Case of the Month #17

Matthew Wright

A 74 year old gentleman is admitted to the critical care unit following a 3 week admission on the medical wards with pyrexia, malaise, lymphadenopathy and thrombocytopenia.  A diagnosis of sepsis of unknown origin has been made and he has been treated with multiple courses of antibiotics.  No clear focus of infection has been ascertained.  He has now developed multi-organ failure with a worsening transaminitis, an acute kidney injury, an increasing CRP and a pancytopenia.

What is the differential diagnosis?

  • Tuberculosis
  • Endocarditis
  • Haematological malignancy
  • Immunodeficiency disorders
  • Autoimmune disease
  • Haemophagocytic lymphohistiocytosis.

What is Haemophagocytic Lymphohistiocytosis (HLH)?

HLH is a life threatening hyperinflammatory condition leading to organ dysfunction and death4. There is a loss of regulation within the immune system leading to inappropriate activation of macrophages and T-cells and a ‘cytokine storm’.  This then results in an uncontrolled hyper-inflammatory state and subsequent tissue damage.1

The true prevalence of HLH is unknown in critical care; sepsis has a large overlap with HLH both in their clinical features and underlying pathophysiology, but also as sepsis can be a trigger for the condition.

It is characterised into primary or familial HLH, which usually presents in infancy, and secondary HLH which will be discussed here. The secondary form is typically triggered by an infection but may also be caused by other conditions detailed below including malignancy and autoimmune disease4.  Both conditions are likely to have an underlying genetic defect; several defective cytolytic pathways have been identified in primary HLH with emerging evidence of genetic variants also seen in secondary HLH.3

Triggers

INFECTIONMALIGNANCYRHEUMATOLOGICALOTHER
Viral (EBV,HIV,CMV)LymphomaSLEMajor burns
Bacterial ( mycoplasma, legionella, e. Coli)Solid organRAChemotherapy
Fungal Stills disease 
Parasite Vasculitis 

What are the clinical features?

The clinical features seen are due to the high inflammatory state and can therefore mimic signs of sepsis. 3

  • Pyrexia of unknown origin
  • Hepatosplenomengaly
  • Skin manifestations including rashes and erythroderma
  • Organ dysfunction including renal impairment, respiratory failure, neurological dysfunction and shock

How is the diagnosis made?

It can be very difficult to differentiate HLH from overwhelming sepsis and so the condition requires a high degree of suspicion.  Secondary HLH should be suspected in any unwell patient with an unexplained fever, cytopenias (especially thrombocytopenia) and organ dysfunction.  A serum ferritin should be checked in these cases, and if >4000 mg/L should trigger further investigations as the likelihood of HLH is increased.  Ferritin levels of >10,000 mg/L are highly concerning and may indicate the need for immediate treatment.  There is no universally accepted diagnostic criteria however there are scoring systems in use including HLH-2004 and Hscore.3 

The following easy to use mnenomic uses some of the parameters from the scoring systems (reproduced with thanks to Dr Gui Tran, Cons Rheumatologist, Harrogate and District Foundation Trust):

CONSIDER A DIAGNOSIS OF HLH IF: 
ALT>100 U/L
BONE MARROW ASPIRATEHaemohagocytosis
CYTOPENIA2 of Hb <9g/dL, platelet count <100×109/L, neutrophil count <1×109/L
DICFibrinogen <1.5g/L
ELEVATED TEMPERATUREPyrexia with no focus of infection
FERRITIN>10,000ug/L
TRIGLYCERIDES>3mmol/L
HEPATOSPLENOMEGALYEvidence on physical or radiological exam

Other markers include

  • Elevated LDH
  • Elevated D-dimer
  • Elevated CRP

Further imaging including PET scans, additional tissue sampling and bone marrow aspiration may aid in the diagnosis, however ultimately the final diagnosis of HLH is a clinical one and requires support from rheumatology and haematology experts. 

What is the treatment?

The management of HLH involves prompt diagnosis, supportive therapy, treatment of any potential triggers and rapid immunosuppression to dampen the damaging ‘cytokine storm’2.  Specific treatment includes:

  1. Steroids or ciclosporin
  2. IV immunoglobulin
  3. Plasma exchange
  4. Biological therapies

Prognosis

The overall mortality on ICU is between 50 to 70 percent.  The presence of shock or severe thrombocytopenia indicates increased risk, as does the maximum serum ferritin level.3   

Take home message

HLH should be suspected, and actively investigated, in any unwell patient with unexplained fever, cytopenias, progressive organ dysfunction and a failure to respond to intensive infection management.3

References

  1.  Bell A, Tattersall R, Wenham T. Rheumatological conditions in critical care. BJA Education 2016;16(12): 427-433.
  2. George MR. Hemophagocytic lymphohistiocytosis: review of etiologies and management. J Blood Med 2014;5: 69–86.
  3. Bauchmuller K, Manson JJ, Tattersall R. Hemophagocytic lymphohistiocytosis in adult critical care. JICS 2020;21(3): 256-268.
  4. HeatonT. Haemophagocytic lymphohistiocytosis [The gasman handbook].