CONTENTS

• Clinical findings:
  • Core clinical & laboratory findings in HLH
  • Other features
    • Ferritin
• Pathology
• Causes of HLH & investigation of cause
  • Studies to evaluate for etiology
• Differential diagnosis: Closest mimics of HLH
• Approach to the diagnosis of HLH
  • Diagnostic criteria
  • Studies to obtain to evaluate for HLH
• Treatment: Overall approach
  • Steroid
  • IL1 antagonism
  • JAK inhibition
  • Calcineurin inhibitors (cyclosporine)
  • Etoposide
• Other topics
  • Pathophysiology: what is HLH?
• Podcast
• Questions & discussion
• Pitfalls

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core clinical & laboratory findings in HLH

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[1] fever

• ~95% of patients are febrile >38.5 (33745765)
• Fever often lasts weeks prior to ICU admission.
• The diagnosis of HLH should be questioned in the absence of a fever.
• ⚠️ Fever may be masked by the use of antipyretics, continuous renal replacement therapy, or ECMO. (30992265)

[2] splenomegaly and/or hepatomegaly

• Splenomegaly occurs in ~70-85% of patients. (30384814, 33745765)
• (Lymphadenopathy isn't associated with HLH. If present, substantial lymphadenopathy should raise a concern for another underlying disease process such as lymphoma, Castleman disease, histoplasmosis, or tuberculosis). (31339233)

[3] cytopenias

• All cell lines may be affected (thrombocytopenia, leukopenia, anemia).
• Thrombocytopenia often occurs first. (38258680)
• Cytopenia in ≧2 cell lines may occur in ~75% of patients. (33745765) In some patients with secondary HLH, patients may begin with baseline leukocytosis and/or thrombocytosis and these counts may subsequently fall as HLH emerges.

[4] ferritin

• Hyperferritinemia is a requisite for diagnosis of HLH in adults:
  • Ferritin is generally >2,000 ug/L. (38258680)
  • Ferritin >6,000-10,000 ug/L are somewhat more specific, but less sensitive.
  • Ferritin has prognostic value in HLH: higher values and failure to improve suggest worse outcomes. (38627860)
  • Serial ferritin levels: in untreated HLH, ferritin will often be increasing rapidly.
  • (More discussion of hyperferritinemia below. ⚡️)
• C-reactive protein and procalcitonin are typically elevated. (28477737) CRP is universally elevated and correlates with disease severity. (38627860)

[5] liver function test abnormality

• Elevated aminotransferase levels can occur early and often track with disease activity. (32387063) 
  • ALT elevation occurs in ~85% of patients with HLH (but is nonspecific). (33745765)
• Bilirubin elevation is common.
• Fulminant liver failure and marked elevation of transaminases can occur.

[6] hyperfibrinolysis

• Activated macrophages appear to trigger fibrinolysis (possibly by secreting ferritin or plasminogen). (32387063, 30384814) This leads to a hemorrhagic form of disseminated intravascular coagulation with hyperfibrinolysis and low fibrinogen levels.
• Markedly elevated D-dimer may be an early sign of hyperfibrinolysis that signals the development of HLH. (33413556)
• Over time fibrinogen levels will decrease, so falling fibrinogen and absolute hypofibrinogenemia may develop later.
• Prolonged INR and PTT may also be seen.

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other clinical features of HLH

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shock, multi-organ failure

• Shock may involve capillary leak and/or myocarditis.
• ARDS and AKI may occur.
• Myocardial involvement may occur (which can mimic myocarditis).

CNS HLH (~25-50%)

• Symptoms may vary widely: (34950412)
  • Delirium ranging in severity from subtle to coma.
  • Focal neurologic deficits (e.g., ataxia, dysarthria, cranial nerve palsies).
  • Headaches, meningismus.
  • Seizure.
  • PRES (posterior reversible encephalopathy syndrome).
• Most patients have neurologic features in the context of systemic findings, but some patients can have isolated neurologic symptoms. (34950412)
• Differential diagnosis includes:
  • CNS involvement from HLH.
  • CNS involvement due to the trigger of the HLH (e.g., direct malignant or infectious infiltration of the brain).
• CSF findings:
  • ⚠️ HLH causes a hemorrhagic form of DIC with increased risk of bleeding due to low fibrinogen levels. Prior to lumbar puncture, consider checking a fibrinogen level, coagulation studies, and complete blood count.
  • Basic chemistry findings may include elevated protein levels and lymphocytic pleocytosis.
  • Cytology for hemophagocytosis: Uncommonly encountered, but you may get lucky. (27292929)
  • Excluding alternative etiologies: Practically speaking, the greatest utility of lumbar puncture is exclusion of alternative etiologies (e.g., bacterial meningitis, HSV or VZV encephalitis).
• Neuroimaging may vary widely, including:(34950412)
  • Multifocal white matter demyelination-like changes.
  • Large, ill-defined confluent lesions.
  • CNS hemorrhage, or microhemorrhages within lesions.
  • Leptomeningeal enhancement.
• Early etoposide therapy should be considered for patients with HLH and neurological manifestations (discussed further below). (34605776)

hypertriglyceridemia

• The test performance of hypertriglyceridemia among critically ill patients with little nutritional intake is unclear (since prolonged fasting may reduce the triglyceride level).

soluble CD25 (soluble IL-2 receptor)

• Causes of elevation include HLH, rheumatologic diseases involving T-cell activation, or hematologic malignancies.
• Overall, it's dubious what this test adds to the diagnosis of HLH. Sensitivity and specificity appear to be poor in the critical care setting. (38258680)
• Soluble CD25 >3900 U/ml with ferritin >1000 ug/L is suggestive of malignancy. (38258680)

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ferritin

interpretation of ferritin elevation

• A ferritin level >500 ng/ml is used as a criterion for HLH diagnosis, but this is derived from pediatric studies. Adult HLH patients typically have much higher ferritin levels (e.g., above ~2,000 ng/mL). More extreme elevations of ferritin are a bit more specific for HLH. However, there are many other causes of severely elevated ferritin (listed below). Therefore, extreme hyperferritinemia alone doesn't necessarily indicate a diagnosis of HLH.
• Rapidly rising ferritin levels may be more consistent with evolving HLH.

causes of markedly elevated ferritin

• Erythrocyte disorders:
  • Hemolysis.
  • Iron overload due to multiple transfusions.
• Renal failure (especially hemodialysis).
• Liver disease:
  • Cirrhosis.
  • Acute hepatitis (e.g., viral, ischemic, or alcoholic).
  • Acetaminophen overdose.
  • Hemochromatosis.
• Inflammatory states:
  • Malignancy (hematologic >> solid tumor).
  • Infection (especially infections that are capable of causing HLH). 📖
  • Graft Versus Host Disease (GVHD).
  • Antiphospholipid antibody syndrome.
  • Rheumatologic disorder (especially adult onset Still's Disease).
  • HLH (often secondary to one of the above triggers). 23965472, 25851400, 27247369, 28762079, 31991015, 31995958

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pathology – hemophagocytosis

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basics of hemophagocytosis

• Macrophages are phagocytosing erythrocytes, platelets, or leukocytes.
• Essentially this serves as histopathological evidence supporting macrophage dysregulation.
• May be seen in various tissues. Most commonly sampled tissues include the bone marrow, lymph nodes, or liver. Source of the biopsy may depend on which organs are involved (e.g., bone marrow biopsy may be most appropriate for a patient with cytopenias, whereas liver biopsy may be more appropriate for a patient with marked liver abnormalities). The optimal site of biopsy may also be constrained by coagulopathies (e.g., a bone marrow biopsy may be safer than a liver biopsy in the context of coagulopathy).

diagnostic role of tissue biopsy

• Not sensitive:
  • Often absent initially.
  • Sensitivity may be in the range of 50%.
  • A repeat biopsy later in the disease course may reveal hemophagocytosis.
• Not specific: Can be seen in infections, blood transfusions, autoimmune disease. (32387063)
• Exclusion of alternative diagnoses: For patients with cytopenias, bone marrow biopsy may be helpful to exclude malignancy or infection (even if it doesn't reveal hemophagocytosis). (38627860)

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mimics of HLH

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The differential will vary depending on each specific patient's presentation. The following entities may mimic HLH closely:

• Liver disease.
• Catastrophic Antiphospholipid Antibody Syndrome (CAPS).
• Septic shock.
• Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) 📖 – although this likely represents a true overlap between DRESS and HLH. (31339233)
• Flare of rheumatologic disease.
• Tick borne illness (e.g., anaplasmosis), which in some cases may also trigger HLH.

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causes of HLH

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HLH associated with rheumatic conditions (Rh-HLH, also called macrophage activating syndrome) 

• More often:
  • SLE.
  • Adult onset Still's disease.
  • Juvenile rheumatoid arthritis (a.k.a., juvenile idiopathic arthritis).
• Less often:
  • Rheumatoid arthritis, mixed connective tissue disorder, scleroderma, Sjogren's syndrome, dermatomyositis.
  • Ankylosing spondylitis.
  • Kawasaki disease.

HLH associated with malignancy (M-HLH) 

• ~90% hematologic malignancies, especially: (38627860)
  • T-cell or NK-cell leukemia or lymphoma.
  • Diffuse large B-cell lymphoma.
  • Hodgkin lymphoma.
  • Intravascular B-cell lymphoma is a rare, but under-recognized driver of HLH. 📖 (38258680)
• ~10% solid tumors (including teratoma, breast cancer).

HLH due to immune-activating therapies or drug hypersensitivity (Rx-HLH)

• Immune checkpoint inhibitors (e.g., nivolumab, ipilimumab).
• Genetically engineered CD8+ cytotoxic T cells, as a component of CAR-T cell therapy.
• Some drugs (e.g., lamotrigine).

HLH due to infection (most often viruses or intracellular pathogens)

• Viruses are the most common infectious cause:
  • EBV is the most common cause, but it's relationship to HLH is complex:
    • [1] EBV infection or reactivation can trigger HLH. In such cases, high viral load is usually detected. (38258680) Genetic testing from primary HLH is advisable in these situations.
    • [2] HLH itself may trigger EBV reactivation.  In such cases, the viral load is usually low. (38258680)
    • [3] EBV-driven lymphoma may trigger HLH.
  • Other Herpes viruses (CMV, HSV, VZV).
  • Disseminated adenovirus.
  • RSV.
  • Influenza (especially H1N1), COVID-19.
  • Adenovirus.
  • Parvovirus B19.
  • HIV.
  • Viral hepatitis (HBV, HCV).
• Bacterial infections:
  • Ehrlichia, Bartonella, Brucella.
  • Tuberculosis.
  • Legionella.
• Anaplasmosis, babesiosis.
• Fungal infections:
  • PJP.
  • Histoplasma.
• Parasites (e.g., Leishmania, Plasmodium, Toxoplasma).

HLH with immune compromise (IC-HLH)

• HIV.
• Immunosuppressive medications.
• Transplantation (may accompany EBV lymphoproliferative disorder).
• Various congenital immunodeficiencies (typically pediatric onset).

familial HLH (F-HLH)

• Patients with a strong genetic inclination to develop HLH may develop HLH spontaneously (without any discernible trigger).
• This occurs predominantly in children.

HLH related to medication

• DRESS syndrome may cause HLH. 📖

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studies to consider when investigating the etiology of HLH

• ✓ CT chest/abdomen/pelvis (evaluation for malignancy or occult infection).
• ✓ HIV serology.
• ✓ Serology for EBV, CMV.
• ✓ Serology for HBV, HCV.
• ✓ Serum PCR for EBV, CMV, HSV, VZV.
• ✓ Nasopharyngeal PCR for COVID, influenza, other respiratory viruses.
• ✓ Serum 1,3-beta-D-glucan level.
• ✓ Evaluation for additional potential infections, depending on exposure history (may include anaplasmosis, babesiosis, PJP, histoplasmosis, parasitic infections, other chronic viral infections). A more complete list of possible infectious triggers is listed above.
• ✓ Antinuclear antibody (ANA).

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approach to the diagnosis of HLH

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diagnostic criteria

• Commonly utilized diagnostic criteria are below. Unfortunately, critically ill patients may not meet these criteria fully until they are moribund. Diagnosis is ultimately a matter of clinical judgement, with careful consideration of the clinical context and competing diagnoses. Different criteria have been designed to identify HLH within the context of known SLE or systemic juvenile idiopathic arthritis. (27292929)
• Sequential evaluation over time may be more important than absolute laboratory values upon admission. (38627860)

HLH-2004 criteria modified for use with critically ill adults

• At least four of the following:*
• [1] Fever >38.2 (32448380)
• [2] Splenomegaly.
• [3] Cytopenia affecting at least two cell lines
  • Hemoglobin <9 g/L.
  • Platelets <100 b/L.
  • Absolute neutrophil count <1000 b/L.
• [4] Hypertriglyceridemia (fasting triglycerides >265 mg/dL or >3 mM) and/or fibrinogen < 150 mg/dL.
• [5] Ferritin >3,000 ug/L. (32448380)
• [6] Hemophagocytosis seen on tissue biopsy of bone marrow, spleen, lymph node, or liver
• [7] Low/absent NK-cell activity
• [8] Soluble CD25 (soluble IL2-receptor) >2400 U/ml

use of the HLH-2004 criteria in critically ill adults

• Among critically ill adults, performance was improved if only four criteria were required. (32448380) Consequently, guidelines recommend that therapy be initiated if four criteria are met (especially if worsening organ dysfunction is present). (34605776)
• Unfortunately, these criteria rely on several tests that are not rapidly available. Consequently, by the time HLH-2004 criteria are officially “positive” the patient may be moribund and beyond the point of optimal intervention. Thus, treatment initiation may need to be considered before traditional diagnostic criteria are met. (28871523, 28631531)

🏆 H-score

• Determining the H-score is the preferred approach. (30075527, 32448380) According to the HiHSAC guidelines, the H-score is the most appropriate scoring system in adult patients. (38258680)
• H-score is easily obtained using an online calculator at MDCalc.
• The single optimal cutoff value for the H-score seems to be 169. (32448380) However, the score may also be used in a continuous fashion to risk-stratify the likelihood of HLH. 🌊

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studies to obtain when investigating for possible HLH 

basic panel

• ✓ Complete blood count.
• ✓ Ferritin.
• ✓ Liver function tests.
• ✓ Fibrinogen.
• ✓ D-dimer level (to evaluate for hyperfibrinolysis).
• ✓ Triglyceride level (fasting).

additional considerations

• ✓ soluble IL-2 receptor (a.k.a. sCD25).
• ✓ INR, PTT, D-dimer.
• ✓ Blood PCR for herpes viruses (especially EBV, CMV, and HSV).
• ✓ Ultrasound of liver & spleen.
• ✓ Lumbar puncture and/or MRI if possible if suspicion of brain involvement.
• ✓ Biopsy of involved sites (especially bone marrow).

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overall approach to treatment

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[1] treatment of the underlying cause

• Perhaps the most essential intervention for these patients is identification and treatment of the underlying cause of the HLH.
• The underlying disease should be aggressively treated if possible. For example:
  • Malignancy: combination chemotherapy may be needed.
  • Infection: appropriate antimicrobial therapy. Rituximab may reduce viral load and improve EBV-associated HLH. (27292929)
  • Rheumatologic disease flare: Management may require pulse-dose steroid or augmented immunosuppressive regimens (more on this below).

[2] immunosuppression

• Dexamethasone:
  • Any patient should get 10 mg/m2 body surface area (~15-20 mg/day) at least.
  • Consider 40 mg/day for patients not receiving other immunosuppressive therapy.
  • Further discussion below: ⚡️
• Secondary HLH: consider 10 mg/m2/day dexamethasone plus one of the following:
  • Anakinra (esp: infection or rheumatologic related). ⚡️
  • Ruxolitinib (esp: malignancy or EBV related). ⚡️
  • Cyclosporine. ⚡️
• Familial HLH: consider moderate-dose dexamethasone plus etoposide. ⚡️

[3] parameters to track response to therapy include:

• Fever curve.
• Ferritin level, C-reactive protein.
• D-dimer and fibrinogen levels.
• Liver function tests.
• Cytopenias (complete blood count). (37486733, 37486733)

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Critical Care Medicine guidelines for HLH in critical illness

There isn't any Level-I evidence on HLH in adult critical care medicine, so it's impossible to make any firm guidelines. Among various guidelines available, these seem to be the most applicable. (34605776) Full text is available here: 📄

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steroid

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steroid is a mainstay of therapy for HLH

• Steroid is the most broadly utilized therapy for HLH. (21366922, 20348529) Most treatment regimens involve some dose of steroid.
• In the absence of definitive evidence, steroid doses vary widely.
• Dexamethasone may have an advantage with regard to superior CNS penetration.

relative contraindications to steroid include:

1. Uncontrolled infection. However, it is often appropriate to combine moderate-dose steroid plus antimicrobial therapy simultaneously.
2. Possible underlying lymphoma. Steroid may suppress the lymphoma, rendering subsequent diagnosis difficult. Ideally, cross-sectional imaging and tissue sampling should be performed prior to the initiation of steroid (potentially using anakinra as a temporizing agent). However, this isn't always possible. (38258680)

moderate dose steroid

• A moderate dose of steroid may consist of dexamethasone 10 mg/m2 body surface area daily (~15-20 mg daily).
• This steroid dose by itself could be adequate for early or impending HLH, but not fulminant HLH.
• For more severe HLH, a moderate-dose steroid may be combined with a second therapy (e.g., anakinra or ruxolitinib). (16937360)

pulse-dose steroid

• This typically refers to IV methylprednisolone (1,000 mg/day for three days) followed by lower doses of steroid (e.g., ~2-3 mg/kg/day). (32387063)
• Potential indications:
  • [1] HLH due to rheumatologic disease (a.k.a. macrophage activation syndrome).
  • [2] Neurologic involvement.
• Advantages include that this is inexpensive and readily available.
• Drawbacks include an increased risk of invasive fungal infection at very high doses of steroid (e.g., Aspergillus).

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IL1 antagonism

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advantages of anakinra

• Several studies in pediatric and adult HLH suggest that anakinra may be safe and effective. (26154908, 24583503, 26584195)
• Anakinra provides immunomodulation without significant immunosuppression and without impairing malignancy workup. (37486733) Anakinra was safe in RCTs involving septic shock even at relatively enormous doses (48 mg/kg/day). (37486733)
• Overall, guidelines tend to recommend anakinra as a second-line agent for HLH following steroid therapy. (37486733, 34605776)

disadvantages of anakinra

• The main disadvantages are in terms of cost and availability.
• High doses of anakinra are required for treatment of HLH (discussed below). Depending on local logistics, this may be difficult to achieve.

use in infection-triggered HLH

• One Phase-III RCT of anakinra in septic shock failed to show benefit. (8196140) However, mortality was improved among subsets of patients with organ failure (figure below). Furthermore, a retrospective re-analysis of the study also found mortality benefit among a subset of patients with features of HLH. (26584195) The dose of anakinra utilized in the study was 100 mg IV bolus followed by 1-2 mg/kg/hour infusion over 72 hours.
• One retrospective study with COVID-19 found that 100 mg s.c. BID was unable to affect inflammatory markers, but 5 mg/kg IV BID might be beneficial. (32470486)

use in HLH due to rheumatologic disease

• Anakinra might to be effective in HLH due to rheumatologic disorders, where it may be used at high doses (e.g., 4-10 mg/kg/day in divided doses). (30992265, 32387063).

pharmacology & dosing of anakinra for HLH

• Anakinra has a half-life of 4-6 hours among patients with normal renal function, but this extends to 8-10 hours in the presence of renal failure (GFR <30 ml/min).
• For outpatient management of stable rheumatologic diseases, a dose of 100 mg s.c. daily is adequate. However, this dose is probably grossly inadequate for patients with HLH.
• For HLH, more frequent dosing (e.g., q12hr or q6hr) and higher doses are likely required (e.g., 5-10 mg/kg/day). (28631531, 36349896, 38627860) Anakinra may be given either subcutaneously or intravenously, but intravenous administration is preferred. (34605776)

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JAK inhibition

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ruxolitinib

• Ruxolitinib is a small molecule inhibitors of Janus kinases (JAK1 and JAK2) – which are involved in numerous cytokine signaling pathways (including signaling from interferon-gamma, IL-6, IL-2, and IL-12). Activity at multiple sites could make this more effective than agents which act on a single cytokine.
• Ruxolitinib is generally used as an outpatient maintenance therapy for myelodysplastic syndrome, but ruxolitinib is being repurposed as an anti-inflammatory agent. For example, it may be used for steroid-refractory graft versus host disease.
• Ruxolitinib overall seems fairly safe (for example, it is used on a chronic basis for fragile outpatients with myelodysplastic syndrome). It may increase the risk of some chronic viral infections (e.g., HBV) and tuberculosis. Ruxolitinib causes a transient impairment in cytokine function, but it could theoretically be rapidly weaned or discontinued if a worsening nosocomial infection were to develop.
• Case series suggest efficacy of ruxolitinib in HLH:
  • An open-label pilot study reported success using 15 mg BID in five patients with secondary HLH. (31537486)
  • Wang et al. utilized ruxolitinib for salvage therapy of 34 patients with refractory or relapsed HLH. Complete remission was achieved in 15% of patients and partial remission in 59%. (31515353)
  • Cases describe the use of ruxolitinib in patients with HLH due to HIV-related EBV and due to histoplasmosis. (32285358, 29417621) This suggests that ruxolitinib might be safe in patients who have an active infection.
• Potential adverse events include: (37486733)
  • Cytopenias.
  • Hepatotoxicity.

baricitinib

• Baricitinib was shown to improve mortality among patients with COVID, a disease that has numerous parallels with virus-induced HLH. This provides strong evidence that baricitinib can be used safely and effectively for the management of critically ill patients.
• Direct evidence regarding the use of baricitinib with non-COVID HLH is minimal. One case reports describes successful use of baricitinib for a patient with HLH secondary to Still's disease who failed to respond to pulse dose steroid, cyclosporin, and etoposide. (36947281) The dose used was the same that has been used for COVID (4 mg/day). 
• Potential adverse events include:
  • Elevation of transaminase levels.
  • Neutropenia.
  • Thrombocytosis.

ruxolitinib vs. baricitinib

• These are both JAK1/JAK2 inhibitors that probably have similar efficacy against HLH.
• In practice, the selection of agent may relate to logistic considerations, such as:
  • Which agent is available?
  • Baricitinib is renally cleared, so dosing can be challenging in severe renal failure.
  • Ruxolitinib is hepatically metabolized by CYP3A4 predominantly and also CYP2C19, so it may have drug-drug interactions.

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calcineurin inhibitors (cyclosporine, tacrolimus)

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basics 💊

• Tacrolimus interrupts T-cell activation and the production of IL-2 (due to effects on calcineurin and MAPK (mitogen-activated protein kinase) pathways. (37126103) 
• Calcineurin inhibitors are not supported by robust evidence in HLH.

advantages of calcineurin inhibitors

• Calcineurin inhibitors may provide multimodal cytokine suppression (potentially avoiding the need for massive steroid doses with the attendant steroid-related side effects).
• Calcineurin inhibitors have rapid onset, as compared to many other immunosuppressive therapies (e.g., mycophenolate, azathioprine).
• Calcineurin inhibitors are widely available (including at centers that lack access to adequate doses of ankinra).

disadvantages of calcineurin inhibitors include

• Risk of kidney injury.
• Potential neurological toxicity, including PRES.
• Narrow therapeutic window requires tight monitoring of levels (which may be logistically challenging at some hospitals, depending on how frequently the laboratory runs cyclosporine levels).

potential indications for calcineurin inhibitors

• [1] Calcineurin inhibitors are primarily utilized in HLH due to underlying rheumatologic diseases (aka, macrophage activation syndrome). (38627860)
• [2] Drug-induced HLH: Cyclosporine appears to be strikingly effective for DRESS syndrome, which has significant overlap with HLH. 📖
• [3] Calcineurin inhibitors may be utilized in HLH refractory to other therapies.
  • Critical Care Medicine 2022 guidelines recommend the addition of either IL-1 inhibition or cyclosporine for patients not responding sufficiently to steroid therapy. (34605776)

cyclosporine dosing

• 2022 EULAR/ACR guidelines recommend 2-7 mg/kg/day divided in two doses.
• Critical Care Medicine 2022 guidelines recommend starting cautiously with 2 mg/kg/day in two divided doses, targeting serum levels of 100-150 ng/ml. (34605776)

tacrolimus

• Some recommendations do indicate that tacrolimus can be substituted for cyclosporine. (30992265) There is little direct evidence regarding tacrolimus, but it's actions are extremely similar to cyclosporine.
• Tacrolimus may be used as an alternative to cyclosporine if necessary due to logistic reasons (e.g., hospital laboratory doesn't allow for close monitoring of cyclosporine levels).
• 2002 EULAR/ACR guidelines recommend a tacrolimus dose of 0.1 mg/kg/day divided q12 hours (i.e., 0.05 mg/kg q12 hours), targeting a trough level of 8-20 ng/ml. (37486733)

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etoposide

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• Traditionally, HLH has been treated with the HLH-2004 protocol involving dexamethasone and etoposide. These therapies were designed for children with congenital HLH due to deficiencies in natural killer cell function.
• Indications for etoposide may include:
  • [1] Etoposide might be most appropriate for patients with familial HLH. (34605776)
  • [2] Severe EBV-related HLH. (37486733)
  • [3] Neurological manifestations: All forms of  HLH may develop severe CNS involvement, for which etoposide is suggested without delay to prevent late neurologic effects. (34605776)
  • [4] HLH that is refractory to other therapies.
• In adults with HLH triggered by a specific disorder, the role of etoposide is unclear. It does seem to work. The question is whether anakinra or ruxolitinib may provide similar efficacy, with less toxicity.
• Potential complications from etoposide include myelosuppression, posterior reversible encephalopathy syndrome (PRES), and delayed development of secondary leukemia.
• Based on the toxicity profile of etoposide, its use requires a greater degree of confidence in the diagnosis of HLH. Alternatively, it may be reasonable to start other therapies (e.g., steroid, anakinra, ruxolitinib) earlier in the disease course when there is a greater degree of diagnostic uncertainty.

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basics – what is HLH?

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what is HLH?

• HLH is a state of pathological immune hyperactivity involving CD8+ T-cells and macrophages as shown above. This involves a number of positive feed-back loops, which can cause inflammation to rapidly spiral out of control.
• There are roughly two factors involved in the development of HLH:
  • (#1) An individual's tendency to develop HLH. Normally, HLH is prevented by feed-back mechanisms which put a brake on inflammation. Rare individuals have various mutations in these mechanisms, creating a tendency to develop HLH.
  • (#2) Inflammatory triggers will tend to push patients into HLH. The more intense and chronic the inflammatory trigger is, the harder it is for the body's immune system to maintain equilibrium. Chronic viral infections, malignancy, or rheumatologic disease seem to be particularly strong triggers of HLH.
• Pediatric HLH is most often due largely to genetic factors which lead to a tendency to develop HLH (#1). In adults, genetic abnormalities tend to be less important, with inflammatory triggers playing a greater role (#2 above). However, it is often difficult to sort this out precisely. Thus, the differentiation between “primary” and “secondary” HLH is falling out of vogue (because many patients who appear to have “secondary” HLH may actually have some underlying genetic mutations if you look carefully enough). (30766533)
• Some immunodeficiency syndromes or immunosuppressive agents may be associated with the development of HLH. The underlying mechanism may be that immunosuppression leads to chronic, persistent infection that then serves as a trigger for HLH.

what is hemophagocytosis?

• Hemophagocytosis is when macrophages eat blood cells (including erythrocytes, leukocytes, or platelets).
• This seems to reflect excessive inflammatory activation of macrophages.
• Hemophagocytosis is a histological hallmark of hemophagocytic lymphohistiocytosis. However, this isn't particularly sensitive (so patients can have HLH without having tissue evidence of hemophagocytosis).

terminology: HLH vs. MAS

• HLH is a broad term which encompasses immune dysregulation due to a wide variety of stimuli.
• Macrophage activation syndrome (MAS) refers to HLH caused by rheumatologic disease. As such, macrophage activation syndrome is one subset of HLH.

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questions & discussion

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To keep this page small and fast, questions & discussion about this post can be found on another page here.

• Failure to consider HLH as a possible differential diagnosis in a patient labeled with “sepsis” who isn't responding to therapy.
• Failure to thoroughly search for underlying triggers of HLH, after the diagnosis of HLH has been made.
• Delaying treatment for HLH until the patient has met formal 2004 criteria for HLH.
• Assumption that a profoundly elevated ferritin proves the diagnosis of HLH.

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