BONUS CASE: Fever and high ferritin

Pip Watson ( BSR Education committee chair) chats with Dr Jessica Manson, Dr Michael Wood and Stella Kotsiopoulou. These experts from rheumatology, haeamatology and infectious disease discuss their approach to the management of the unwell patient presenting with fever and a high ferritin.

Other resources:
Spotlight on HLH - https://www.rheumatologylearning.com/course/view.php?id=306 
GIRFT guidelines https://gettingitrightfirsttime.co.uk/wp-content/uploads/2025/06/HLH-Guide-final-version-v1.3-June-2025.pdf

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Transcript

Welcome to this talking rheumatology bonus case based episode. Today, we're going to explore the case of it with fever and high ferritin. I'm delighted to be welcomed by three colleagues who will now ask to introduce themselves and their specialties. Jess, could we start with you, please?

Yes. Hi. I'm Jess Manson. I'm a rheumatology consultant, and I lead the UCLH, HLH service.

Thank you. And Mike?

Mike Brown. I'm an infectious diseases and, general medicine consultant at UCH and at the hospital of tropical diseases there.

Thank you and Stella?

Hello I'm Stella Kotsiopoulou, haematology consultant at Croyden Health Services NHS Trust.

That's wonderful. Well thank you so much for joining me today and it's a familiar ensemble for dealing with the condition that we're going to come to and great to have all of your expertise. So let's get to the case. So our patient this week is a 52 year old man of Chinese origin, and he was admitted to hospital with quite a long history. So two months of increasing abdominal pain, myalgia, lethargy, and weight loss of 10 kilograms with an associated fever. He worked in water sanitation, which got us rheumatologists excited in terms of possible causes. His past medical history was pretty unremarkable, as was his travel history. So we hadn't been anywhere exciting recently. And as we'd always do with these patients, we did a really thorough clinical examination but weren't really able to find any localising signs. So it'd be interesting just to hear people's thoughts at this stage. Stella, I wonder if I could come to you. What hematological differentials would you would you be thinking about in this patient?

So due to the duration of symptoms, the seemingly significant weight loss, I mean depending on his baseline weight, the 10 kilogram weight loss, if it is more than 10% of his total weight within six months and temperatures, these would fit the criteria for constitutional symptoms and would make us worry about an underlying hematologicality. For example, in for proliferative processes or leukemias manifesting with intra abdominal soft tissue masses, constitutional symptoms, less often myeloproliferative neoplasms such as chronic myeloid leukemia may manifest with these generalized symptoms but also abdominal discomfort because of progressive hepatosplenomegaly. Very very rarely, paroxysmal nocturnal hemoglobinuria may manifest with these symptoms. So, this is a clonal hematology disorder where due to glycoprotein anchored proteins deficiency in the red cells, there is susceptibility to complement mediated lysis. So these patients may have bouts of intravascular hemolysis and a dark urine discoloration but other symptoms are far more prevalent such as abdominal discomfort, malaise and a hypercardiabile state causing both arterial and venous particularly in a typical site including intra abdominal veins. But as I said this is a far less prevalent disease compared to hematological malignancies.

Thank you for that, and Jess from the from the rheumatology side this is quite a familiar history probably, isn't it, for you?

Yeah. I do. 

In in a rheumatology clinic this patient was a bit more unwell than the ones we often get, but we do quite often see these patient, don't we, who are just kind of nonspecifically unwell. And I just wondered if you had any sort of further thoughts on anything you'd be looking particularly for just to to try and give us a clue?

Yeah. So a PUO workup essentially, and this man who's not yet, you know, not acutely unwell, but unwell enough to be in hospital from what you describe. So it makes us think of any of our systemic autoimmune rheumatic diseases, particularly perhaps of the vascularities given he doesn't have any signs, but you'd want to do a full examination, a urine dipstick, full autoimmune screen, and then consider he's just on the cusp of, the right age for a larger vessel vasculitis, so you might also think about whether you can get pet imaging or some other temporal artery ultrasound or something to look at bigger vessels.

That's really helpful, so thanks very much for those initial thoughts. I'm going to, give you a bit more information about the case. So the admission bloods, for our patient showed a haemoglobin of 9.6, platelets of a 102, white cells were normal ish at 10, ALP was 356, Billy Rubin, 68, and CRP, 306. They're quite high. We had listened to your spotlight pod Jess so we did a ferritin. And also we are, you know, increasingly in our trust doing this on any patient that comes in the door that's really not looking very well as this patient wasn't. And he was started on some treatment for biliary infection while we were waiting for various other tests to come back. And they sort of started to come through. It's always a bit frustrating isn't it when you're waiting and you've got the patient in front of you. So we found discovered a positive hepatitis b serology so that was both surface and core antigen but with a low PCR positive EBV serology with a low viral titer Leptospira PCR on blood and urine and Leptospira IgM were negative. Our rheumatology antibodies, so ANA ANCA, double stranded DNA, anti GBM were all negative when they eventually came back. They can sometimes be a bit later, which can be frustrating, but I'm just giving it all together. We did a CT scan looking for a malignancy, and didn't find any malignancy or widespread lymphadenopathy. There was some a small degree of splenomegaly. We went on to do a mesenteric CT angiogram, because of the nonspecific presentation and the abdominal pain and the hepatitis b, and that did show some changes. So it demonstrated, bilateral renal artery aneurysms and mesenteric aneurysms. So quite a lot, going on there. Mike, I wonder, do you just want to tell us a little bit about the, the EBV serology perhaps, at this stage just because that's something we're often interpreting trying to work out whether there's an acute chronic infection and how significant it is in an in a patient who's unwell.

Yes. Sure. So, of course, most people will acquire their EBV infection in late teens, early twenties at the latest. And, you know, well over ninety percent of us beyond that stage will have a serology pattern that suggests that past infection years before. When you first acquire EBV when you've got infectious mononuclear angina fever, very early on, you can have negative serology. But after a few days, you then develop an IgM, and then you will soon develop a VCA IgG. And then after a few weeks, months, the IgM goes away. You always have the VCA IgG, but then you get this Ebner IgG. So you or I, at our stage, you'd expect a normal, antibody once of someone who for whom they had EBV a long time ago to have a positive EBVNA IgG, a positive VCA IgG, and a negative IgM. Acute EBV infection does and can drive HLH, and so, certainly, in the younger patient, we often consider that. And a clue will be the right serological pattern for that and having a very high level of EBV virus in the blood. And I'm talking hundreds of thousands of copies per mil, millions of copies per mil. Much more commonly when we're discussing, EBV in an HLH MDT, the story is someone who's got evidence of past infection. They've got their EBVNAIgG that's positive, and they often have a bit of virus in their blood, an EBV viral load of hundreds, thousands, maybe 10 thousands, and that's really not significant. That means that that EBV is really nothing really to do with this illness except in very rare circumstances that we might come on to later where someone's already been on lots of immunosuppression. They may have a EBV driven hematological process. And, again, in that situation, you'd expect there to be hundreds of thousands, millions of copies per mil. So our patient here, has a low level virus in their blood because it's a latent virus and will be expressed whenever they have an activate immune system. But the positive EBVNA, suggests that this is a past infection, certainly isn't an acute infection, and it's not likely to be anything driving this process. Is that that made that clear.

That's really helpful. Thank you so much for that. So, we'll come back to the hepatitis b as well, which is important to pick up, as we get as we get further onto the case. So we diagnosed the the patient with, with polyarteritis nodosum on the basis of the CT angiogram, which we'd requested, as I said, because of this history of abdominal pain and of hepatitis b. And, Jess, I just wondered whether you had anything to add about polyarteritis nodosum.It's something, as a consultant, I've come across really only a handful of times, often quite tricky to diagnose and and picked upon imaging or in one case on a biopsy that we managed to get of a of a subcutaneous lump.

So I think we probably diagnose about one a year here. I do a lot of acute rheumatology, and almost, you know, I'm embarrassed to say that almost always I'm not necessarily expecting to find it. I mean, I'm looking for it, but I'm not really expecting to find it. So it'll be in a patient who I've been investigating for Pyrex of unknown origin, often in whom I suspect a malignancy actually. So these patients often are really off to hell of a lot of let of weight, have no particularly localizing symptoms or signs often. And like you say, you pick it up on imaging. I've also picked it up twice on skin biopsy, actually, once with a sort of vasculitic like palpable rash over the thigh. And once actually a lesion that felt like, polyarteritis and a that felt like, pyoderma gangrenosum.

So one woman presented actually with a puo and a very tender breast lump that felt like erythema nodosum that was actually polyarteritis nodosum worth biopsy.So those are my main PAM patients I can remember.

That's really useful. Thanks. And I think it just shows the value of getting a biopsy, doesn't it, of anything that you can Oh. Particularly in these patients where you're struggling, to to kind of get to a diagnosis. 

I'm really relieved when somebody has a skin rash, actually, because it says safe as blessed biopsy biopsying targets for biopsy is so helpful.

Absolutely. Thank you. So just coming back to the patient.So, unfortunately, he deteriorated clinically quite rapidly with reducing haemoglobin and platelets, increasing ferritin and triglycerides, and we went on to calculate his h score, which was 210, so obviously very high. He did also have a bone marrow, the result of which was obviously a little bit delayed, but when that did come through it did show haemophagocytosis without malignancy and a diagnosis of haemophagocytic lymphohistiocytosis or HLH as we'll call it from now on was made. Stella, I wonder just before we get on to talking about the  H score and the diagnosis, if you could tell us a little bit about undertaking a bone marrow biopsy please because it's something that we quite often request and something as rheumatologists I don't think many of us know that much about it. Is it important? Are there any risks? And sort of practically is it tricky or painful for patients if we're sort of talking to them about it?

Yeah so a bone marrow aspirate and refined biopsy is an important part of HLH investigations and diagnosis and it's obviously key in diagnosing and staging many hematological conditions, it's malignant and non malignant. So it's done as a as a day case, patients are not admitted, it's done by local anesthesia, usual site we go for is the posterior iliac crest with a patient lying on the lateral side or prone position less often. Very few absolute contraindications to it, such as severe bleeding disorders such as severe haemophilia, severe DIC, thrombocytopenia regardless of severity is not a contraindication and that's important to consider because often we are faced with quite significant cytopenias in HLH that should not delay bone marrow investigations. So we administer local anesthesia. Pain perceived by the patient is usually low to moderate, approximately zero to three on a pain scale of 10. Possible complications, some bleeding, mostly external which is easily managed by applied direct pressure, very rarely internal, which in extreme rare cases can be life threatening, but as I said that that's extremely rare. And then there is obviously the possibility of a local infection, everything that is used is sterile in single use, and there is a very small chance of kind of more protracted pain especially if kind of we've imitated and have a long kind of a course. So in HLH all patients ought to have a bone marrow aspirate and refined biopsy to evaluate the cause of cytopenias, to detect hemophagocytosis although the diagnosis, the confirmation rather of suspicion and the treatment for HLH should not be solely based on that. It also helps with cultures and examination for infectious organisms and identifying any malignant drivers so that we can direct causative treatment accordingly.

That's really helpful, thanks. Jess did you want to come in?

Yeah I just want to just reiterate Stella's point, it's so important for us rheumatologists who don't do bone marrows and don't necessarily, feel confident about the analysis but such an important point that you don't need to see hemophagocytosis on the bone marrow to have HLH, and it can be dangerous to make that assumption because patients can, you know, inappropriately not being treated And the argument for doing it, if you ever have to have an argument with a hematologist, I'm sure nobody ever does, is about understanding why it's happened to the patient. And we again, we've had surprises multiple times, Stella and us, where you'll find an infection or you'll find, you know, a hematological diagnosis on that bone marrow. So it really does need to be done but it shouldn't delay, the treatment for HLA nor cause the cause the diagnosis of HLA to be called into question if there's no hemophagocytosis there.

Thank you, we'll just come back to you Stella. 

Yep, just to offer some kind of numbers to support Jess's argument, So hemophagocytosis on the bone marrow is reported anywhere between twenty five to one hundred percent of case of HLH, so there is great variability in recognizing it. It's not pathognomonic for HLH, but the finding dose of nucleated cells or multiple nucleated cells more strongly correlates with diagnosis of HLH and actually some patients may only develop hemophagocytosis later in the disease course often during the improvement stage. So that kind of proves, Jess's arguments, yeah, even more. So in and actually it's something, another statement that kind of strengthens the bone marrow investigation to identify the trigger. So our review of adult patients with hemophagocytosis in bone marrow aspirates revealed that at least sixty four percent had lymphoproliferative process. And so that strengthens the value of performing the bone marrow and actually as early as possible in the investigation and treatment course of this condition.

That's really helpful. Thank you. And I think, Mike, did you want to come in?

Yes. And to add to that, there's a number of infection diagnoses that are easily and rapidly made, on the bone marrow. Some just from the aspirate, and you don't even need to wait for the trephine to the result for the result. One is leishmaniasis, which is one of our top, infection causes and often not necessarily thought about because you don't need to have traveled beyond the Mediterranean to acquire that. As long as you're asking the question of the hematologist, they'll will often be able to spot the, leishmania notes there. And the other is, tuberculosis, and making sure that the right cultures are done and the right, stains are done, etcetera, early on from the bone marrow can get you to that diagnosis early, and it may be the only site that you find the infection.

Thank you. So that's a a strong clear message coming through in favor of of bone marrow. And Stella, just before we move on from the bone marrow, how long would we expect to wait for results for that? We'd obviously always try to process that urgently but there is a little delay isn't there?

Yeah, so when it comes to morphology, it literally is available on the same day of the bone marrow because we can look for macrophages literally engulfing nucleated red blood cells and red cells and platelets on the aspirate. The bone marrow refined biopsy results usually take a week to come back. And then, there are potentially longer, periods needed for, cytogenetics and molecular tests. 

That's really helpful, thank you. And Jess I wonder if I could bring you back in just to chat a little bit about the age score, so I mentioned that we wouldn't be waiting for the bone marrow, we'd like to get one but wouldn't be waiting in terms of treating. Is there a particular age score at which you would jump in and how would you go about that in your trust? Would you usually have a sort of an MDT in order to discuss starting treatment or how would that work? And I realize you were a bit unusual because you're obviously involved in the national MDT as well but I guess maybe if we could talk about a patient in your hospital.

Yeah so to go to the age school first of all, so the it involves mainly, so whether the patient is immunosuppressed, what how high their fever is, an assessment for organomegaly and then the rest of blood test results, so cytopenias, ferritin, triglycerides, fibrinogen, you can use online calculators, it honestly takes only a couple of minutes if you have all those results available and I ask upon people that the that actually it's really easy to do and I would do it even before you have the the bone marrow back. So just make the calculation using the age score parameters that you have. So in the literature there's a sort of accepted cutoff that a score of more than 169 is sort of consistent with HLH. Of course, this is a score and it's really down to clinical judgment And in the wrong circumstance, you could get all the numbers of an age score consistent with HLH without having HLH. So if you had liver failure and a fever and you could easily meet the cutoff. So it's about clinic where you use the clinic the age score in clinical judgment. But if you feel the patient in front of you has a hyperinflammatory syndrome and they have an h score of one more of more than 169, then depending on the confidence level of the person looking at the patient, I think treatment can be started at that point. It doesn't require an MDT. So there are setups in some trust with, you know, really good local guidelines and confidence in med regs to say, this is a hyperinflammatory syndrome with an h score of 100 and a 200. I'm gonna give a slug of methylpred, and then I'll think about all the other things and I think that's really good medicine if you can get that set up. There are also circumstances where you might not wait for the age score to be a 169 and that comes probably with confidence and experience that you think to yourself, gosh, this is a patient with, you know, lupus or stills who is going the wrong way and I'm watching the ferritin get worse and I'm watching the patient get worse and I know which way this is going because I've seen it often and then it would be silly to wait for an age score at once. So you might start treatment more quickly than that. I think that at some point, all of these patients should be discussed in a multidisciplinary, meeting. But I do think that increasingly, clinicians are confident to start treatment on their own and that's appropriate.

That's great. Thank you. Can we just talk a little bit about anakinra as well? When would you introduce that?

Yeah. So often in practice, we start anakinra and steroids pretty much at the same time. And there is funding to use anakinra across, The UK, in every trust and you don't have to wait for approval from anybody. You should just be able to prescribe it and use it. So our first line of treatment tends to be high dose steroids. Often rheumatologists will use methylprednisolone and sometimes hematologists will use dexamethasone, but really I don't think it matters very much. And then to start with anakinra at a sort of sensible dose. Now again, you want to assess the the unwellness of your patients. And just so you know in in paediatrics in America they use up to twelve milligrams per kilogram, in the NHS we're approved milligrams per kilogram. I tend to start at a sort of middle ish dose four mgs per kg, often when you give it, when we're used to giving it in outpatients, you know, we use a hundred milligrams subcut once a day. That's because subcutter has a really good long half life. So IV, when these patients are ill, they're not absorbing. They have low platelets.They can't have multiple injections. We use it IV, and it has a very short half life. So you have to give it either BD or TDS. So we would tend to give two mgs per kg BD with high dose steroids to start with and then see how if they don't get better quickly, we would go up probably the next day to a full eight mgs per kg. And, obviously, if they do get better quickly, we would start to wean off.

That's great. Thank you. Mike, I wonder if we could talk a little bit, please, about screening for and treating any latent infections alongside giving this immunosuppression and I guess perhaps particularly with regard to our patient and his positive hepatitis b, testing?

Yes.Okay. So, you know, a lot of you as rheumatologists and others are very screening for latent infection and making sure that you look out for, those results and treat fairly promptly. Hepatitis b are one of the classic ones, isn't it? Because, people with low level infection like this patient, a familiar story in someone born in China who may well have been infected at birth and have a low level, hepatitis b infection that may not have been causing any problems throughout his life, could react the amount of immunosuppression that he's gonna get. And so talk to your local infection services, virologists, etcetera, and probably you'll be able to totally avoid any problems by getting monso appropriate antiviral, be it, tenofovir, tachavir, etcetera. There are a range of other infections that are a bit more geographically restricted that might require specific testing. We're often very strong loyalties, which you can pick up anywhere in the tropics and can reactivate later. So we, as per the national guideline, we encourage testing for that. If people have been in certain parts of the world, particularly in Central South America, we look for exotic things like Chagas disease, treponosomiasis, and, tuberculosis is clearly something to think about, and that can be quite a challenge to diagnose as a latent infection. People are already immunosuppressed because the tests we use, QuantiFERON tests, etcetera, depend on a intact immune system. So sometimes some has to be given as to the epidemiological risk and not relying on the data. Maybe we'll come back to it later, but, latent infections like herpes virus infections are clearly something that can become quite a problem, and that's why, we have a pretty robust prophylaxis, guideline to make sure that all our patients get acyclovir, for example, among other things that we could talk about.

Too much.

Yeah. I was gonna ask about that as well. So we're obviously starting these patients on significant immunosuppression. They're acutely unwell often ending up on ITU, what other prophylaxis in addition to the acyclovir would would we recommend to try and prevent future infections?

Yeah so we have a a guideline that's, what we use here and that we've made available for, other any other hospitals that's got three real arms to it in terms of standard. We've got the acyclovir for to prevent HSV, VZV reactivation. We need something to prevent pneumonia, because that's a significant risk of the amount of steroids that are being used. And our preference is cotrimoxazole, but sometimes that can be a challenge haemtologically and there are various other, options that we might use. And the third one, these patients that are at significant risk of invasive fungal infection, be it aspergillosis, be it even rarely mucormycosis. We've recent changed our guideline, to use pozoconazole as our first line as that risk, but there are other circumstances where, for example, amphotericin b, ambasome as an appropriate alternative because of drug interactions. But really key is to as soon as we've got patients on significant immunosuppression associated with the HLA itself, the underlying hematological diagnosis and the treatment that we get them onto those three lines of, prophylaxis.

Thank you very much. Jess, did you want to come in?

I I just wanted to reiterate that point because I think in rheumatological practice, often using a bit of anakinra and a bit of steroid, we wouldn't do this. But this is not that circumstance. So this is a much more unwell patient, whose actual disease is so immunosuppressive, and we're using these drugs at much higher doses than we would in our standard outpatient practice. So, as soon as you've got someone kind of over pred of 20 and anakinra of 100, you should start to think about this.

Thanks. That's a really good point. And I think for those of us that have looked after these patients, unfortunately, it is often infection that will, you know, end, isn't it? If they do, you unfortunately have a poor outcome. So, yeah, really important to think of that early. And I think lots of trust will have local guidelines. I just wanted to give a shout out to the GIRFT HLH guideline as well as we're talking about, guidelines, which was published in July and is linked to in this at the bottom of this episode. So I'm just going to come back to the Mike, did you wanna come in?

Yes. One thing that often comes up is a question is should the patient be on broad spectrum antibiotics? And you can often you know, early on in the illness, you're not sure what the diagnosis is. There is an understandable reason to give that until you got your cultures back, etcetera. But we wouldn't encourage just being on broad spectrum antibiotics just in case because all that will do is mean that when they do have a breakthrough infection, it'll be, you've got less options available and you're encouraging the risk of fungal infections and and resistant organisms. So we don't in general have our patients on broad spectrum antibiotics simply for the sake of, worrying about, sepsis.

That's a really good point, Mike. So just coming back to our patient, so he was diagnosed with polyarteritis nodosum and HLH. He was treated with IV methylprednisolone and anakinra. He was given some hepatitis b prophylaxis alongside that in the form of tenofovir. And I'm pleased to report that he did really well. He was weaned off the anakinra and more slowly the steroids, and made it out of hospital and was coming to see us in outpatients. He was subsequently treated with azathioprine, which, as is relatively common, he didn't tolerate. So we switched to methotrexate, and was relatively stable for a good period of time. However, fifteen months later, his symptoms returned, and he was admitted with a similar pattern, really, of symptoms with breathing difficulty, fever, weight loss, and cytopenias. And I wonder, Stella, maybe if you'd like to tell us what would be your sort of thoughts at this stage when he when he's reemitted with a bit of deja vu.

Yeah. So, I mean for the cytopenias I look into whether there is bone marrow toxicity from the malosuppressive medication itself. I would also worry about opportunistic affections due to the duration of immunosuppression and HLH recurrence because immunosuppression is literally the first kind of criterion on the age score and of course secondary malignancy, which is also a big concern, when people are on long term immunosuppression. So, at this point we would, kind of check EBV, CMV titers, HBV PCR, perform imaging, see if we can wean off the immunosuppression to see whether there's county and repeat HLH markers.

Thank you, yeah that's a really nice summary. And I think as the treating rheumatologist I was really worried that having sort of weaned his treatment for the polyarteritis nodosum it was it was me that had caused this flare and so I was quick to repeat a CT angiogram which didn't show any progression of disease, which obviously didn't exclude that as a cause, but I guess made it less likely given the significant interval with the previous scan. And his EBV serology remained detectable at that stage. Though, again, he was very quickly started on treatments, and this time with methylprednisolone and anakinra. We subsequently added encyclosporin because, he wasn't doing so well on that initial treatment. And unfortunately, despite that, he did continue to deteriorate with a rising age score. We were sort of waiting for his bone marrow results to come back and when they did they revealed they had diffuse large b cell lymphoma, which I have to say actually was a surprise because obviously it's a change of diagnosis. So at the time it was a bit of a surprise but we were pleased in as much because it gave us something to treat because we were really looking for a cause of HLH to treat. So Stella I wonder if you could just tell us a little bit about this diagnosis please because it's not really one that I come across very often as a rheumatologist.

Yeah so diffuse large B cell lymphoma is a common one for us. It's one of the commonest types of aggressive B cell lymphomas and it kind of comprises of twenty five percent of all Lund Hodgkin's lymphoma cases, so incidence around seven in ten thousand per year, Melbourne's, and then, incidence increases with age, with a median age around 65 years. So it arises from a tubal lymphocytes, and it can arise either de novo or from transformation of low grade b cell lymphomas or in the setting of immune deficiency. So for example, it is an age defining malignancy, DLBCL, and also it can arise, within the country called post-transplant lymphoproliferative disorders in people who have had immunosuppression post transplants. And, in that case, these are associated with Epstein Barr virus proliferations at very high titis as Michael said at the beginning of our discussion. So it presents with soft tissue masses which can grow literally anywhere in the body. So, it doesn't the most usual presentation is nodal enlargement, in the neck or abdomen or in the mediastinum but also involving any other organ and obviously the bone marrow. Extranodal involvement is common. People, often present with constitutional symptoms, and also, most of them present with advanced stage disease because it's a very aggressive lymphoma. So it is treated with, or rather it's diagnosed with biopsy, it's staged with PET scan, and then it's managed with chemotherapy or chemo immunotherapy rather as the golden standard. And depending on the staging and prognostic score there are two options for treatment classical RCHOP combination chemotherapy for lower and low intermediate prognostic patients or RPolatuzumabCHP which is a newer more effective combination for intermediate and high risk patients.

Thank you that's really helpful. Mike I don't know if you want to come back on the EBV any further comments on that?

No. I think illustrating again, you know, looking at EBV viral load, because occasionally, a significant degree of immunosuppression can one of those, EBV driven processes. But, if it is, one would expect the EBV viral load to be very, very high. And I think, Stella, you'd agree those sort of PTLD type things tend to occur, you know, in a fairly circumscribed group of patients on pretty severe immunosuppression rather than outpatient be unusual in this situation.

Thank you That's really helpful. So just again coming back to our patient. So he was, treated with our top chemo on ITU. Oh, sorry. Mike, do you wanna come back?

Sorry.

I just forgot the other you know, when people have been on even relatively low level things like methotrexate, etcetera, CMV, reactivation is an important thing to look out for. So CMV viral load can be important and look for any evidence of organ, dysfunction, because that also can be a trigger of HLH.

That's really useful. Thank you very much. Yeah. So our patient was treated on ITU and it was really a very, very rapid response to that treatment. So his HLH treatment was able to be weaned over a couple of weeks he was discharged successfully and has now received a further five cycles of R CHOP, and remains well under close rheumatology and hematology follow-up. So really nice to have a happy ending to the story. Just a couple of more general questions and then and then we'll wrap up. Stella, I wonder whether you could just talk us through a couple of other common hematological triggers of HLH if we're examining patients with this condition, what might we be thinking of? So it's usual hematological triggers of HLH are most likely hematological malignancies and their treatments, for lymphomas either B cell, T cell or NK lymphomas and leukemias. With regards to treatments, bone marrow transplants can trigger HLH and also some of the newer treatments such as CAR T therapy, CAR T stands for chimeric antigen receptor T cells. They are genetically engineered patient T lymphocytes, that are trained to attack cancer cells and also the by specific antibodies. So these are monoclonal antibodies that are to bind two different antigens and so one part binds on the lymphoma cell or the myeloma cell, for example, and the other part engages a T cell lymphocyte. So we are expecting cytokine release syndromes with the latter two treatments, and you know people get, or patients rather receiving these treatments are being closely monitored and treated accordingly. Very rarely fortunately may encounter hyper inflammation states in nonmalignant conditions and we've seen this in sickle cell disease and in people presenting with vasocclusiveness crisis, fat embolism syndrome evolving into multi organ failure. There are a lot of similarities in the two conditions and this is also something to keep in mind when treating these patients as well.

Thank you, Jess and then Mike, I wonder if we could have maybe just some of the commoner rheumatological and then infective causes and then and then we'll just we'll tie up.

So Still's disease, lupus, but I've actually seen it complicated or complicate all of our diseases. Okay. So rheumatoid, psoriatic, vasculitis, dermatomyositis and actually we've had some patients who've had, HLH complicating, you know, rheumatoid on a TNF inhibitor with methotrexate and then get TB HLH. So it's also partly what we're, you know, what we're treating the patients with.

Thanks. And Mike?

Yeah. And I get just before coming to the infection ones, the other group don't haven't we seen, Jess and Stella, is drug related toxicity for example, lamotrigine and a bit of an overlap with DRESS syndrome that we often, struggle with a little bit. So just worth bearing those ones in mind.

Really good point. Thanks for reminding me. And also this miscellaneous group of things like post postpartum surgery. They're anything that messes up your immune system. And then about ten plus percent of our cohort who are 30 have a primary genetic form of HLH, so these are not children's diseases anymore, if ever they will.

Thanks, Mike. Well, sorry. We'll just come back to you for the final words of infection.

I've said before, sort of, you know, just like Jess said, any rheumatological disorder, any infection can cause it, and sometimes, you know, it can be as little as some influenza. But, to go through again the viruses, the herpes viruses, the EBV and CMV, and in the context of advanced HIV, HIV associated Castleman's is often the one being driven by human herpes virus eight. Tropical viruses, dengue, tropical conditions, top, not uncommon at all, and murine typhus and maybe scrub typhus. I like to call those doxycycline deficiency diseases because they're things where you really wanna get in with some antibiotics early before it progresses to an HLH setting. We talked about crotcheons, mycobacterium tuberculosis, fungal infections, cryptococcus, histoplasmosis, for which it's important to do specific tests to try and make that early. Leishmaniasis, we talked about, and you only need to have traveled as far as, the Mediterranean, to get that. What have I missed out in my list of infection diagnosis? I think those are our key ones. As I mentioned, dengue as a sort of tropical arbovirus that, can do that. And is with climate war change moving north, and is being described in France, for example, now. Malaria, another one, crops up once or twice a year with us as well.

Thank you. Jess, did you wanna come in?

Yeah. And we just we've seen it complicate almost every infection, any bacterial infection can potentially cause HHL. Brill that's really helpful, thank you all. 

So this was a really interesting and challenging case and with two episodes of HHL occurring fifteen months apart, the first attributed to polyarteritis nodosum and the second triggered by B cell lymphoma. Huge thanks to the patient for allowing us to share their story. And also thank you to my guests. I'm just going to come to each one of them in time for some key take home points. Jess, could I start with you, please?

Yes, so rheumatological diagnosis to think of we've just listed but I guess that this is such an excellent example of why it's so important for us to work across specialty to look after these patients.

Thanks. Totally agree and so grateful to my colleagues for helping with this. Stella, can we come to you next?

Thank you, yeah so I would like to reiterate that HLH is and should be regarded as a medical emergency. So once suspected, the treatment needs to start to mean investigations conducted urgently. So I would like to emphasize this sequence of events, not the other way around, because usually as doctors, we go the other way around when diagnosing patients. We start with investigations and then treatment. Well, in HLH, it's the other way around. So once suspected, we need to initiate treatment and immediately progress with investigations in order to identify the drivers, and that this really makes a big difference in patient outcomes.

That's great. Thank you. And Mike?

Yeah. Think about invoices and get some help with interpretation of, serological results and, that we can cause, really significant infections which can be fatal with all the treatment and therefore making sure we're dotting i's and crossing t's with early screening and prophylaxis for immunosuppression.

That's great. Thank you so much. All I've really learned a lot from talking to you, and thanks everyone for listening. And for more information on this topic, please check out our spotlight podcast, which we recorded last year with Jess, and we'd also recommend reviewing the GIRF guidance, on HLH, and we'll include the link in the episode blurb. Bye for now.