Mapping the Storm: Defining Disease Trajectories in Adult HLH Using Longitudinal Clinical and Proteomic Biomarkers

Haemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory/cytokine storm syndrome caused by uncontrolled immune activation. HLH can be genetic (primary HLH), but in adults HLH is more commonly secondary to conditions including haematological malignancy, infection and autoimmune/autoinflammatory disease. HLH is under-recognised and difficult to diagnose and treat. People with HLH present with a syndrome resembling sepsis but paradoxically require significant immune suppression, alongside identification and treatment of the HLH driver. Patients are cared for by a variety of specialities and this has hampered a co-ordinated research approach, particularly in adults. Overall, one-year survival from HLH is 50%, reduced further in HLH triggered by haematological malignancy. There is an urgent need for improved management pathways.
Though my clinical role as Senior Clinical Fellow (SCF) in the UCLH HLH service, I observed a distinct bimodal pattern of mortality in adult HLH. Early death (=14 days) appeared to occur in a subgroup of all patients with HLH, irrespective of the underlying disease whereas later death was predominantly seen in patients with associated haematological malignancy. My preliminary data confirmed this clinical observation. I intend to focus on this novel concept as I believe that this is crucial for driving forwards advances in patient management.
We lack a single diagnostic test for HLH and little is known about disease trajectory and stratification. Delayed diagnosis and treatment initiation of immunosuppression in HLH increases the risk of organ failure and death, whereas inappropriate immunosuppression in patients with HLH mimics, or over-treatment in lower risk patients, can cause harm.
I hypothesise that improving the identification of patients at risk of early HLH death will lead to improved patient outcome by appropriate aggressive immunosuppression in this subgroup and a reduction in overtreatment and iatrogenic harm in those with a different pattern of disease.
My overall aim is to improve patient outcomes by identifying those at risk of early sudden death and facilitate appropriate stratified treatment. I will integrate clinical features with serum proteomic biomarker analysis to refine diagnosis and enable early risk stratification in the following objectives:
Objective 1: Map distinct patterns of HLH progression by defining clinical signatures and disease trajectories related to outcomes in adults using retrospective longitudinal data:

1.1  Baseline clinical features: routine and widely available blood tests and clinical observations
1.2  Longitudinal patterns: trends in blood results and clinical observations, especially within the first 14 days of HLH diagnosis

Objective 2: Use targeted proteomics and clinical data to improve the confidence of HLH diagnosis and risk stratify patients at baseline

2.1  Baseline proteomic biomarker analyses: distinguish HLH from clinically similar mimicking conditions
2.2  Biomarkers predictive of early HLH-related mortality: stratifying patients according to clinical outcomes

 
Through prompt dissemination of my data in the HLH community, I envisage real changes in practice through:

Improved management of patients at risk of early death with appropriate use of currently available treatments
Accelerated research into new therapies using novel diagnostic biomarkers and disease stratification

I am uniquely capable of delivering this innovative, novel and clinically urgent work. I have generated robust preliminary data, underscoring the feasibility and potential impact of my project. My current dual role as SCF with the UCLH HLH service and as honorary research fellow in the Jury Lab, UCL enables me to bridge both clinical and research environments - essential for the success of this project.