Hemophagocytic Lymphohistiocytosis
Last updated 7th April 2020 - Tom Heaton
Hemophagocytic lymphohistiocytosis (HLH) is a life threatening clinical syndrome of immune hyperactivity leading to organ dysfunction and death.
It is generally categorised into a familial (genetic) and secondary form.
It is potentially a much underrecognized condition in adult critical care.
These notes will primarily focus on the secondary form.
Macrophage activation syndrome (MAS) is often the term applied to this clinical syndrome when triggered by a rheumatological trigger.
It is generally categorised into a familial (genetic) and secondary form.
It is potentially a much underrecognized condition in adult critical care.
These notes will primarily focus on the secondary form.
Macrophage activation syndrome (MAS) is often the term applied to this clinical syndrome when triggered by a rheumatological trigger.
Pathophysiology
There appears to be some overlap between HLH and some forms of sepsis.
Essentially, there is an excessive immune response, relating to loss of some of the negative feedback mechanisms that modulate the normal immune response.
This results in a self-perpetuating cycle of inflammatory mediators (cytokines), which results in host damage as a result.
This cytokine storm arises from an abnormal response between the antigen presenting cell and the cytotoxic T cells, probably on a background of some predisposing status.
The consequences of this hyperinflammatory state include blood cell destruction (resulting in the cytopenias) and organ damage.
Macrophages are an important mediator of this injury.
The trigger of this can be from a wide variety of sources, but with some triggers being more common.
Essentially, there is an excessive immune response, relating to loss of some of the negative feedback mechanisms that modulate the normal immune response.
This results in a self-perpetuating cycle of inflammatory mediators (cytokines), which results in host damage as a result.
This cytokine storm arises from an abnormal response between the antigen presenting cell and the cytotoxic T cells, probably on a background of some predisposing status.
The consequences of this hyperinflammatory state include blood cell destruction (resulting in the cytopenias) and organ damage.
Macrophages are an important mediator of this injury.
The trigger of this can be from a wide variety of sources, but with some triggers being more common.
Triggers
- Infection
- Viral
- EBV
- Other Herpes viruses: CMV, VZV
- HIV
- Parvovirus B-19
- Hepatitides
- Influenza A
- EBV
- Bacterial
- Mycoplasma
- Legionella
- E. Coli
- Mycoplasma
- Fungal
- PJP
- Candida
- PJP
- Parasitic
- Leishmania
- Toxoplasma
- Malaria
- Leishmania
- Viral
- Malignancy
- Haematological - especially lymphomas
- Solid organ
- Haematological - especially lymphomas
- Rheumatological disease
- Systemic juvenile idiopathic arthritis
- Adult onset Still’s disease
- SLE
- RA
- Vasculitides
- IBD
- Systemic juvenile idiopathic arthritis
- Trauma
- Major burns
- Major burns
- Interventions
- Chemotherapy
- Stem-cell transplant
- Novel cancer treatment
- Chemotherapy
Presentation
This is likely to be in the context of the presenting condition.
This can be particularly challenging in critical care practice, where there may be severe systemic disturbance arising from the primary condition.
The overlap with sepsis syndrome here is especially commented upon, and needs to be clearly born in mind.
The key clinical features are:
Fever could be considered to be a cardinal sign of the condition and is almost always present at some point.
Organomegaly is less common (although still common), and more associated with children, lymphoma and a viral cause.
The nature and extent of organ dysfunction is variable.
Pulmonary (occuring in 50%) and neurological dysfunction are associated with a poor prognosis.
Renal dysfunction can be common and require RRT, with a risk of persisting dysfunction.
There may also be skin manifestations of the disease (in about 25%).
This can be particularly challenging in critical care practice, where there may be severe systemic disturbance arising from the primary condition.
The overlap with sepsis syndrome here is especially commented upon, and needs to be clearly born in mind.
The key clinical features are:
- Fever
- Cytopenias
- Organomegaly
- Lymphadenopathy
- Splenomegaly
- Hepatomegaly
- Lymphadenopathy
- Organ dysfunction
- Pulmonary - ARDS
- CVS - shock, cardiomyopathy
- Renal - AKI
- Neurological - confusion, seizures, coma
- Pulmonary - ARDS
Fever could be considered to be a cardinal sign of the condition and is almost always present at some point.
Organomegaly is less common (although still common), and more associated with children, lymphoma and a viral cause.
The nature and extent of organ dysfunction is variable.
Pulmonary (occuring in 50%) and neurological dysfunction are associated with a poor prognosis.
Renal dysfunction can be common and require RRT, with a risk of persisting dysfunction.
There may also be skin manifestations of the disease (in about 25%).
Investigations
- Bloods
- FBC - cytopenias in 2 or more lineages
- U&Es
- LFTs - raised transaminases, ALK
- Ferritin - raised
- Triglycerides - raised
- Fibrinogen - low
- LDH - raised
- Clotting - deranged
- Blood gas
- Immunology
- FBC - cytopenias in 2 or more lineages
- Imaging
- CXR - evidence of ARDS or infection
- CT - source of infection. Organomegaly
- CXR - evidence of ARDS or infection
- Tissue biopsy
Cytopenias on FBC are a common feature of the disease.
This is usually in 2 or more lineages and more severe than that commonly seen in sepsis.
The presence of this should be a trigger for thinking about HLH.
A blood film can give more information, such as towards differential diagnoses.
An elevated ferritin is a common feature of the condition, usually being moderately to significantly elevated.
A value over 500 microg/l should spark suspicion, with increasing values becoming increasingly diagnostic (>4000 being described as a convincing threshold, and >10,000 pathognomic).
This is probably one of the most useful tests when the condition is suspected.
The hemophagocytosis which lends the condition its name may be seen on biopsy of bone marrow or the reticuloendothelial organs (spleen, lymph nodes).
It is not, however, required for the diagnosis.
Diagnostic Criteria
There is not currently a universal diagnostic criteria for HLH.
This is especially the case for the critical care environment.
Two recognised ones include:
This is especially the case for the critical care environment.
Two recognised ones include:
- HScore - https://www.mdcalc.com/hscore-reactive-hemophagocytic-syndrome
- HLH-2004 criteria
Management
Much of this is derived from the treatment of the familial form, with minimal evidence base.
The early involvement of specialist advice is essential
The approach to management can be summarised as:
Specific therapy
The focus of therapy here is to aggressively and rapidly gain control of the cytokine storm.
This strong immunosuppression approach can be challenging in the context of an infective trigger.
Components of specific therapy may include:
The early involvement of specialist advice is essential
The approach to management can be summarised as:
- Early identification - high level of suspicion needed
- Supportive care
- Identification and treatment of trigger
- Specific HLH therapy
Specific therapy
The focus of therapy here is to aggressively and rapidly gain control of the cytokine storm.
This strong immunosuppression approach can be challenging in the context of an infective trigger.
Components of specific therapy may include:
- Steroids
- Anakinra - IL-1 receptor antagonist
- IVIG
- Cytotoxics
- Etoposide
Prognosis
The mortality for acute HLH is high - around 40% for all groups.
That associated with malignancy is particularly bad.
The condition in the intensive care setting appears to be associated with an in hospital mortality of over 50%.
Some poor prognostic features include:
That associated with malignancy is particularly bad.
The condition in the intensive care setting appears to be associated with an in hospital mortality of over 50%.
Some poor prognostic features include:
- Associated with malignancy
- High ferritin
- Shock
- Severe thrombocytopenia
Links & References
- Internal Medicine. Hemophagocytic lymphohistiocytosis. Youtube. 2018. https://www.youtube.com/watch?v=l1FA0WU8rZk
- Bauchmuller, K. et al. Hemophagocytic lymphohistiocytosis in adult critical care. JICS. 2020. https://journals.sagepub.com/doi/full/10.1177/1751143719893865
- Bell, A. et al. Rheumatological conditions in critical care. BJA Education. 2016. 16(12):427-433. https://academic.oup.com/bjaed/article/16/12/427/2632745
- MDCALC. HScore. https://www.mdcalc.com/hscore-reactive-hemophagocytic-syndrome
- Nickson, C. Hemophagocytic lymphohistiocytosis. LITFL. 2019. https://litfl.com/haemophagocytic-lymphohistiocytosis-hlh/
