Trends in mortality due to haemophagocytic lymphohistiocytosis across 29 European countries from 2011 to 2021: a retrospective, international, population-based study.

BACKGROUND

Previous research has suggested that the incidence of haemophagocytic lymphohistiocytosis is increasing in Europe. We aimed to examine rates of mortality due to haemophagocytic lymphohistiocytosis across 29 European countries from 2011 to 2021.

METHODS

In this retrospective, population-based, descriptive study, we applied to EUROSTAT for publicly available death certificate data for mortality due to haemophagocytic lymphohistiocytosis in countries in Europe. We defined haemophagocytic lymphohistiocytosis mortality as any death recorded with ICD-10 codes of D76.1 or D76.2 as the underlying cause. We calculated age-specific and sex-specific death registration rates from Jan 1, 2011, to Dec 31, 2021, for each country and used Poisson regression to compare Europe-wide rates over time. We used direct standardisation to compare rates between countries. We also searched Scopus Analytics to establish the number of haemophagocytic lymphohistiocytosis publications for each country from Jan 1, 2000, to June 11, 2024, and analysed the correlation between mortality rates and research activity measured by the number of relevant publications.

FINDINGS: Of 34 European countries that provided data, five were excluded from the analysis because the data had been censored due to small numbers of deaths. Analysis of 3345 deaths from the remaining 29 countries showed that crude haemophagocytic lymphohistiocytosis mortality increased from 3·9 per 10 000 000 person-years in 2011, to 6·6 per 10 000 000 person-years population in 2021. The age-sex-standardised mortality rate across Europe was 4·7 (95% CI 3·0-6·4) per 10 000 000 person-years, with the highest recorded rate in France (10·1, 0·0-27·3) and the lowest in Romania (0·5, 0·0-13·6). Crude mortality rates were highest in infants aged 0-4 years (17·5, 95% CI 16·1-19·0) and adults aged 80-85 years (15·6, 13·7-17·6). Mortality was higher in male than in female individuals (adjusted rate ratio 1·5, 95% CI 1·4-1·6). Increased haemophagocytic lymphohistiocytosis-related research activity often occurred in countries with higher rates of mortality recorded due to haemophagocytic lymphohistiocytosis than countries with lower rates (Pearson's correlation coefficient 0·4968; p=0·012).

INTERPRETATION: Recorded rates of mortality due to haemophagocytic lymphohistiocytosis have nearly doubled over the past decade in Europe. Deaths were most common at the extremes of age and were more common in male than in female individuals. Age-standardised rates between countries differed substantially, suggesting potential under-recognition of the diagnosis of haemophagocytic lymphohistiocytosis. There is a need to increase awareness among clinicians together with implementation of evidence-based guidelines for diagnosis and urgent treatment.

FUNDING: Medical Research Council Rare Disease Platform Node for Histiocytic Disorders.