A simple laboratory test capable of diagnosing and predicting the severity of secondary hemophagocytic lymphohistiocytosis (HLH), a rare and sever hyper-inflammatory syndrome, until now very difficult to recognize. This is now possible thanks to the study conducted by Bambino Gesù which has identified a subpopulation of T lymphocytes which is greatly increased in patients with secondary HLH and is able to distinguish these patients from those with auto-inflammatory diseases. “A discovery that has relevant clinical implications that will change the diagnosis and management of patients with various forms of HLH” explains Dr. Fabrizio De Benedetti, Head of Rheumatology at the hospital and corresponding author of the research. The results were published in the scientific journal Blood.
HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS OR HLH
Hemophagocytic lymphohistiocytosis (HLH) is a disease characterized by excessive activation of macrophages, the scavenger cells that usually clear away infected cells, but which in this disease also clear out healthy cells. This leads to systemic hyper- inflammation and multi-organ failure. It is a disease that can be fatal if not diagnosed and treated in time. This is why it is important to recognize it immediately, which has been very difficult up to now.
There are two forms of hemophagocytic lymphohistiocytosis: the primary or familial form and the secondary or acquired form. The primary form has a genetic cause, while the secondary can occur as a complication of various pathologies. Triggers can be viral infections (e.g. Multi-system Inflammatory Syndrome or MIS-C caused by Covid-19), malignancies, immunodeficiencies, metabolic diseases and auto-inflammatory diseases. When secondary HLH is associated with rheumatic disease, it is commonly referred to as macrophage activation syndrome (MAS).
THE STUDY
The study conducted by the Immunology research area in collaboration with the Oncohematology area demonstrated that in the blood of patients with secondary HLH there is a subpopulation of T lymphocytes that allows for a reliable diagnosis of the disease and for predicting its evolution. The research was conducted on peripheral blood cells from 99 pediatric patients, 46 of whom had secondary HLH.
For the investigation of the samples, cytofluorimetry or flow cytometry was used, a multi- parametric laboratory technique which provides numerous data for each cell (vitality, size, complexity, phenotype, etc.).
THE RESULTS
The study demonstrated that in patients with secondary HLH, activated T lymphocytes (expressing membrane markers CD38, HLA-DR and CD8) are present in significantly higher numbers than in patients with auto-inflammatory diseases, such as patients with idiopathic arthritis systemic juvenile.
The researchers also identified a new cellular subpopulation of T lymphocytes (called CD4dimCD8+), whose high blood counts predict the severity of secondary HLH. The more this cell subpopulation is numerous, the more serious the prognostic outcome will be.
“One of the most important aspects of the results obtained with this study – explains Dr. Giusi Prencipe, medical biotechnologist of Bambino Gesù and coordinator of the study – is the immediate translationality. That is to say that is is possible, as we are already doing at our hospital, to immediately transfer the results into clinical practice to the benefit of children and their families”.
THE PROSPECTIVES
The results of the study have immediate implications on the diagnosis and management of patients with secondary HLH. It is now possible with a simple laboratory test to diagnose the disease and its evolution with great reliability and in a very short time: in fact, a small blood sample and the use of flow cytometry are enough. This allows for early management, which is essential for rapidly initiating the use of the most appropriate treatments and therefore for improving the prognosis.
“It is not always easy to recognize HLH through the symptoms and classic laboratory tests, especially at the onset – comments Dr. Fabrizio De Benedetti, head of the Hospital’s Rheumatology operating unit – With the identification of this cell population it is instead possible to carry out both the diagnosis and the prognosis early. An even more important result if we consider the possibilities offered by new biological drugs, such as the monoclonal antibody emapalumab”.
In the past, Bambino Gesù has already coordinated the clinical trial on the use of this drug for primary HLH. A new trial on the use of emapalumab for the treatment of secondary HLH has just concluded. The results of this latest trial will be previewed at the upcoming European Rheumatology Congress EULAR 2022, which will be held from 1 to 4 June in Copenhagen, Denmark.
