Haemphagocytic Lymphohistiocytosis in an English Nationwide Cohort Confirms Increasing Incidence and Variation in Trigger Factors

Background: Haemophagocytic Lymphohistiocytosis (HLH) is a rare, life-threatening hyper-inflammatory syndrome triggered by constitutive and acquired risk factors including haematological malignancy, infection, auto-immunity and rheumatological disease. There is little evidence regarding incidence or the underlying trigger factors of HLH on a whole population basis over time.

Aim: In partnership with the National Congenital Anomalies and Rare Disease Registration Service (NCARDRS) we aimed to identify cases of HLH for the whole population of England (~56 million), examine the temporal trends in the incidence of the disease and quantify the relationship with patient demographics and associated diseases.

Methods :Using national linked electronic health data from hospital admissions and death certification we identified cases of HLH that were diagnosed in England between 2003 and 2018 using a previously validated approach. Patients of all ages who were admitted to hospital and had an admission coded with HLH ICD-10 codes D76.1 and D76.2, or who died with a death code of D76.1, D76.2 or D76.3 provided in the latter situation there was confirmatory free text on the death certificate indicating HLH, were included. We calculated incidence rates per million population based on the ONS mid-year population estimates by calendar year, age group, sex and associated non-infectious comorbidity (haematological malignancy, rheumatological or inflammatory bowel diseases) associated with the diagnosis of HLH. We modelled trends in incidence and the interactions between calendar year, age and associated comorbidity using Poisson regression.

Results: From 2003 to 2018, we identified 1674 patients diagnosed with HLH, 1091 (65.2%) identified via hospital admission coding and 183 (10.9%) by death certificate and the remainder in both. 1154 (68.9%) patients were aged >15 years and 945 (56.5%) were male. 988 patients (59%) had at least one associated comorbidity recorded, and 484 (28.9%) at least one underlying haematological malignancy. The commonest recorded malignancy was lymphoma (n=279 [16.7% of the total], comprising B-cell lymphoma n=121 [7.2%], T-cell lymphoma n=84 [5%], Hodgkin n=45 [2.7%] and NOS n=32 [1.9%]) followed by leukaemia (n=131 [7.8%]). Other diagnoses included rheumatological or inflammatory bowel disease (n=392 [33.7%]) and non-haematological malignancies (n=112 [9.7%]). Reported crude incidence rates of HLH increased from ~1/million person years in 2003 to ~4/million in 2018, an annual increase of 11%. There was a rising trend in all age groups except for those aged <5 years, the group most likely to have a genetic risk factor for HLH. Diagnoses of HLH with an associated haematological malignancy or auto-immune disease increased by almost ~20% per year during the study period. Across age groups, the greatest increases in diagnosis of associated comorbidities were seen in HLH associated with auto-immunity for those aged 5-14 years old, and haematological malignancies for those aged >55 years (table 1).

Conclusion: The incidence of HLH in England has quadrupled between 2003-2018, increasing 11% year on year. These nationwide estimates of the incidence of HLH across all ages show important temporal trends by both age and HLH-associated underlying diseases. These trends imply that some of the rise in frequency of the diagnosis of HLH is due to either underlying diseases or their treatments, although increased recognition is likely a significant factor. The incidence of auto-immune disease and blood cancer suggests that these specialities should be involved early in treatment pathways.

Bishton:Celltrion: Honoraria; Roche Pharmaceuticals: Consultancy, Honoraria; Gilead: Honoraria; Lilly: Consultancy; Incyte: Consultancy. Lanyon:Vifor Pharma: Research Funding.