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SOE 619: Fever & Lymphadenopathy

Introduction

An 18-year-old man is admitted to intensive care for vasopressor support. He has recently been assessed in the rheumatology clinic for worsening joint pains over the past 6 months. He presented with a 3-day history of fever, dyspnoea and lymphadenopathy. He is treated initially for sepsis with broad-spectrum antibiotics…

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Case Information

Over the next two days his condition continues to worsen. He has rising vasopressor requirements and is noted to have hepatomegaly and a widespread erythematous rash…

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Laboratory Investigations

Bloods taken 48 hours after admission show…

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Question No. 4

Q: What do you consider as your differential diagnoses?

Answer No. 4

Infectious Disease
  • Bacterial Infection (failure of antibiotic therapy due to organism, patient or drug factors)
  • Viral infection (EBV, CMV, Parvovirus, HIV)
  • Fungal infection
Inflammatory Disease
  • Systemic juvenile idiopathic arthritis
  • Kawasaki disease
  • Systemic Lupus erythematosis
  • Hemophagocytic lymphohistiocytosis (HLH)
Neoplastic Disease
  • Lymphoma
  • Acute lymphoblastic leukaemia (ALL)

Case Information

A colleague suspects a diagnosis of haemophagocytic lymphohistiocytosis…

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Question No. 6

Q: What is hemophagocytic lymphohistiocytosis (HLH)?

Answer No. 6

  • 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

Question No. 7

Q: Why is HLH relevant to intensive care?

Answer No. 7

  • 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

Question No. 8

Q: How common is HLH?

Answer No. 8

  • 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

Question No. 9

Q: What is the prognosis of HLH?

Answer No. 9

  • 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

Question No. 10

Q: What are the causes of HLH?

Answer No. 10

Primary

Primary

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

Secondary (Acquired)

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

Question No. 11

Q: What are the underlying pathophysiological mechanisms in HLH?

Answer No. 11

In the standard-setting:  
  1. Cytotoxic T Lymphocytes (CTLs) and Natural Killer (NK) cells eliminate infected or tumour cells via apoptosis
  2. When the cells are cleared, the CTLs will inhibit further antigen presentation by removing antigen‐presenting Dendritic Cells (DCs)
  3. T-Regulatory Cells (Tregs) compete with and limit the proliferation of CTLs. They may also directly eliminate activated CTLs
  4. NK cells likewise control the size of the activated CTL pool via induction of apoptosis
  5. 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:

 

  1. 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
  2. The activated CTLs produce massive amounts of IFN‐γ:
    • Induces excessive macrophage activation
    • Directly provokes haem phagocytosis.
  3. 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)
  4. Results in ongoing cycles of inflammation and cytokine release:
    • Exacerbated by failure to clear cells via apoptosis resulting in necrosis and further inflammation

Question No. 12

Q: What are the common clinical features of HLH?

Answer No. 12

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

Question No. 13

Q: What are the common laboratory features of HLH?

Answer No. 13

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

Question No. 14

Q: When should you suspect HLH in the ICU?

Answer No. 14

  • 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

Question No. 15

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

Answer No. 15

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

    • Question No. 16

    Q: What levels of ferritin are seen in HLH?

    Answer No. 16

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

    Question No. 17

    Q: How can HLH be diagnosed?

    Answer No. 17

    • 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

    Question No. 18

    Q: What is the diagnostic criteria for HLH?

    Answer No. 18

    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

    Question No. 19

    Q: What is the H-score?

    Answer No. 19

    • 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)

    Question No. 20

    Q: What is the ICU management of HLH?

    Answer No. 20

    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

    Question No. 21

    Q: Which drugs have been used in the management of HLH?

    Answer No. 21

    The classical HLH-94 protocol includes:

    • Corticosteroids - usually dexamethasone in primary forms and methylprednisolone in secondary forms
    • Etoposide - a chemotherapy agent with high specificity against T-cells
    • Cyclosporin A
    • Methotrexate

      Other drugs that are commonly used include

    • Anakinra (an interleukin-1 inhibitor)
    • Immunoglobulin
    • Alemtuzumab
    • Tocilizumab

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