Haemophagocytic Lymphohistiocytosis (HLH)
(References at bottom)
A rare and often fatal syndrome that combines a predisposing immunodeficiency (e.g. perforin gene mutation) with excess immune activation (e.g. a trigger illness) that results in characteristic systemic abnormal immunopathology.
Median of 19 days pyrexia unknown origin until time of diagnosis
Untreated survival is less than 2 months from diagnosis
55% 3 year overall survival (HLH-94)
WHO 2016 Classification
Familial (Primary) HLH
Incidence: 1 per million children per year / Estimated 1 per 3000 inpatient admissions
Autosomal recessive inheritance of mutations affecting NK and T cell function
Multiple causative mutations identified for familial HLH (FLH):
PRF1 (Perforin) – first gene linked to HLH, 1999 - defect in NK and T cell cytotoxicity (reduced perforin/granzyme B expression)
UNC13D, STXBP2, STX11, Rab27a – defects in cytolytic granule formation (reduced CD107a mobilization)
SH2D1A & BIRC4 (both males only) – defects in SLAM-associated protein (SAM) and X-linked inhibitor of apoptosis (XIAP) protein expression
Other primary genetic disorders are also included in the definition of primary (as opposed to familial) HLH:
X-linked lymphoproliferative disease (XLP)
Griscelli Syndrome Type 2 (GS2)
Chediak-Higashi syndrome (CHS)
Hermansky-Pudlak syndrome (HPS)
A macrophage activation syndrome occurring with haemophagocytosis, where an alternative underlying disease process is causing the immunodeficiency required to make patient vulnerable to developing HLH.
It may or may not resolve with treatment of the underlying cause, and HLH-specific treatment is still often required.
The presence of an identifiable infection does not exclude a diagnosis of primary or familial HLH, as these are commonly present as triggers for the acute episode in familial cases.
EBV – most common
CMV, Influenza, other viral infections
Bacterial and fungal infection
May cause an acquired immunodeficiency (e.g. NK and T cell lymhpomas)
May produce cytokine-like paraneoplastic proteins
May be the result chemotherapy-induced immunodeficiency
Rheumatological – Macrophage Activation Syndrome (MAS)
SLE, JIA, Adult onset Still disease, Other inflammatory immune disease
E.g. Fat overload syndrome 2o to long-term parenteral nutrition
Clinical Presentation & Diagnostic Work-up
The diagnosis of HLH requires a high index of suspicion, but once identified it is characterized by a unique pattern of clinical signs and symptoms
Haemophagocytosis may not be present at diagnosis, and is not sensitive or specific à Do not delay diagnosis or treatment looking for this.
Liver dysfunction is a frequent and prominent feature, on a spectrum from mild to fulminant liver failure.
Neurological dysfunction is common, 50% of patients have abnormal CSF examination. Seziures, meningism, psychomotor retardation, ataxia, irritability, hypotonia and complex peripheral neuropathies have all been reported.
Platelet function defect may be present – explained by the underlying genetic granule release defects (see associated with Chediak-Higashi and Hermansky-Pudlak above)
Rash – many different appearances, including Kawasaki. Skin biopsy may show lymphocyte infiltration or haemophagocytosis
HLH-2004 Diagnostic Criteria
Important: This was written as inclusion criteria for a trial, and was not originally intended as a diagnostic tool although it is frequently used in making a decision to treat. As a result:
There are notable omissions such as the hepatic and neurological signs that are often present.
It is sometimes necessary to treat even if not meeting the criteria as waiting for late-occurring features to present could delay life-saving therapy.
Since 2004, it is now possible to test for additional HLH-associated gene mutations and/or the proteins expressed as a result of gene mutations (see familial HLH section above)
Summary of the HLH-2004 treatment protocol
Core components of initial treatment:
Anti-inflammatory and pro-apoptotic properties
Better CNS penetration than prednisolone
Initiates cell apoptosis, with selective deletion of activated T-cells and suppression of inflammatory cytokine production
CNS disease occurs in 50% of cases, IT chemo aimed to prevent neurological complications and relapse of disease
Inhibits T-cell activity and production of IFN-gamma
Added after the 8-week induction block.
Allogeneic Stem Cell Transplant
Only curative treatment for familial HLH, but carries high treatment-related mortality
Bacterial / Fungal / PJP prophylaxis
Early ICU involvement
IVIg in select viral infections
Remember: Patients need treatment targeted at the underlying trigger (infection etc) but this may not be sufficient and HLH-specific therapy should also be started in severe cases.
Prognosis / Outcomes
Histiocyte Society HLH Registry 1989
122 patients, 21% 5-yr survival
113 patients <15 y.o.
55% 3-year Overall Survival (54% 5-yr predicted survival (pSu)
20-25% mortality in the pre-transplant phase
Transplant (n = 65) – 62% 3-year survival
No Transplant - 20 children still alive and off treatment for >1 year without having transplant
Long-term neurological complications
369 patients <18 y.o.
(Excluded certain 2o causes – malignant, rheumatoid, LCH, Kawasaki, leishmaniasis)
Ciclosporin introduced upfront + hydrocortisone added to ITs ?reduces pre-HSCT mortality and morbitdity
62% 5-yeat pSu
Transplant (n = 188) – 66% 5-year pSu
No benefit of the two protocol changes
For patients with EBV-HLH
Anything from spontaneous resolution to unrelenting disease requiring HSCT
Even seemingly spontaneously resolving case can relapse aggressively at a later date
HLH-2004 – 74 patients had EBV. 17 transplanted (5 confirmed familial HLH), 9 survivors. 11 died without transplant and 46 alive without HSCT
No prospective trial data, treatment is based on HLH-94 and HLH-2004
Poor outcomes, mortality rates of 50-75% reported