For physicians/ intensivist / infectious disease specialists: don’t miss macrophage activation syndrome (MAS) this fever season

Disclaimer

• This article is intended for practicing medical professionals involved in taking decisions / involving pathways to diagnose and treat patients independently (eg physicians or any specialty medical doctors, pathologists etc.). This article is not intended for general public or medical professionals who cannot take decisions in direct clinical care. So please read ahead only if you fit the said criteria.
• The information provided here is streamlining what is known and inferencing from expert opinion and literature available. The writer hasn’t researched in Macrophage activation syndrome but considers himself knowledgeable enough to write on the subject. References are mentioned as appropriate.
• Please do not base or take your clinical opinions based on this article. Kindly take due diligence and read original articles to make your decisions. The writer here won’t be responsible for any clinical decisions so taken based on this article alone.
• This article has been specifically written taking current Indian scenario (monsoon and fever season) and current literature in mind. Obviously, with changing literature and scenarios, the things mentioned in this article might or might not hold true in near future.
• As such, the general principles of MAS (like diagnosis) might be applicable to above specialists all over the world. To reiterate, kindly make sure that clinical decisions are based on appropriate understanding of the subject.
• Many a times in this article, we have asked to consider taking help of rheumatologist or hematologist. The author is a rheumatologist. There is no conflict of interest here. For obvious reasons, hematologist and rheumatologist are experienced in diagnosing & managing macrophage activation syndrome.

Some background : Why this blog article ?

Macrophage activation syndrome (MAS) has traditionally been considered to belong to domain of hematologists [who are more familiar with the term hemophagocytic lymphohistiocytosis (HLH)]. Rheumatologists have also known it for quite some time now and they use word MAS more frequently as it is related to autoimmune diseases. MAS, is possibly quite under-diagnosed in any patient in intensive care, infectious diseases or multi-organ dysfunction based clinical scenarios. Many of these patients are treatable and often an opportunity to do so is missed due to lack of knowledge on the subject. This article is to make concerned doctors aware of this entity in simple language (as much as possible) and take appropriate measures to diagnose and treat it. The current monsoon season is around in India. From hindsight, it does appear that we miss a lot of MAS cases in infectious diseases and / or critically ill patients. The association of Dengue, which often reaches epidemic proportions around this season in India, with MAS is well recognized (Reference no 2).

Macrophage activation syndrome (MAS) or secondary hemophagocytic lymphohistiocytosis (HLH) if often missed or diagnosed very late in routine physician or intensive care practice. It is not uncommon to see MAS in patients with infectious diseases like Dengue, tuberculosis etc and it can be a significant cause of mortality in such patients. The association of MAS with malignancies and autoimmune diseases is well known. Many such patients can present to physicians or intensivists to begin with.

Main references:

We are mentioning them at the start. This article is heavily influenced by article number 1. The author has had experience directly listening to one of the reference article’s (no 1) author quite a few times.

• Carter SJ, Tattersall RS, Ramanan AV. Macrophage activation syndrome in adults: recent advances in pathophysiology, diagnosis and treatment. Rheumatology (Oxford). 2018 Feb 21;PubMed PMID: 29481673.
• Pal P, Giri PP, Ramanan AV. Dengue associated hemophagocytic lymphohistiocytosis: a case series. Indian Pediatr. 2014 Jun;51(6):496-7. PubMed PMID: 24986293.
• Henter JI, Horne A, Aricó M, Egeler RM, Filipovich AH, et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007 Feb;48(2):124-31. PubMed PMID: 16937360.
• Strauss R, Neureiter D, Westenburger B, Wehler M, Kirchner T, et al. Multifactorial risk analysis of bone marrow histiocytic hyperplasia with hemophagocytosis in critically ill medical patients–a postmortem clinicopathologic analysis. Crit Care Med. 2004 Jun;32(6):1316-21. PubMed PMID: 15187513
• Fardet L, Galicier L, Lambotte O, Marzac C, Aumont C, et al. Development and validation of the HScore, a score for the diagnosis of reactive hemophagocytic syndrome. Arthritis Rheumatol. 2014 Sep;66(9):2613-20. PubMed PMID: 24782338.

Pathophysiology and why such complex names?

Let’s not complicate, to put it simply, this is what happens in MAS (very simplified version to show basic mechanism and why treatment is needed. We haven’t shown many other things happening, one can refer to references for same).

So basically,

• For some reason immune system cannot clear infected cells or malignant cells (important for physicians and intensivists). Or sometimes the immune system goes into extreme overactivation on its own (like in hereditary or autoimmune cases)
• These overactivation stimulates macrophages (histiocytes). These macrophages produce lot of cytokines (cytokine storm) and eat (phagocytose) many hematology cells (neutrophils, RBC’s, platelets etc). These leads to more and more cytokines released causing excess / ‘hyper’ inflammation. This excess inflammation damages the tissues more than original pathology.

Simply put, in most cases in routine practice, a primary aetiology (like infection, malignancy or autoimmune diseases) leads to excessive stimulation of killer T cells which leads to widespread activation of macrophages. These leads to damage in various tissues by causing excessive inflammation (we hence call it MAS). It becomes kind of totally new disease in itself, which needs treatment on its own, besides tackling the primary disease itself. If not treated separately, it can contribute to high degree of mortality irrespective of adequately treating the primary disease.

Now, do you understand the name / terms of hemophagocytic lymphohistiocytosis or Macrophage activation syndrome ?

Hemophagocytic : because there is phagocytosis or eating of hematology cells
Lymphohistiocytosis : because it involves macrophage or histiocytes and lymphoid cells
Macrophage activation : macrophages are activated

For all practical purposes, macrophage activation syndrome and HLH are same things (some experts might argue that, but this article is to simplify daily practice for physicians. It might be primary (mostly genetic defects and starts very early) or secondary (due to many causes).

Some children are born with genes which cannot control immune system. This leads to HLH in infancy even without trigger or minor trigger. This is not routine in practice and mostly hematologists should be involved. This is known as hereditary HLH (hHLH) or primary HLH . Now, this is not important for routine practice of physicians.

• Macrophage activation syndrome and secondary HLH (sHLH) are same things. They may occur in autoimmune diseases, viral infections (dengue, ebola, influenza) and any other infectious disease.
• MAS is totally different from original disease : Please understand that whatever the primary pathology or disease, once this process gets activated, most damage is due to ‘hyperinflammation’ and not necessarily due to primary disease itself.

To put in simple terms, it basically starts due to some trigger and forms a totally new disease in itself. So, one has to treat primary disease, but also has to treat this new disease (MAS) at same time. Once MAS develops, if you just treat primary disease, uncontrolled MAS might still damage and kill patient.

Some children are born with single gene mutations that leads to uncontrolled killer T cell activation or other mechanism which can lead to Hemophagocytic lymphohistiocytosis (HLH) in them. We usually use the word primary HLH for them and they usually present at an early age. Most pediatricians and hematologists are aware of this entity. For all practical purposes, the terms, secondary HLH and MAS can be used interchangeably. The term is meant for patient developing HLH without any of the single gene mutation as in primary HLH. Most common causes of secondary HLH are infections, malignancy and autoimmune causes.

How is MAS / HLH diagnosed ?

The following is the HLH criteria which was primarily designed for primary or hereditary HLH patients. This is to just give an idea on what forms a part of primary or hereditary HLH. Features are similar in secondary HLH / MAS.

In real life physicians or intensivists often fail to recognise MAS in some common settings as they attribute various abnormalities to the primary disease and don’t realise it’s MAS. The aim of this article is to concentrate more on secondary HLH / MAS and help physicians or intensivists to recognise and treat it early.

Table : HLH-2004: Revised diagnostic guidelines for HLH (Reference 3)

The diagnosis HLH can be established if one of the two criteria below is met:

• A molecular diagnosis consistent with HLH (i.e., reported mutations found in either PRF1 or MUNC13-4); or
• Diagnostic criteria for HLH are fulfilled (i.e., at least five of the eight criteria listed below are present:

• Persistent fever
• Splenomegaly
• Cytopenias (affecting ≥2 of 3 lineages in the peripheral blood):
  
  • Hemoglobin <90g/L (in infants <4 weeks: <100g/L)
  • Platelets <100 x 109/L
  • Neutrophils <1.0 x 109/L
• Hypertriglyceremia and/or hypofibrinogenemia:
• Hemophagocytosis in bone marrow* or spleen or lymph nodes, no evidence of malignancy
• Serum ferritin ≥ 500µg/L (i.e., 500 ng/ml)
• Low or absent NK cell activity (according to local laboratory reference)
• Increased serum sIL2Rα (CD25, according to local laboratory reference)

HLH-2004 criteria can help routine physicians to understand what are the clinical features in HLH. HLH criteria were meant for primary / genetic HLH, most patients satisfy criteria very late. Also, most of these manifestations develop and not all things can be present early. Trying to do all tests in HLH criteria is not practical and not required in routine practice. A physician should start suspecting MAS / secondary HLH much earlier and not wait for full blown disease. By the time, somebody tries to satisfy the criteria, it might be already too late to treat.

Key things to understand in diagnosis of MAS/HLH in routine practice of physicians / intensivists

• Point no 1 in the criteria is for genetic or primary HLH causes, which is not usually applicable for intended population here. In any case when someone sees a very young child with features of MAS, find a haematologist/expert in same. Remember clinical features of primary or secondary HLH are similar except for the fact that secondary HLH might have additional features to suggest triggering disease.
• The above findings may occur together very late in real life, hence one should start suspecting HLH much earlier. International experts realised this and hence try to get a probability score for HLH. Look at Fardet score below and why ferritin should be used for screening.
• Hemophagocytosis can be seen in many scenarios and occurs very late. Though it is mentioned in the name, most times bone marrow is not possible and not required in most cases. On the contrary, if somebody has done a marrow examination for evaluation of cytopenia and found hemophagocytosis, start thinking HLH/MAS. Hemophagocytosis itself can be seen without patient developing MAS, it can be a normal finding.
• Low NK cell activity and CD25 cannot be checked in routine practice and hence again not given importance while doing Fardet score.
• Fibrinogen probably decreases due to inflammation and triglycerides probably increase due to liver dysfunction.
• Patients might also have bleeding (due to low platelets and fibrinogen), Acute respiratory distress syndrome (lungs), neurological involvement (confusion, seizures) etc – may be confused with disseminated intravascular coagulation (DIC), thrombotic thrombocytopenic purpura (TTP), CNS infections etc. Many a times there will be very minute differences or things might overlap.

Start to suspect MAS (or sHLH) in any critically ill or infectious disease patient with any / combination of these – persistent fever, cytopenia’s (anemia, leukopenia, thrombocytopenia) multi organ dysfunction, falling platelets, falling ESR – Consider ferritin screening even if slightest doubt (an even check triglycerides and fibrinogen)

Now one would say, this is overkill. Any critically ill patient might commonly have one of these and does it make sense to screen ferritin in everyone?

Argument in favour of screening ferritin levels in such patients

• Ferritin is cheap, and most labs can do it in around 1000 rupees (Indian context). Find a lab which can give you ferritin levels in hours (time is of essence here).
• MAS remains a diagnosis which is very difficult to make, and things develop rapidly. Most classical criteria of MAS / HLH develop late, by that time significant damage has already occurred. Never say that this cannot be MAS because it doesn’t fit criteria. If you are thinking about it, get ferritin or do serial blood tests monitoring CBC, ESR and ferritin.
• MAS/sHLH mortality is high (~40-50%). If we can recognize and treat it early before complications develop, it can be lifesaving.
• A 2004 ICU study found 64 % of 107 consecutive mortalities to have some evidence of histiocytosis and hemophagocytosis. Now hemophagocytosis can be seen even without full blown MAS. But at least there are definitely some serious patients in ICU which have MAS and could be their cause of mortality (Reference 4).

At the least screen ferritin – when there is unexplained or unusually persistent fever with progressive cytopenia and falling ESR (Now if you are suspecting MAS, you can order fibrinogen, triglycerides at same time. Most other things will have been already done).

A relatively low or falling or non-rising ESR (even with rising or relatively high CRP’s) due to decrease in fibrinogen level can be very important predictor of a patient developing MAS.

Suspect MAS / secondary HLH in any patient with various combinations of fever, cytopenias (low Hb, platelets, neutrophils or whole white cell count etc), organomegaly, falling ESR. Suspect this even if you have diagnosed primary disease to be an infection like Dengue which can explain all this. Remember MAS can develop in any infectious disease and becomes a totally new disease in itself. MAS might complicate the primary disease with lung, kidney, liver or brain injury and is not an uncommon cause for death in these patients. If recognised early, it can be treated with a regimen different from treating primary disease which can be life saving.

What after screening ferritin ?

As Carter et al (Reference 1) have suggested, screen ferritin levels in appropriate situation

If Ferritin < 500 – MAS unlikely If Ferritin 500 – 10000 ug/L – MAS possible – This is most tricky area where people will get stuck as ferritin > 500 can be quite common in any inflammation due to infections or other causes.

In such cases – try to do HS score as suggested by Fardet et al, which gives diagnostic probability of secondary HLH (sHLH or MAS) (there is a very easy web calculator on this link – – Reference 5 and 6 ). Take a clinical call. One might have to additionally check serial ESR, fibrinogen levels, triglyceride levels (again not very expensive tests in critical care settings), serial ferritin and serial CBC. Please remember hemophagocytosis may not be seen, it is very difficult to do marrow examination and most times bone marrow examination is not required to diagnose MAS (or sHLH). If in doubt, try calling a haematologist or rheumatologist (don’t wait for them to arrive, might be too late).

If Ferritin > 10000 ug/L – MAS likely – do as above – confirm with other favourable supporting tests (may need serially as above). Do HS Fardet score.

[Fardet score (Reference 5, 6) was developed from cohort of patients with malignancies, autoimmune diseases and infection. So, it can be used to make a probability of MAS in any settings. Scores > 169 have 93 % sensitivity and 86% specificity. That is with that score one will miss diagnosis in 7 % cases and that would be wrong diagnosis in only about 14% cases.]
However, the diagnosis of MAS/HLH mostly remains clinical and depends on overall picture. You can see how many of these symptoms / signs might be seen in many critically ill patients. That is the basic point. We can possibly prevent them complicating at-least if we recognise and treat MAS/HLH. At least think about it in any critical care, autoimmune, malignancy or pyrexia of unknown origin settings. With some suggestive signs, get the required blood tests. Call your rheumatology or haematology colleagues if unsure.

MAS / HLH is a mostly a clinical diagnosis or it is based on combination of whole picture (including various tests). To suspect in right setting is the first important step. Despite it’s name, bone marrow examination or hemophagocytosis is not necessarily required to diagnose MAS. In fact, most experts can diagnose secondary HLH / MAS without that. Ferritin can be a very useful screening test and may need to be repeated serially. High ferritin is common in critical care settings even without MAS, but very high ferritin has very few causes. Take rheumatologist or hematologist help in diagnosis & management.

How to treat MAS/HLH ?

Again, we will refer you to reference 1. There are not many trials and treatment based on expert opinion. But following needs to be considered.

• Treat primary disease – eg infection as much as possible
• Supportive care for bleeding, ventilation etc
• IV pulse steroids (methylprednisolone) – usually recommended in all MAS/HLH even with infections, as long as latter is being treated
• Experts now recommend IVIG 2g/kg over two days (not 5 days) – this might be very expensive and hence difficult to give in Indian scenario
• If primary HLH suspected – involve hematologists, they might consider an etoposide based regimen.
• If autoimmune diseases – Rheumatologist will consider cyclosporine (iv based regimen).
• Anakinra (IL-1 receptor antagonist) – is a drug not easily available in India, but 100mg/day dose can be very effective in severe MAS cases and can give dramatic results. Again, can be very expensive, but worth it.

Pulse steroids remain the mainstay of secondary HLH / MAS and might be only thing required in early MAS. Hence, the importance to catch it early. Be reasonably sure of diagnosis before using high dose steroids in a setting of infectious diseases. We want to treat real cases and not complicate things by giving high dose steroids in every patient with slightly high ferritin. Fardet score can be helpful in calculation probabilities. Involve rheumatology and/or haematology colleagues. Do not delay treatment if overall picture or probability is very suggestive.

To summarise,

• Macrophage activation syndrome (MAS) and hemophagocytic lymphohistiocytosis (HLH) are same things for all practical purposes – it might be quite underdiagnosed entity in clinical care settings.
• One needs to think about this entity in all critical care settings irrespective of primary cause (the eyes don’t see what the mind doesn’t know). Secondary HLH has high mortality rates.
• MAS / HLH needs separate treatment than primary cause – hemorrhagic fevers (eg : Dengue), all common infections and malignancies have been reported well in case series to be associated with MAS. MAS can also be a presenting feature of autoimmune diseases.
• Think MAS/HLH in any patient with persistent fever, progressive cytopenias, falling / stable /non-increasing ESR in a worsening patient – screen ferritin, do Fardet score, serially monitor ESR, counts and ferritin if in doubt. It might be too late to wait for full blown MAS/HLH development based on HLH -2010 revised criteria.
• Judicious treatment of primary etiology with steroids could be helpful in most cases. Involve hematologist / rheumatologist early (call, not wait for them to see, might be very late).
• Consider IVIG or anakinra – take rheumatologist / hematologist help in complex cases