then the other bug comes in so and the one at the top NTHi
that comes in second. So, it's a secondary infection in the presence of HRV and the one in the middle is
where you have colonizing bacteria, and then suddenly you get a cold. Now the bottom rhinovirus alone,
then there, you've got a tenfold increase of having an exacerbation. So the interesting one is actually at
the top, isn't it? That where you have the bacteria alone, that's actually you know, it's less than a
twofold increase in your chance of exacerbating a virus on its own gives you a tenfold increase, and both
together an 18-fold increase. So actually, this bacteria is sort of laying an unfortunate groundwork in the
lungs, so that if you get a virus on top, that's really bad news. So, coming back to the question, what
should we do about this and coming back to the case

Dr. Sujeet 12:13

Yeah

Dr. Dave 12:13

Although this publication is 2017, I think it lays some justification for what I did with this lady and I
focused on eradicating colonizing bacteria from this patient. And this patient remember did not have
bronchiectasis. So, I think it's another thing that's talked about. You have COPD, chronic infection, you
should look for bronchiectasis, but you may not find it but COPD patients can still have chronic bacterial
infection. And there's all sorts of pathological mechanisms for that that we can get into.

Dr. Sujeet 12:55

Okay, I just need to stop you here for a moment Dave. NTHi, not something our microbiologists often
report. I can't see my microbiologists report that. So do we have to push our microbiologist to tell us this
is NTHi? And what about HRV serology? Is that commonly done in your practice?
Dr. Dave 13:21

Yeah, yeah. Great, great point. So, from standard culture, you can only say it's Haemophilus influenzae.

Dr. Sujeet 13:28

Okay.

Dr. Dave 13:30

So, the, so this… So, the serotype B that you refer to is the encapsulated form. So, for the encapsulated
form, you can type it. So, you, you can do further tests to find out which type you have. So Nontypeable
is the non-encapsulated form. So, I'm laying out sort of simply.

Dr. Sujeet 13:57

Okay.

Dr. Dave 13:58

The nontypeable form doesn't seem to cause any problem to most healthy people. So, it's the
encapsulated form, and that's the one that causes middle ear infections and severe pneumonia. And
you're quite right, the microbiology is quite right, when they do a culture that will just tell you it's
Haemophilus influenzae, they won't tell you which form. So, the way you get the form is you either have
to do a biochemical test, or we did it here by PCR. So, we did, we were able to look at the gene
structure. Now in reality in clinical practice, if you have a COPD patient who has a positive culture, from
their sputum, I think you can more or less assume it's NTHi because that that's the common pathogen,
but some of the encapsulated forms do cause problems. Now, in the end, the practicality of it is that the
local microbiologist, if you engage with them, will do the culture give you the antibiotic sensitivity. And
that's actually what you need.