Though many advances have been made in neutropenias, diagnosis and management are still based on physicians’ experience or local practices. Prof Francesca Fioredda and Prof Helen Papadaki, two co-authors of the HemaSphere published article The European Guidelines on Diagnosis and Management of Neutropenia in Adults and Children: A Consensus Between the European Hematology Association and the EuNet-INNOCHRON COST Action, discuss with host Dr Stephen Hibbs the challenges and outcomes in creating a guideline for diagnosis and managing neutropenia in adults and children. Read the referenced article on the HemaSphere website and watch on YouTube.

So today I'm joined by Francesca Fioredda and Helen Papadaki, hematologists based in Italy and Crete respectively. And they're the first and last author on the European Guidelines on Diagnosis and Management of Neutropenia in Adults and Children, published in April in Hemasphere.

So today we're going to hear about them and about the story of this guideline, current practices in neutropenia work-up and where there's significant variation. We're going to hear about neutropenia and people with dark one polymorphisms and how we approach that, areas of controversy, and finally, where they see the greatest potential for future research.

So thank you both so much for joining me today.

Perhaps I'm going to start off by asking Francesca this question. Could you tell me a bit about where the story of this guideline started? How did it first get going? How did you get involved and how long did it take to reach the finished piece?

I actually treat adults - and I always had, in my mind, that concept that you know neutropenia in adults, for example, is a matter of acquired neutropenia. However, across and during this long way, I realized that this is not the case. I have learned how to better use diagnostic tools such as the genetic testing and molecular testing. I realized that you can diagnose patients with genetically-based neutropenia in adulthood.

So I really -- And I also learned how to better appreciate the family history. For example, traditionally, when we see patients with neutropenia in adulthood, we always ask: Well, when did it start and do you have any other family members who have neutropenia. And either they say no and we go further...

However, I learned that it is very important to insist on the family history and ask if you have other members in the family with infections, with early death, with miscarriages etcetera.

So I actually -- To summarize, I enjoyed this interaction with the pediatricians and the pediatric hematologists, and I now have learned how to better diagnose patients with congential neutropenias that present in adulthood - and I think vice versa. I think that also the pediatricians learned how to diagnose children with acquired neutropenias.

It is not so easy with all the people with all the people that you meet on your way, but with Helen it was possible. It was really possible to exchange, for example, for a pediatric, how to catch some element that may be useful to manage the patient that is growing, growing up, and how to manage the disease in adult age.

And so, this is really an important thing. My previous experience was in the field in pediatrics, in neutropenia, in the Italian Guidelines... but at that time we were only pediatricians - and this was something new for me and for us.

And you know, there we realized that although we were, let's say, people that have focus on neutropenias, however we have absolutely different approaches in different areas. And you know, this depends on what kind of diagnostic tools you have available. What are the local practices? What is the experience of the physicians?

So we've had this kind of collaboration with other people - and we realized that, you know, what we think as a standard, you know, in specialized centers... it's not the case in other parts of the world.

For example, the genetic testing, which is so important not only for the diagnosis of specific types of neutropenias, but also to cover a very -- Follow-up. The appropriate follow-up in these patients - is not the case in many parts of Europe.

So of course, we need to have a more widely available genetic testing in as many countries as possible. Another issue is the antineutrophil antibody testing, which is very important to characterize some types of neutropenias, the autoimmune neutropenias, which are very common in children (but also, they can be found in adults). However, you know the test for antineutrophil antibody is so typical to be standardized.

So, we have to make available the genetic testing. We have to make, you know, more friendly use of the antineutrophil antibody testing. And of course, we have other needs such as the better diagnosis of some telomeropathies, which may be the case not only in children but in adults. So these are some examples of how some very important tests are not widely available and how there is actually a need to make them available and widely used.

And another idea is that any of us probably started from a different point, but we tried in any way to overcome the differences and the obstacles in order to reach a consensus. And if I can say that the phases of our consensus were not so easy for this reason, because we needed the time to explain our methods, our reason. At the end, we catch some useful things from one to others.

So the process was not so smooth at the beginning, but at the end we were able to reach some consensus, on some tools, for example, genetics, that may be available in one country more easily and another country less easily and so on. But it was, at the end, quite useful for everybody, I think.

So the Duffy -- What is it? Duffy antigen receptor for chemokines, 1 polymorphisms, which, as I understand it, is the main reason why a lot of people who are of Black African heritage or some people from Arab heritage, or a few other ethnicities, have lower circulating neutrophil counts than others - and why the reference ranges may not make sense for all populations.

This seems to be a really important area to get some clarity on, and I just wonder, how did you approach that in the guideline and what work do you think needs to be done to really have an approach to neutropenia that makes sense for patients with this polymorphism?

However, we have realized that this type of neutropenia may be also found in not the traditional parts of the world, but can be also found in Europe, for example, and this is the reason because, you know, people are moving around and also, you know, marrying. We have marriages between people.

For example, we have identified this type of neutropenia in our cohort of patients in Greece and we have a cohort of neutropenia patients not only from Greece but also from Balkan countries, and we have identified that 5% of the population (which are not traditionally originating from Africa or the Middle East, but are Europeans) that present this polymorphism.

So what will happen, introducing these guidelines, is that we have to insist on investigating or on exploring the presence of this polymorphism. And if we do not have access to the genetic testing - which is very simple because you just perform a PCR analysis to identify the polymorpism, but if you cannot do that, at least you can make the phenotype of the red blood cells and identify these Dark-1 phenotypes are, you know, associated with this type of neutropenia.

So it's not actually the limit of the neutrophilus that makes you to have the suspicion of this type of neutropenia. And just perform the phenotype - and of course, if you can, the genotype - to identify this polymorphism.

Yeah. How would -- If we don't have them, how do you approach someone who has got a low neutrophil count? But is it because of the polymorphism or is it too low for that? Those are the sort of questions that I think people perhaps often grapple with.

And one of the goals, even of the guideline, was trying to lighten (as much as possible) the controls in a person who are not really needing all this stuff. And also the consideration of the threshold of the neutrophils probably will change; as considering, for example, a patient being treated with chemotherapy or other kinds of treatment.

And so, I think we must deepen and enlarge the cohort in order to have a better idea on how it works and how we can manage all these things.

Of course, we have a follow-up in these patients, particularly if their white blood cell counts are lower than those that you expect in such types of neutropenia. However, at least you do not need to perform, you know, these exhaustive investigation that you have when you have these otherwise identified neutropenias.

Were there any areas that you just couldn't find agreement on and you had to sort of set aside as a recommendation, or were there others that it was quite difficult to reach a consensus because of differences in opinion within the writers?

So, yes, given that we had children and adults and we had decided that both should be included in these guidelines - we had many rounds in this particular area, which should be the investigation that should be included in each level.

Also, we discussed a lot about how often we should perform bone marrow aspiration in congenital neutropenia patients that come to adulthood. You know, where there you have people that are going to get married, you know? They have their first relationship etcetera and they do not want to, you know, to be in touch with their doctor.

Because in the past these children, you know, they didn't live a lot because of the infections etcetera and because of acute myeloid leukemia etcetera. But now these people live as the rest of the population. So we have these young adults that need a specific approach.

So we had this kind of discussion. However, for me it was the best experience because these kinds of discussions between people that are experts in their own field... it was so deductive for each of us and so educational etcetera, that we really enjoyed.

And finally, we had the broad consensus in all topics. But we had, of course, many rounds of discussions, frankly.

And also, we had a lot of discussion on classification in relationship with these new provisionally acquired - likely acquired - neutropenia, which seemed promising to describe and to connect those neutropenias that rise in infancy and goes on without remission since adulthood.

And so, this is really an interesting field and it is also a matter of collaboration for me with the adult world. Also, I confirmed the concept of the frequency of controls. It was a matter, really, of discussion - because, as pediatricians, we are in a habit to do more frequently some procedures because sometimes parents ask some for some answers.

In adulthood, a neutropenic patient learns how to live and how to manage and he has, or she has, a lot of things to do and does not have the time (or doesn't want to have the time) to check her or his bone marrow. And so, it was quite a challenge.

So Francesca, I'll start with you on that.

And this is something that would help us to consider a person with a disease or without a disease. And this is true not only for ethnicity, but I think for other kinds of genetic characteristics probably; that are active or inhibit some, for example, receptors that can allow the neutrophils to go in other places other than the vessels.

So I totally agree with Francesca. And also, for me it's a challenge to further investigate these idiopathic patients as well - because you have the patient, you perform a number of investigations and exams and finally we say "Well, in 60% of this" -- I don't say patients -- "of these people, you do not identify anything". However, neutropenia is there.

So I would like to perform my whole examination/analysis in every neutropenia patient, because as long as it's apparent, as deeper as you investigate these patients, you identify some, you know, variations. And then, it would be very interesting to join data from different databases and to see if other people in other labs and other areas (etcetera) display the same variation that you identify.

So the whole exome sequencing for me would be, you know, I would like to perform it in every idiopathic neutropenia patient, because I believe that some of these patients have congenital disease that has not been identified. You know, not traditional congenital neutropenias, but some variations that result in the neutropenia.

And also another challenge for me is to further investigate these variants of a known significance; that we identified in our genetic testing. And it would be very interesting, again, to combine data and also to perform functional analysis to identify which of these, you know, rules or variants of a known significance are pathogenic in these patients.

So these are my, you know, research dreams and experimental dreams in the field.

We'll be back soon with another episode of the Hemasphere podcast.