Hemophagocytic lymphohistiocytosis deaths in Europe almost doubled over past decade

medwireNews: Deaths due to hemophagocytic lymphohistiocytosis across Europe remain rare, but have almost doubled over the past decade, demonstrates a population-based study that also revealed large differences between countries, potentially through under-reporting.

Fiona Pearce (Nottingham University Hospitals NHS Trust, UK), and colleagues write in The Lancet Rheumatology that “these findings highlight the need to increase awareness among clinicians of haemophagocytic lymphohistiocytosis, especially in older adults and in countries with low reported haemophagocytic lymphohistiocytosis mortality.”

They add: “Under-recognition of rare diseases is well documented and affected individuals often have unmet healthcare needs, such as delayed diagnosis, little access to specialist expertise, and restricted access to treatment.” The team suggests that “[l]inking mortality data with clinical registries and hospital discharge data would further clarify the contribution of triggers, comorbidities, and treatment outcomes.”

In an accompanying editorial, Cornelia Lachmann and Gunnar Lachmann, both from Universitätsmedizin Berlin in Germany, say that the study “substantially advances the field and its public health implications are considerable.” They echo that there is an “urgent need for greater awareness of haemophagocytic lymphohistiocytosis, improved diagnostic training, and harmonised reporting systems across Europe.”

Hemophagocytic lymphohistiocytosis arises from the dysregulated activation of natural killer cells, cytotoxic T cells, and macrophages. It results in systemic inflammation and multi-organ failure, the researchers explain, with 1-year survival as low as 30% in people older than 75 years.

They note that, as patients can present with signs related to pulmonary, renal or cardiac involvement, it may be mistaken for sepsis.

The researchers analyzed publicly available death certificate data from EUROSTAT for mortalities due to hemophagocytic lymphohistiocytosis in European countries to calculate age-specific and sex-specific rates from January 2011 to December 2021.

Although data were obtained from 34 countries, five countries were excluded due to the small number of deaths in each, leaving 29 countries with 3345 deaths due to hemophagocytic lymphohistiocytosis.

The crude mortality rate per 10,000,000 person–years across Europe was 5.3, rising from 3.9 in 2011 to 6.6 in 2021, representing an increase of 5% per year. This equates to a 1.7-fold increase in the mortality rate of hemophagocytic lymphohistiocytosis over the study period.

The researchers determined that death rates due to hemophagocytic lymphohistiocytosis decreased by 6% per year in people aged up to 19 years but increased by 9% per year in individuals aged 20–49 years, and in those 50 years and older. The highest mortality rates were in infants aged up to 4 years, at 17.5 per 10,000,000 person–years, and in adults aged 80–85 years, at 15.6 per 10,000,000 person–years.

The age–sex-standardized mortality rate across Europe was 4.7 per 10,000,000 person–years, with the highest recorded rate in France, at 10.1 per 10,000,000 person–years, and the lowest in Romania, at 0.5 per 10,000,000 person–years. The mortality was higher in men than women, at an adjusted rate ratio of 1.5.

The authors conclude that further research is needed to “explore whether observed mortality trends reflect true changes in incidence or improved recognition and reporting.”

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Lancet Rheumatol 2025; doi:10.1016/S2665-9913(25)00292-9
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