Precision medicine: evidence-based medicine 2.0? – an interview with Mathias Pletz

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Precision medicine is an approach to patient care that aims for the right intervention, in the right patient, at the right time – but what impact could this have on the treatment of infectious diseases? We asked Mathias Pletz about this approach to treatment, the research he’s directing at his institute and what the challenges are in this field.

First, could you just introduce yourself and tell me a bit about your background?

I’m qualified in internal medicine, respiratory medicine, infectious diseases and I have additional training in hospital hygiene. I did my training in Berlin (Germany), Houston (TX, US) and Basel (Switzerland) and I did a postdoc in Atlanta at the CDC and Emory University (GA, USA). I then finished my medical training at Hanover Medical School (Germany).

In Germany, infectious diseases are not yet really developed – there is not a specialty, just a sub-specialty – however, 9 years ago there was a program from the government offering grants to create divisions for infectious diseases at six selected academic centers. Jena was one of these centers. The ID division was supposed to support the long-standing sepsis research in Jena. I applied for this program and was successful. I was given the chair of this novel division at the University of Jena (Germany). At the beginning, it was a division within the department of gastroenterology and hepatology but with time I negotiated the division to become independent. This started 7 years ago and now I am the chair of this independent institute and we have two associated professors – one for hospital hygiene and one for clinical sepsis research – and almost 55 co-workers.

Could you introduce the work you do at the Institute for Infectious Diseases and Infection Control?

What we do is carry out consultations across the entire hospital. Before I applied for the grant from the government I went to Switzerland to learn from the well-developed infectious disease community there and I saw that they had started departments with their own beds in the 1970s , however, they had then developed from a classical department with beds to a more consultation-driven, hospital-wide service. So, they gave up the beds, but the team spread all over the hospital and I think this is the future for infectious diseases because you find it in basically every department – from pulmonology to psychiatry.

At the University of Jena, we started out with approximately 180 consultations per year in 2011, but now we have over 2300 every year, and every consultation is written and stored in the electronic patient file. Initially we had to do a lot of work to gain trust from our colleagues and to prove we could add value to what was already done, so, every consultation was referenced with guidelines and recent studies – sometimes it was like a small review article! As other teams saw that our recommendations improved the clinical outcome, they ordered more consultations.

In addition to this, we have an outpatient unit for HIV and vaccinations etc., we’ve started an antibiotic stewardship program – doing weekly rounds with our colleagues from microbiology and pharmacy and issuing hospital guidelines – and we have created a group on diagnostic stewardship. We see that many of the lab tests that are ordered are not helpful, they are expensive, and they may decrease the quality of clinical decision making. So, we are building up syndromic panels that will allow clinical colleagues, for example, to hit the panel for community-acquired pneumonia and get all the barcodes for blood culture, urine antigen tests, sputum etc.

Finally, we have a strong research focus both in both basic and clinical research, particularly on Staphylococcus aureus bacteremia. In 2014, we went to the heads of the departments and asked permission so that we could go to every patient with S. aureus in the blood culture. We did this for 3 years and then we analyzed our data, discovering that we could decrease mortality from 23 to 11%; with every eight consultations one prevented an intrahospital death. This was very rewarding and now we’ve started to extend this to Candida bloodstream infections and to enterococcal bloodstream infections.

Could you give an overview of what precision medicine is and the rationale behind this approach?

Personally, I think evidence-based medicine improves the quality of medicine in general, but it is a medicine of averages. Particularly in sepsis research, we have seen a lot of negative results over the last few years; however, negative studies with wide confidence intervals do not mean that the procedure you tested has no effect, it can mean that there are the same number of patients who benefited from the intervention as those who didn’t benefit or even may be harmed.

I think precision medicine is evidence-based medicine 2.0 – we have to better define patient phenotypes and the stage of disease the patient is in. This is particularly difficult for the dynamic course of sepsis as the treatment requirements today may be totally different from those tomorrow, depending on the current degree of inflammation, organ failure, volume load etc. So, we need to change our approach from patient-to-patient but also from time-to-time within the same patient. I think this requires precision medicine and it can only really be achieved with improved and rapid diagnostics.

That bring me on to my next question – what role do diagnostics play?

I sometimes feel frustrated when I hear the discussion around, for example on multiplex viral PCR for respiratory samples in patients with confirmed pneumonia. Many people are arguing that it is not cost effective because there’s no treatment decision you can make based on it because you still have to give antibiotics for bacterial superinfection. This argument prevents the increase of knowledge. For instance, PCR has identified respiratory syncytial virus (RSV) as a substantial burden not only in children but also in adults. Pharmaceutical companies are now starting to build vaccines against RSV for adults, and this would never had happened were it not for these diagnostics. I also think artificial intelligence (AI) might play a role in advancing ID diagnostics.

So, do you think AI will help clinicians to make treatment decisions?

Yes, I am absolutely convinced of that. Let me give you an example: I’m interested in community-acquired pneumonia (CAP) and all major guidelines say, for patients with moderate disease on the regular ward, we do not know if you really benefit from macrolides in addition to beta-lactams. The problem is that a clinician knows all the advantages and disadvantages of the macrolide – for example, macrolides cover atypical pathogens, however, elderly patients rarely have atypical pathogens, in addition, macrolides attenuate pulmonary inflammation but they can also provoke cardiac arrhythmia – which can be deadly when the patient is not monitored- and some have a strong reaction with statins, which are frequently used in the elderly. But when you are stood in front of a 70-year-old patient with comorbidities and moderate pneumonia, do you give them the macrolide to attenuate the inflammation or will you harm them by provoking cardiac arrhythmia and interactions?

We recently published a paper where we took the CAPNETZ database, a database with 12,000 patients with community-acquired pneumonia, and we used AI to try and resolve this macrolide problem for moderate CAP. AI came up with three simple questions in the right order: does that patient have pulmonary co-morbidity, do they have an increased leukocyte count in the sputum and does the patient have a cardiovascular comorbidity? By following this algorithm, we were able to show that we could decrease mortality by 30% compared with doing the opposite of it.

So, I think this could be the future for infectious diseases; having large patient cohorts with individual risk profiles and computerized decision support systems at the bedside. When it comes to personalized treatment, oncology is far ahead of infectious diseases. The only difficulty compared with oncology is that in cancer we have time – it’s a subacute to chronic disease. We can do extensive diagnostic testing before starting treatment and we can easily get informed consent forms, because in contrast to severe infections, most patients are still able to sign. Whereas for sepsis or for pneumonia you only hours before starting treatment and I think that’s why oncology is much further in their progress compared with infectious disease.

What do you think are the main challenges facing the implementation of this precision approach?

I think it depends on the particular subject and country-to-country. Money is certainly one issue.  Precision medicine is not possible without rapid and advanced diagnostics. These diagnostics have yet to be developed and has to be made available as point of care – because most hospitalized infections require rapid start of treatment. But getting advanced diagnostics into clinical practice, such that you can start clinical studies on personalized treatment is currently an issue of costs. As pointed out above. Science is a self-propelling process but if no one starts to use novel diagnostic tools for cost reasons, there will be no gain of knowledge that creates ideas for further interventional studies.

Furthermore, for me, a major issue in Germany is exaggerated data protection in clinical studies. One reason that enrolment into e.g., sepsis studies is so difficult because with data protection we always need a signed consent form, and often even obtaining one from the next of kin is not enough, it has to be the legal representative, who has to be appointed by a lawyer, and this makes things difficult. It is also difficult to link up all electronic medical data from different sources for on individual patient – so it is currently legally impossible in Germany to get a huge population-based comprehensive medical database. There are so many questions that such a database could answer.

How do you think that might be overcome in the future?

I don’t really know how to overcome this, but I think there are some example of places in the world that have better systems, such as the Scandinavian countries. They have one number for every individual patient, and they collect all the medical data to this one number lifelong. I think that’s perfect for clinical studies and for personalized medicine and it would certainly benefit the patient. However, it’s probably hard to exclude that no one uses those data to for financial gain and I don’t really know to protect those data, but I think it’s possible.

Where do you hope to see the field in 5–10 years’ time?

I think next-generation sequencing combined with AI will play a big role. However, I do not really know if next-generation sequencing to detect pathogens alone is sufficient to turn around infectious disease diagnostics because there are a lot of hurdles. One example is, if you have non-sterile materials how do you overcome the innocent bystanders? For instance, if you identify S. aureus in a respiratory sample, is it just there because the patient’s colonized or does the patient have S. aureus pneumonia?

For me, a possible solution could be to combine two things together – the detection of the pathogen and the host response to this pathogen. There was a recent paper showing that Aspergillus PCR together with IL8, which is typically increased when Aspergillus is involved and could be a better marker than PCR itself. So, combing the microbiome with the patients’ genome and transcriptome in a rapid test analyzed by AI could be the future. When we have better diagnostics then we can do better personalized medicine.

Regarding novel treatments, I think there is time for novel concepts beyond the traditional approach of ‘find bug and kill bug’, which always has the risk of resistance development. Novel approaches that try to cure without killing the bug are e.g., virulence blockers or the novel concept of tissue resilience in septic organ failure.

Is there anything else you’d like to add?

To me ID is one of the most intellectually fascinating subjects in medicine; moreover, there was a study that showed that nephrologists and infectious disease physicians have the most complex patients in their consultations.  ID is different to all other medical subjects because we don’t have a bilateral relationship – patient and treatment – we have the patient, the treatment and the pathogen, and the pathogen within this triangular relationship is always changing. To me, ID is a kind of applied evolutionary biology and evolution is constantly ongoing, not always predictable and mercurial. So, there will always be a new challenge for ID physicians.

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