Focus on lung transplant with Professor Paul Corris

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Speaking at Hospital Healthcare Europe’s Clinical Excellence in Respiratory Care event, Professor Paul Corris discussed the milestones and remaining limitations of lung transplants, what non-transplant physicians can do to help support these patients, and how a lack of usable donor lungs is being addressed with impressive innovations and results.

Having been at the forefront of the transition of lung transplantation from an experimental procedure to routine therapy, Professor Paul Corris’ contribution to respiratory medicine is unparalleled, and not just in the UK but worldwide. What he doesn’t know about lung transplantation isn’t worth knowing.

Co-author of all the major guidelines in the field and on many key clinical trials and original research, the emeritus professor of thoracic medicine at Newcastle University and the University of Oxford, UK, has made it his mission to champion the critical importance of respiratory physicians in the management of lung transplant candidates and recipients.

Indeed, as he says, ‘the gradual improvement of lung transplant techniques was very much based on the teamwork of surgeons, physicians, microbiologists, technicians and nurses, all working together’.

And this teamwork is more important now than it has ever been as new innovations are increasingly being adopted and revolutionising the field.

How has lung transplantation evolved?

If we go through the milestones, it’s interesting that vascular anastomosis was all done and dusted in the 1930s but airway anastomosis was a problem. In the 1940s and 50s, work to try and improve bronchial anastomosis was carried out and the first human lung transplant attempt was actually in 1963 before the first heart transplant.

After that, something like 40 attempts were recorded in the literature, all of which ended in abject failure. So, there was a very uncertain start to lung transplantation.

Interestingly, the first success actually came via a heart-lung transplantation in 1980 for a patient with what was, in those days, called primary pulmonary hypertension, now known as idiopathic pulmonary hypertension.

Although successful lung transplantation started with a heart-lung transplant, overall, there are only around 3,000 heart-lung transplants that have been carried out, whereas we’ve now got a world experience of around 70,000 lung transplants.

Lung transplantation is now a fully validated clinical treatment and improves both survival and health related quality of life for patients in terms of exercise tolerance and symptoms and functional class.

Data shows the functional status of surviving patients at five years and 80% of patients were in functional class one or two. In other words, really living normal lives. And I think this is a very important take home message: not only are we prolonging life, but we’re transforming the quality of life. And there’s very good data showing that this procedure has a dramatic impact. Patients can not only return to normal sedentary life, they can return to very active life, and this is the goal of what we’re seeking to achieve.

What’s the rationale behind choosing a single or bilateral lung transplant, and what other criteria are considered for candidates?

Generally, surgical techniques for transplants have not changed since the early 1990s but in modern times, there’s a favourable move towards undertaking bilateral lung transplants rather than single lung transplants.

Now, that does have a knock-on effect in the sense that in the past a donor with two potential lungs for transplantation could be used for two recipients, whereas if you’re going to put both lungs into one recipient, it halves the number of patients who may benefit and that’s an issue for us.

The choice for surgery now is that a single lung transplant is used principally for patients where there is a low risk, either through infection or from leaving that native lung behind and, in our view, that should be selected patients with lung fibrosis and some patients with COPD, particularly older patients. Virtually everything else is treated with bilateral lung transplants.

There are national guidelines on age criteria and we all get together and look at the evidence. We are transplanting patients over the age of 60 now, but we look at frailty, because chronological age is probably not the issue, it’s the frailty and degree of comorbidities that count.

So, there’s reasonable evidence showing that frailty and official ways of assessing frailty can predict five-year survival and we don’t undertake transplantation in anybody who doesn’t look like they would have a five-year potential for survival.

Most patients would be under the age of 60, but we are taking patients over the age of 60 and they’re highly selected. That goes for all indications and because of the interaction, particularly with the kidney.

We don’t take patients who have pre-existing renal disease that can’t be sorted pre-transplant. We don’t want to have to do a follow-up kidney transplant in our patients. There’s a chronic shortage of organs anyway for patients with primary renal disease requiring kidney transplant so we don’t want to increase the pool of potential recipients through poorly selected patients.

How common is acute cellular rejection and how is it managed?

Around 93% of patients will have an episode of rejection, and acute lung rejections are much more common in the first six months. After six months, you very rarely see any evidence of acute rejection.

We can control the acute cellular rejection very well with immunosuppression and, clearly, if you stop the immunosuppression, then we would see acute episodes. And, indeed, this is one of the hallmarks of a lack of adherence.

As in most diseases, there’s a group of treatment-resistant patients who don’t like to take their treatment or forget. But there are big consequences for the lung transplant population if they do that.

Acute rejection is principally a T-cell process and involves the lung parenchyma and the perivascular structures within the lung parenchyma and the small airways. Acute rejection still occurs, but it’s controlled by the calcineurin inhibitors cyclosporine and tacrolimus.

Patients are always on triple therapy, usually a calcineurin inhibitor, mycophenolate or azathioprine and a small dose of corticosteroids. The mTOR inhibitors sirolimus and everolimus can be introduced because they’re much less nephrotoxic than cyclosporine and tacrolimus. So, in a patient who had no rejection but was developing renal toxicity we’d switch to sirolimus or everolimus.

On that note, what complications relating to immunosuppression are most common post-transplant, and what is being done to tackle these?

Around 80% of patients will have hypertension requiring therapy within five years, and 53% of patients develop some form of abnormal renal dysfunction, which is largely related to cyclosporine or tacrolimus therapy, which is one of the principal core pillars of immunosuppression.

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Hyperlipidemia is extremely common at 58%, as is diabetes at 40%. And then bronchiolitis obliterans syndrome, which is an airway lung allograft dysfunction complication, seen in nearly 50% of patients by five years.

So, there are challenges for those of us managing these patients in terms of minimising the levels of immunosuppression and individualising the dosage. We’ve moved away from a one-size-fits-all approach so a patient who doesn’t reject very much would be given the immunosuppressive drugs at much, much lower levels than a patient who was regularly rejecting. And we hope with this shift towards a more personalised approach to the post-operative management, we will see decreases in these in these complications as we go on.

But it’s also important to say that around 16 or 17% of our first cohort of patients who could survive 20 years post-transplant did survive 20 years. That’s a remarkable figure, really, when one considers most of these patients would have a life expectancy of 18 months or less at the time of their transplant.

The six-minute walking distance of our 20-year survivors was around 600 metres, which is normal. And, yes, the median creatinine is high, and some patients required renal transplantation between the 15- and the 20-year survival, but we’ve improved our techniques within immunosuppression.

Malignancy is also an increased problem in 20-year survivors, but the majority of these are quite treatable problems such as non-melanoma skin malignancies, and a lymphoma-like programme due to Epstein Barr Virus or post-transplant lymphoproliferative disease, which is also completely curable.

And indeed, the therapy to treat post-transplant lymphoproliferative disease is rather more gentle than one sees in a standard lymphoma or Hodgkin’s patient.

Tell us more about bronchiolitis obliterans syndrome

As I mentioned, virtually all patients will have an episode of rejection and, certainly, the chronic long-term problem of bronchiolitis obliterans syndrome (BOS) – or chronic lung allograft dysfunction (CLAD) – is directly related to the number of acute episodes of rejection.

A fibrinoid cellular inflammatory plug blocking the airway is the hallmark histology of CLAD, principally related to episodes of acute rejection. Our understanding of the absolute mechanisms of this fibrosis-accelerated disease are not fully known, but we do recognise the development of airflow obstruction. And, obviously, the more airways that are affected like this, a progressive worsening of the airflow obstruction takes place.

There’s a subgroup of patients who early on when they’re developing these lesions develop a response to the macrolide antibiotic azithromycin. I’ll mention macrolide antibiotics and increasing immunosuppressive drug toxicity later, but azithromycin, interestingly, has anti-inflammatory properties, particularly against neutrophilic infiltration. But this is only in a minority of patients – maybe up to 20% of patients – so, for the 80%, there is still no curative treatment for BOS and it unfortunately, remains the Achilles heel of lung transplantation.

We have shown some improvements, but these are pretty small, and we’d certainly like to see a bigger difference. And really, we’ve made no impact in the last the last 15 years or so. There’s a lot still to do, I’m afraid, if we’re going to get survival from lung transplants up to what we expect to see in liver and kidney transplants, for example.

We have, in recent years, noticed a second form of CLAD called restrictive allograft syndrome, it’s a lot worse than BOS. It’s associated not just with the airway obstruction, but evidence of scarring within the lung parenchyma. And, again, our understanding of the mechanisms, despite intense research, is so far proving quite elusive.

What should non-transplant physicians take note of in terms of managing transplant patients?

If we look at the adult lung transplant causes of death, number one remains BOS, or graft failure due to obliterative bronchiolitis and restrictive allograft syndrome. But the second most important issue is non-cytomegalovirus infection.

Infection is a big issue and prompt treatment is imperative as these patients get sick very quickly. There’s no such thing as a non-serious infection in these patients because their immune systems are so damped. Any sign of infection requires instant action, no delays.

And certainly, all transplant patients if they ring up looking for an appointment should get an urgent appointment and not have to wait two or three weeks for an appointment. It’s all very well me saying that, of course, but the reality is these patients can go from apparently well to near death’s door in a matter of days if they have a significant pulmonary infection, for example.

If a patient – and it doesn’t matter what transplant they’ve had – comes in and you think they have an infection, do not prescribe macrolide antibiotics. Macrolide antibiotics interact with calcineurin inhibitors in a very, very positive way, causing huge elevations in the toxicity of the immunosuppressive drugs. Many cases of acute renal failure are precipitated by that event.

So, even though azithromycin is rather different and doesn’t have the same characteristics as clarithromycin or erythromycin as I mentioned earlier, whatever you do, do not prescribe macrolide antibiotics. Penicillins and drugs like ciprofloxacin, for sure, they’re fine. But no macrolides, please.

So the first message is: if a patient appears to have an infection, you need to treat early. And secondly, every transplant centre will welcome and give advice. We want to know when our patients aren’t well. What we don’t want to find is two weeks down the line of patients being treated, deteriorating and then having to be transferred to the transplant centre for further therapy.

Speak early, treat early, react early and give early appointments if patients are sick. I cannot emphasise how quickly an apparently well patient following a transplant can deteriorate.

What is the status of the lung transplant waiting list at present, and what innovations are being used to improve it?

A big problem is that we just don’t transplant enough patients due to a lack of usable donor lungs. Data of a cohort of UK patients waiting three years on the transplant list shows that although 69% had actually been transplanted, 23% of patients had died, four patients had to be removed from the waiting list because they had become too sick and there were only five patients still waiting. So, we really do need to improve the number of donor organs if we’re going to satisfy the need.

The lung is very vulnerable in a potential donor. Often, the kidneys, the liver and the heart can be used, but because most patients are on a ventilator, infections and injury to the lung are prominent. So, in multi-organ donors, the lung is the least used organ, but we can take a damaged lung now and repair it using ex vivo lung perfusion (EVLP) and that’s a very exciting prospect.

So, lungs that are not deemed suitable for implantation into patients are taken from the donor, we bring them back to our lab ventilated and perfused and we repair those lungs. They couldn’t have been used before for transplant, but they’re now suitable for transplantation. It’s a bit Frankensteinian, maybe, but it works beautifully.

And we can do all sorts of clever things with EVLP in terms of treating infections, reducing inflammation, and, in the future, we may well be changing those lungs so that they become less recognised as foreign by the recipient, thus may be obviating the need for anti-rejection therapy. And this is a real time thing; most transplant centres are now doing this.

Our first patient in Newcastle was dying from cystic fibrosis and he would never have had this transplant if we hadn’t repaired those lungs on the EVLP. It’s a very promising technique to improve the numbers of lung transplants.

Every talk on transplantation now includes a question or a discussion on xenotransplantation and this is also being done quite a lot now. The pig lung would be suitable for lung transplants, and we’ve now managed to humanise, if you like, the endothelium of organs so the heart and kidney, particularly, with lung coming along. There have been, as you know, two heart xenotransplants with recipients surviving something like six months – still with some problems, but things are working really pretty well down that route. There was a time when I thought xenotransplantation would never deliver. I’m not so sure now.

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