Increased knowledge about hemophagocytic lymphohistiocytosis can save lives

A research article, published in the New England Journal of Medicine on February 6, highlights the life-threatening disease hemophagocytic lymphohistiocytosis (HLH) and the importance of its early diagnosis and treatment. The disease, which can be difficult to recognize, is underdiagnosed so many patients do not receive appropriate treatment in time. Jan-Inge Henter, professor and senior consultant at Karolinska University Hospital, emphasizes the importance of increased awareness among healthcare professionals in order to save lives in both children and adults.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening inflammatory syndrome that, without prompt and adequate treatment, often quickly leads to multi-organ failure and death. Although the disease is treatable, it is markedly underdiagnosed. Thus, many lives are lost unnecessarily. Now researchers want to increase awareness of HLH and its complex clinical presentations.

HLH can be divided into two main types:

• Primary HLH is an inherited form that often has its onset during infancy and early childhood and is caused by genetic mutations that affect the regulation of the immune system.
• Secondary HLH, which is much more frequent, is an acquired form that can be triggered by infections, cancer, and autoimmune diseases, and is more common in adults.

Early detection and treatment are crucial to saving lives. The disease resembles a serious infection with fever and poor blood counts. Elevated levels of the laboratory test ferritin are common in HLH, and this simple test can therefore serve as a screening test for HLH.

Jan-Inge Henter, professor and senior consultant at Karolinska University Hospital, is one of the leading researchers in the field, and has played a crucial role in the development of today's treatment of the disease. The therapy includes chemotherapy, which may be perceived as counter-intuitive for critically ill patients, corticosteroids and/or specific immunosuppressive drugs. In the case of primary (genetic) HLH, a stem cell transplantation is performed to replace the dysfunctional immune system.

"HLH is a complex and often overlooked condition, but with increased awareness more patients can be diagnosed early and thereby save many lives", says Jan-Inge Henter. As an example, he mentions cancer-associated HLH, where the number of reported cases in Sweden has increased 10-fold from the period 1997-2007 to 2008-2018. Even during the period 2012-2018, the number of diagnosed patients was 3-4 times more common in some parts of the country than in other parts, indicating that many patients may still not be diagnosed and treated adequately.

A success story in modern medicine 

Familial HLH, the most common form of primary HLH, has gone from being an unknown and rapidly fatal disease to now being treatable so that three out of four can be cured. The discovery of the underlying genetic and cellular causes has paved the way for a better understanding of the regulation of the immune system, in particular its down-regulation.

"That we now can cure a disease that previously was rapidly fatal is a success story - and a hopeful example of how clinical research can develop treatments that save numerous lives", says Jan-Inge Henter.

A prototype for hyperinflammation 

HLH also serves as a model for many other hyperinflammatory conditions, where collaboration between different medical specialties is crucial to diagnose and treat patients effectively.  

"HLH is a reminder of how important it is to understand the regulation of the immune system and how a disruption of this can have serious consequences in many different diseases", continues Jan-Inge Henter.

Facts on HLH

• HLH is a life-threatening syndrome of overwhelming inflammation (hyperinflammation) that causes multiorgan failure and death, making prompt and appropriate treatment imperative.
• Primary (mendelian) HLH, an inherited deficiency of immune down-regulation mainly seen in children, is typically caused by defective cytotoxic lymphocytes (natural killer cells and cytotoxic T cells) with various defects in the perforin-granzyme cell-death pathway.
• Secondary (nonmendelian) HLH is an acquired condition, mainly seen in adults, that is most often triggered by infections, cancers, or autoimmune diseases.
• In all patients with the HLH syndrome, a search for and treatment of the underlying trigger (or triggers) is crucial; if the trigger is difficult to find in an adult, it is often a cancer.
• Although life-threatening and treatable, HLH is still underdiagnosed, and numerous lives could be saved through increased awareness of the disorder.
• HLH should be considered, and ferritin levels checked, in patients with sepsislike critical illness that does not respond to adequate empirical treatment.
• Long-term survival of primary HLH has increased from 0% to approximately 75% over the past 40 years. 
• In Sweden, the number of reported cases of cancer-associated HLH has increased 10-fold in recent decades, indicating increasing awareness.
• In 2012–2018, the number of cases of cancer-associated HLH was 3-4 times more common in some parts of Sweden than in other parts, indicating varying degrees of awareness.

Future directions

• Although life-threatening and treatable, HLH, particularly secondary HLH, is still underdiagnosed. Numerous lives could be saved with increased awareness of the disorder.
• The pathophysiology of secondary HLH is not yet fully understood, and best practices for diagnosis and treatment of the various forms of secondary HLH deserve further attention.
• Finally, the identification of additional medical conditions that can cause secondary HLH may improve our capacity for early detection and intervention.

Read the study in the New England Journal of Medicine here.

For more information, contact:

Jan-Inge Henter, professor and senior consultant  

Karolinska University Hospital  

E-mail: jan-inge.henter@ki.se

Mobile: +46 70 633 3557 (8 AM - 10 PM Central European Time; i.e., 2 AM - 4 PM Eastern Time)

Karolinska University Hospital

Press Officer 

+46 8 517 740 10

presstjanst.karolinska@regionstockholm.se

Karolinska is one of Europe's largest university hospitals and together with Karolinska Institutet we have a leading role within the field of medical breakthroughs. Our aim is to always put the patient first by providing the best possible medical expertise, treatment and care. Through innovation and active collaboration with industry and academia, we are committed to being internationally prominent in medicine, research and education.