RESOURCES

Guidelines

American Society of Haematology (2019) – Recommendations for the management of hemophagocytic lymphohistiocytosis in adults

Review Articles

Astigarraga et al, An Pediatr (2018); Haemophagocytic syndromes: the importance of early diagnosis and treatment
Schram et al, Blood (2015); How I treat hemophagocytic lymphohistiocytosis in the adult patient
Brisse et al, Cytokine & Growth Reviews (2014); Hemophagocytic lymphohistiocytosis (HLH): A heterogeneous spectrum of cytokine-driven immune disorders
George, J Blood Med (2014); Hemophagocytic lymphohistiocytosis: review of etiologies and management
Usmani et al, BJH (2013); Advances in understanding the pathogenesis of HLH

OBJECTIVES & QUESTIONS

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Introduction

What is hemophagocytic lymphohistiocytosis (HLH)?

Hemophagocytic lymphohistiocytosis (HLH) is an aggressive and life-threatening hyperinflammatory syndrome, which requires prompt and aggressive treatment
It is termed macrophage activation syndrome (MAS) when associated with rheumatic disease and secondary HLH (sHLH) when associated with other triggers, including malignancy and infection
HLH represents a group of conditions with different pathogenetic roots but a shared common final pathway
It most frequently affects infants up to 18 months of age but can be seen in children and adults of all ages

What is haemophagocytosis?

Defined by the presence of intact hematopoietic cells (erythrocytes or leukocytes) within the cytoplasm of phagocytic macrophages (histiocytes) in any tissue
The identification of hemophagocytic histiocytes in bone marrow is a fundamental diagnostic feature of HLH:
- However, the diagnosis can be made even without the presence of haemophagocytosis in biopsied tissue (non-sensitive)
- Other causes can lead to the presence of haemophagocytosis, including prolonged sepsis, infection (viral, fungal, parasitic) and malignancy

Why is HLH relevant to intensive care?

Usually requires ICU management given the severity of clinical features
Often first diagnosed in patients with known sepsis or multi-organ failure:
- Has non-specific symptoms and laboratory findings
- Requires ICU clinicians to have a high index of suspicion
- Has specific treatments available but a poor prognosis without

Epidemiology, Clinical Course & Prognosis

How common is HLH?

Estimated at <1 per 100,000 children under 18
Likely to be significantly under-recognised
Incidence may be as high as 1 in 2000 adult admissions at tertiary medical centres

Which age groups is HLH seen in?

Traditionally considered a disease of children, particularly those <18 months
Adults now comprise up to 40% of cases of HLH:
Median age of diagnosis being mid-40s to 50s
Cases are even seen above age 70

What is the prognosis of HLH?

Primary HLH is almost universally fatal without treatment
Mortality improved with treatment
Approximately 50% with HLH-94 based treatment
Secondary HLH and HLH in adults without treatment has high mortality:
Overall mortality of 50% to 75%
Stem cell transplant has resulted in significant improvements in long term survival and cure

What are the poor prognostic factors?

Younger age
CNS involvement
Failure of therapy to induce a remission before HCT
Association with malignancy

Aetiology

What are the causes of HLH?

Primary

Genetic defects – usually autosomal recessive:
- Function of cytotoxic T cells or NK cells
- Inflammasome regulation

Secondary (Acquired)

Viral Infections

EBV
HSV
HIV
CMV

29%

Other Infections

Bacterial
Protozoal (Malaria, Leishmania)
Fungal (Candida, Aspergillus)
Mycobacteria
Mycoplasma

20%

Malignancies:

Natural killer (NK) cell lymphomas
B-cell lymphomas
Hodgkin lymphoma
Leukaemia
Other hematologic neoplasms
Solid tumours

27%

Rheumatological Conditions

Juvenile idiopathic arthritis
SLE
Adult-onset Still's Disease
Rheumatoid Arthritis

7%

Immune Deficiency States

Stem or bone marrow transplant
Solid-organ transplant
Severe combined / common variable immunodeficiency

6%

Other

Haemodialysis
Pregnancy
Vaccination

Rare

Pathophysiology

What are the underlying pathophysiological mechanisms in HLH?

In the standard-setting:

Cytotoxic T Lymphocytes (CTLs) and Natural Killer (NK) cells eliminate infected or tumour cells via apoptosis
When the cells are cleared, the CTLs will inhibit further antigen presentation by removing antigen‐presenting Dendritic Cells (DCs)
T-Regulatory Cells (Tregs) compete with and limit the proliferation of CTLs. They may also directly eliminate activated CTLs
NK cells likewise control the size of the activated CTL pool via induction of apoptosis
This limits the amount of CTL‐derived IFN‐γ. This is required for macrophage activation and additional cytokine production, and so this becomes limited.

In the setting of HLH:

Dysregulated immune system unable to restrict the stimulatory effect of various triggers (due to single or combined defects):
- CTLs and NK cells fail to eliminate tumour cells or infected cells, which continue to replicate, resulting in persistent antigenemia
- CTLs no longer remove the antigen-presenting DCs, leading to prolonged and heightened antigen presentation
- T Regulatory Cells are unable to regulate CTLs due to imbalanced cytokines. T regulatory cell numbers drop, and CTLs continue to proliferate.
- NK fail to control the size of the activated CTL pool due to loss of cytotoxic activity
The activated CTLs produce massive amounts of IFN‐γ:
- Induces excessive macrophage activation
- Directly provokes haem phagocytosis.
Activated macrophages release vast amounts of pro-inflammatory cytokines (a ‘cytokine storm’):
- Interleukins: (IL)-1, IL-6, IL-10, IL-12, IL-16, IL-18
- Tumour necrosis factor (TNF)
Results in ongoing cycles of inflammation and cytokine release:
- Exacerbated by failure to clear cells via apoptosis resulting in necrosis and further inflammation

How does the cytokine storm lead to the clinical syndrome?

Cytokine

Effects

TNF-α

Fever
Cachexia
Depression of haematopoesis
Hypertriglyceridaemia
Elevated serum transaminases
Disseminated intravascular coagulation
Suppression of NK cell activity

TFN-γ

Fever
Haemophagoctytocis
Depression of haematopoeisis
Macrophage activation
Stimulation of antigen presentation
Disseminated intravascular coagulation

IL-1β

Fever Hyperferritinaemia
Depression of haematopoeisis
Acute phase proteins
T-cell activation

IL-6

Fever
Anaemia
Acute phase proteins
Renal failure

IL-10

Suppression of T-cell activation
Regulation of haemophagocytosis

IL-18

Hepatic damage
Supression of NK cell activity

Presentation

What are the typical clinical features of HLH?

Febrile illness (prolonged) associated with multiple organ involvement:

Reticuloendothelial manifestations:
- Hepatosplenomegaly (95%)
- Lymphadenopathy (33%)
CNS dysfunction (35%):
- Seizures
- Cranial nerve palsy
- Altered sensorium
Respiratory dysfunction:
- Respiratory failure
- Alveolar / interstitial infiltrates
Cutaneous manifestations (up to 65%)
- Maculopapular erythematous rashes
- Generalised erythroderma
- Oedema
- Panniculitis

What are the features of severe disease?

High serum ferritin (>500, usually higher)
Haematological abnormalities:
- Thrombocytopenia
- Anaemia
- Coagulopathy
- Hypofibrinogenemia
Deranged LFTs:
- Hyperbilirubinaemia
- Transaminitis
Hypertriglyceridemia

When should you suspect HLH in the ICU?

Diagnosis can be challenging to make:
- Features are non-specific
- Physiological macrophage activation occurs in sepsis, malignancy and autoinflammatory disorders
- HLH is characterised by pathological macrophage activation
Consider HLH in any critically ill patient with an inadequate response to treatment or unusual progression of symptoms:
- Persistent fever
- Unresponsive to vasopressors
- Inexplicable cytopenias
- Organ failure not responding to appropriate therapy and aggressive supportive care

Work-Up Summary

How do you work-up the patient with suspected HLH?

To Determine Diagnosis

Clinical history and findings
Use of Clinical Scores:
- HLH Diagnostic Criteria (primary HLH)
- H-Score (secondary HLH)
Laboratory evaluation:
- FBC
- Ferritin
- Fasting triglycerides
- Coagulation screen (fibrinogen, PT, aPTT)
- LFTs, LDH, albumin
- Immunological testing
- Bone marrow biopsy

Definitive testing:
If suspected, do not wait to treat!

ADAMTS13 activity
Anti-ADAMTS13 Ab
Sequencing of ADAMTS13 gene

To Determine Aetiology

Infection work-up:
- Relevant imaging
- Bacterial and viral studies
Cancer work-up:
- PET-CT
Tissue biopsy
Tumour markers

Autoimmune panel

Genetic testing

Diagnostic Criteria & Scoring

How can HLH be diagnosed?

Should be diagnosed based upon clinical judgement and history in conjunction with a diagnostic score/criterion
Scoring systems available include:

HLH Diagnostic Criteria

Produced in 2004 by the histiocyte society
Developed for diagnosis of primary HLH in paediatric population
Frequently applied to adult population though poorly validated

H-score

Weighted criteria developed in 2014
Only validated for secondary forms of HLH in adults

What are the diagnostic criteria for HLH?

The 2004 revision of the diagnostic criteria for HLH requires:

Molecular testing consistent with HLH
or
5 of 8 clinical or laboratory criteria

Clinical / Laboratory Criteria

Fever
Splenomegaly
Cytopenias of at least 2 cell lines
Hypertriglyceridemia
Hypofibrinogenemia
Elevated ferritin
Elevated soluble IL-2 receptor (sCD25)
Decreased or absent NK-cell activity
Demonstration of hemophagocytosis in bone marrow, spleen, or lymph nodes

Supportive But Not Definitive Criteria

Elevated transaminases
Elevated bilirubin
Elevated LDH
CSF pleocytosis and/or elevated protein

What is the H-score?

A set of weighted criteria, producing a score out of 337
Score ≥169 commonly used as a cut-off as a likelihood for a diagnosis of HLH
Produces a % risk of HLH based upon weighted score

No. of Points
Parameter

No. of Points
(Criteria for scoring)

Known Underlying Immunosuppression

(HIV or Immunosuppressive therapy)

0 (no)
18 (yes)

Fever (C)

0 (<38.4)
33 (38.4-39.4)
49 (>39.4)

Organomegaly

0 (no)
23 (hepatomegaly or splenomegaly)
38 (hepatomegaly and splenomegaly)

Number of Cytopenia

(Hb <9.2 g/L / WBC ≤5 x 10⁹/L / plat ≤110 x 10⁹/L)

0 (one lineage)
24 (two lineages)
34 (three lineages)

Triglycerides (mmol/L)

0 (<1.5)
44 (1.5-4)
64 (>4)

Ferritin (µg/L)

0 (<2000)
35 (2000-6000)
50 (>6000)

Laboratory Investigations

What are levels of ferritin seen in HLH?

The Texas children’s study (Allen et al) suggested:
- >500 has 100% sensitivity
- >10,000 has 90% sensitivity and 96% specificity

What is the role of ferritin in HLH?

Believe that the very high ferritin levels are not just the product of the inflammation but instead may have a pathogenic role
May be involved in some sort of a loop mechanism where ferritin’s inflammatory proprieties are exacerbated, leading to an extreme expression of additional inflammatory mediators that are characteristic in the cytokine storm.

Management Summary

How do you manage the patient with HLH?

Key Principles

Provision of supportive care for organ failure
MDT approach towards management
Treatment of underlying cause
Specific management based on HLH-94 protocol

Initial Resuscitation & Supportive Care

Aggressive approach to organ support - may require:
- Invasive ventilation
- Vasopressor support
- Renal replacement therapy

Specific Management

Treat the underlying cause:
- Rheumatological - corticosteroids
- Infectious - antimicrobials
For primary / refractory secondary disease HLH therapy based on the HLH-94 protocol:
- Etoposide
- Dexamethasone
- Intrathecal methotrexate
If failure to respond additional treatments may be required haemopoietic stem cell transplant

Referral & Deposition

Senior MDT approach - input from:
- Haematology
- Rheumatology
- Cardiology
- Microbiology / Infectious Diseases