SCCM Resource Library-Hemophagocytic Lymphohistiocytosis

Video Transcription

Hello, and welcome to Expecting the Unexpected, Critical Care Management of Uncommon Immunologic Syndromes.  My name is Brian Deem, and I'm a clinical pharmacy specialist in critical care and nutrition support at the University of Texas MD Anderson Cancer Center in Houston.  My portion of the presentation will cover hemophagocytic lymphohistiocytosis, or as I will refer to it throughout the presentation, HLH. I have no conflicts of interest to disclose.  By the conclusion of my presentation, you will be able to review common causes, identify key diagnostic criteria, and recall important therapeutic options for HLH.  I'll be using a patient case throughout the presentation to help illustrate these concepts. J.S. is a 45-year-old male with a history of peripheral T-cell lymphoma who has received  two cycles of induction chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone.  He presents to the hospital with altered mental status, respiratory distress, fever, and hypotension,  eventually requiring ICU admission for septic shock and respiratory failure requiring intubation and mechanical ventilation.  Despite empiric broad-spectrum antimicrobial therapy, aggressive fluid resuscitation, and vasopressor therapy, he continues to decline.  The ICU team is growing concerned given his unrelenting fever, pancytopenia, splenomegaly noted on a CT scan of his abdomen and pelvis, grossly elevated ferritin level, and evolving  multi-organ dysfunction syndrome. So you might be asking yourself, what's going on here?  We're doing everything right to turn the situation around, but the patient is clearly getting worse despite our efforts.  Which brings me to the rare, life-threatening, and often under-recognized immunologic syndrome of HLH.  HLH's pathophysiology is derived from a myriad of acquired and or inherited factors, but converges upon a common pathway leading to hyperactivation of T lymphocytes and macrophages.  This dysregulation leads to hypersecretion of cytokines and a massive pro-inflammatory  cascade that can result in multi-organ dysfunction syndrome if left unrecognized and untreated. HLH can be divided into two main categories, primary and secondary.  Primary or familial HLH is an autosomal recessive genetic disease. Mutation in genes responsible for cytotoxic function and regulation of natural killer  cells and T lymphocytes lead to the hyperactivation of macrophages, causing hypersecretion of cytokines and a resultant pro-inflammatory cytokine storm.  Primary HLH typically develops in the first two years of life and is rarely seen in adults.  In contrast, secondary HLH is an acquired disease and can be caused by a number of factors.  The most well-documented are malignancy, infection, particularly viral infections, autoimmune disorders, and organ transplantation.  Secondary HLH is more classically seen in critically ill patients, so the focus of the  remainder of my presentation will be on the etiology, diagnosis, and treatment of secondary HLH.  Starting with the etiology of secondary HLH, it's based on the presence of an underlying disease or predisposing condition as well as a trigger or second hit that leads to the  development of HLH. The underlying disease and the trigger may also be one and the same, which contributes to the difficulty in definitively diagnosing HLH.  This table includes some of the underlying diseases and triggers most often implicated in the development of secondary HLH.  Common underlying diseases and conditions include malignancies, lupus, and other autoimmune disorders, diabetes, hemodialysis, and pregnancy.  Common triggers include viral infections such as herpes simplex, varicella, influenza, and HIV, as well as rickettsia infections.  The third column includes conditions that have been associated as both an underlying disease and trigger for secondary HLH.  These include high-grade lymphomas such as T and natural killer cell lymphomas, viral  infections such as Epstein-Barr and cytomegalovirus, as well as tuberculosis, fungal, and parasitic infections.  Although not included in this chart, HLH has also been seen in the context of COVID-19 infections, as well as with immune effector cell treatments such as chimeric antigen receptor  or CAR T cell therapy. As a reminder, the patient in our case, JS, has T cell lymphoma, which is one of the most  common malignancy-associated underlying diseases and triggers for secondary HLH. Let's return to the patient case.  Included on this slide are some of JS's laboratory and imaging results. He has pancytopenia, acute kidney injury, elevated liver function tests, and elevated  triglyceride and ferritin levels. He also has a positive cytomegalovirus blood titer. He continues to have fevers with a maximum temperature of 38.9 degrees Celsius.  And as previously mentioned, a CT scan of his abdomen and pelvis is positive for splenomegaly.  Given the suspicion of HLH based on his oncology diagnosis and active cytomegalovirus infection, a bone marrow biopsy is obtained, and those results are currently pending.  So the million-dollar question is, does JS have HLH, and can we definitively diagnose it?  Let's spend a few minutes reviewing the diagnostic criteria for HLH and discuss some of the challenges with diagnosing it.  The historic approach to diagnosis is based on the HLH 2004 criteria, which includes the eight criteria listed on the slide.  In order for a patient to be diagnosed with HLH, they must meet five of the eight criteria,  including fever greater than 38.5 degrees Celsius, splenomegaly, which occurs from infiltration  of lymphocytes into the spleen, cytopenia in two of three cell lines, hypertriglyceridemia,  which occurs from cytokine-driven lipoprotein lipase suppression, and or hypofibrinogenemia,  which occurs from plasminogen activator production for macrophages, evidence of hemophagocytosis  on bone marrow aspiration, an elevated ferritin level, which occurs from macrophage activation,  reduced or absent natural killer cell cytotoxicity, and elevated soluble CD25 or interleukin-2 receptor, which is released from activated T cells.  The final two diagnostic criteria can be difficult to obtain in a timely manner, depending on the capabilities of your institution's laboratory.  For example, at my institution, both of those tests are send-outs and take several days to be reported.  Another important limitation of the HLH 2004 criteria is that it was largely based on data derived from pediatric patients with primary HLH, so its applicability to adult critically  ill patients with secondary HLH is not well understood. Returning to the patient case, JS currently meets five criteria for HLH, fever with maximum  temperature of 38.9 degrees Celsius, splenomegaly on imaging, pancytopenia, elevated triglycerides  of 350 milligrams per deciliter, and elevated ferritin of 2,800 micrograms per liter. His bone marrow biopsy is currently pending, which is another challenge of definitively  diagnosing HLH. It typically takes several days for a bone marrow pathology to be reported, making the initial diagnosis of HLH more clinically and laboratory-driven.  Another method for diagnosing HLH, which may be more helpful in adult critically ill patients,  is the H-score, which assigns a weighted severity score to several of the HLH 2004 criteria. It also accounts for the presence or absence of underlying immunosuppression, which is  defined as HIV-positive or receipt of long-term immunosuppressive medications, such as glucocorticoids or cyclosporine.  A recent publication in Critical Care in 2020 found that the H-score has a sensitivity of 100% and a specificity of 94%, using a score cutoff of 168 in adult patients admitted to  the ICU. Specifically for JS, his H-score would be calculated as follows. 18 points for underlying immunosuppression due to his peripheral T-cell lymphoma being  treated with chemotherapy, 33 points for a maximum temperature of 38.9 degrees Celsius, 23 points for isolated splenomegaly, 34 points for pancytopenia, 35 points for a ferritin  of 2,800 micrograms per liter, 44 points for triglyceride of 350 milligrams per deciliter,  0 points for fibrinogen of 267 milligrams per deciliter, 19 points for AST of 313 units per liter,  and 0 points for hemophagocytosis on a bone marrow aspiration, since the result is currently pending.  If you do not have a calculator handy or are not proficient at fast-paced mental addition like me, the total comes out to 206.  The probability of HLH is further delineated based on H-score ranges, and a score of 206 correlates to an 88 to 93% probability of having HLH.  The $10 million question is, should JS receive HLH-directed therapy? For the final portion of the presentation, I will cover some treatment options for HLH  and discuss clinical applicability to a critically ill patient similar to JS.  The general treatment algorithm for HLH involves several key components, with modality selection based on severity of disease.  Patients with no evidence of organ dysfunction outside of hematologic and coagulation system abnormalities are considered to have mild HLH.  Identifying and correcting the underlying cause and providing best supportive care may suffice for these patients, and targeted therapy for HLH may not be necessary.  Patients with evidence of organ dysfunction, for example, SOFA score of 2 or less, are considered to have moderate HLH.  The addition of high-dose corticosteroid therapy is often required for these patients.  Severe HLH is defined by higher SOFA scores and or the need for therapies to manage organ  dysfunction, such as mechanical ventilation, hemodialysis, vasopressor therapy, and extracorporeal membrane oxygenation.  For patients with severe or refractory HLH, treatment with etoposide and adjunctive or salvage therapies may be required.  I will briefly cover each of these treatments over the next few slides.  Supportive care principles include best practices for critically ill adult patients, including broad-spectrum empiric antimicrobial therapy, with particular focus on the potential  for viral infections as a cause and or trigger for HLH, aggressive fluid resuscitation, blood product replacement, and vasopressor therapy if necessary, correction of any underlying  coagulopathies, positive pressure noninvasive or invasive mechanical ventilation for patients with respiratory distress or failure, and support of end-organ dysfunction with renal  replacement therapy, extracorporeal membrane oxygenation, and other modalities as necessary or available.  Many critically ill patients with secondary HLH will have signs or symptoms of end-organ dysfunction, meaning they will have moderate to severe disease.  In these patients, high-dose corticosteroid therapy is often employed in an attempt to reduce the cytokine storm and resulting inflammation.  Commonly used regimens and doses include methylprednisolone, 2 milligrams per kilogram per day, or dexamethasone, 10 milligrams per meter squared per day, divided every 12 hours.  A common theme over the next few slides will be the lack of randomized comparative trials between agents to help guide HLH-directed therapy.  Conversely, the level of evidence for many of these therapies, including corticosteroids, is largely based on expert opinion, as well as case reports, case series, and extrapolation  from clinical literature of primary HLH.  This lack of high-level data remains one of the main challenges with managing HLH.  Etoposide is another option for the treatment of severe HLH, particularly when it's malignancy driven.  Etoposide is a topoisomerase II inhibitor, which specifically depletes activated T lymphocytes, which is why it is particularly helpful in HLH.  It is dosed between 50 to 100 milligrams per meter squared once weekly, with the elderly and those with renal and or hepatic dysfunction requiring more conservative dosing.  As many critical care practitioners may be unfamiliar with etoposide, some key adverse effects include myelosuppression, as well as the development of secondary malignancies,  such as acute leukemia with prolonged use.  Evidence for etoposide use in HLH is based on low-level evidence, similar to that previously mentioned with corticosteroid therapy.  There are a number of adjunctive and salvage therapies available, a few of which I've highlighted on this slide.  Again, all of these therapies are largely used on the basis of low-level evidence and expert opinion.  Intravenous immunoglobulin, or IVIG, provides passive immunity by increased IgG levels, which can be low in HLH patients.  IVIG is potentially helpful in secondary HLH due to infectious and or malignant etiologies.  Anakinra is an interleukin-1 receptor antagonist, while tocilizumab is a monoclonal antibody, against the interleukin-6 receptor.  Both therapies aim to suppress the cytokine storm associated with HLH, and likely sound familiar, as their use has also been applied to the management of the hyperinflammatory  state seen in severe COVID-19 infections.  L-mtuzumab is a monoclonal antibody against CD52, which is expressed on B and T lymphocytes, macrophages, and natural killer cells.  The place in therapy for all three agents tends to be in secondary HLH that is refractory to conventional therapies.  This certainly is not meant to be an exhaustive list of adjunctive or salvage therapies, as there are several others mentioned in the HLH guidelines published in Critical Care  Medicine in 2021, which I encourage you to take a look at.  The final few slides cover a really interesting systematic review on the treatment and mortality  of HLH in adult critically ill patients that was published in Critical Care Medicine in 2020 by Knack and colleagues.  They reported and analyzed 661 HLH cases in adult patients admitted to the ICU from 65 studies and case series, excluding single patient case reports to avoid bias.  Excluding single patient case reports to avoid bias in reporting only surviving patients.  This pie chart summarizes the reported HLH trigger, with 50% of cases being due to infection, 28% due to malignancy, and 12% due to autoimmune disorders.  Interestingly, approximately 10% of HLH cases had an unknown trigger. The table on this slide reviews some of the most common treatments utilized, either alone or in combination.  I've included the top five treatments here for brevity, but a total of 17 types of treatment were reported.  Corticosteroids were used in two-thirds of patients, etoposide in over half of patients, with lower percentages of patients receiving IVIG, cyclosporine, and cyclophosphamide.  Overall mortality was high at 57.8%.  Multivariable logistic regression analysis was performed, and IVIG was associated with a statistically significant decrease in overall mortality, with an odds ratio of 0.55.  On the other hand, cyclosporine was associated with a statistically significant increase in overall mortality, with an odds ratio of 7.6.  The authors point out that patients who received IVIG likely had an excellent prognosis, as  their HLH was presumably due to a reversible underlying trigger, such as a viral infection.  Conversely, cyclosporine was always utilized as part of a combination regimen, presumably in patients with more severe disease and a poor overall prognosis.  It's a very interesting study, nonetheless, one I encourage you to also read.  Let's close out the patient case. Because of high suspicion of HLH, JS is initiated on HLH-directed therapy while awaiting the results of his bone marrow aspiration.  He is started on dexamethasone, 10 mg IV, every 12 hours, and etoposide, 150 mg IV, once weekly.  Additionally, he is initiated on induction dose ganciclovir for treatment of CMV.  The diagnosis of HLH is eventually confirmed by hemophagocytosis noted on his bone marrow aspiration.  After initiation of HLH-directed therapy and ganciclovir, his fevers resolve, and his ferritin levels begin to decrease.  His clinical course gradually improves, vasopressors are weaned to off, he is extubated, and discharged to the regular medical floor.  In conclusion, HLH is an under-recognized, life-threatening syndrome caused by the over-activation of T lymphocytes and macrophages, resulting in a cytokine storm.  Establishing the diagnosis of HLH is difficult because of a wide differential. Treatment relies upon swift identification and correction of underlying causes and or triggers.  Finally, cornerstones of therapy include modulating the immune response with high-dose corticosteroids etoposide, and adjunctive therapies in severe and refractory disease.  Citations are listed on the slide for your reference.  Thanks for viewing my presentation. I hope you found it helpful. Please feel free to email me with any questions, and I look forward to interacting with you  during the live Q&A session at the Virtual Critical Care Congress.

Video Summary

Hemophagocytic lymphohistiocytosis (HLH) is a rare and life-threatening immunologic syndrome characterized by the over-activation of T lymphocytes and macrophages, leading to a cytokine storm. HLH can be divided into primary (genetic) and secondary (acquired) forms. Secondary HLH is more common in critically ill adults and can be caused by factors such as malignancy, infection, autoimmune disorders, and organ transplantation. The diagnosis of HLH can be challenging and is based on a set of diagnostic criteria, including fever, splenomegaly, cytopenia, hypertriglyceridemia, and hemophagocytosis, among others. Treatment options for HLH depend on the severity of the disease and may include supportive care, high-dose corticosteroids, etoposide, and adjunctive therapies such as intravenous immunoglobulin, anakinra, tocilizumab, and L-mtuzumab. Mortality rates for HLH are high, but treatment with intravenous immunoglobulin has been associated with a decrease in overall mortality. Prompt identification and intervention are crucial for improving outcomes in patients with HLH.

Asset Subtitle

Immunology, 2022

Asset Caption

Primary immunologic disorders are infrequent but devastating causes of morbidity and mortality in the ICU. The rapidity with which these conditions can progress requires equally swift recognition and intervention. These rare conditions can go unrecognized, leading to increased harm to patients. This session's expert panel will discuss key features of three uncommon but important immunologic disorders for the critical care clinician, with a goal of ensuring quick initiation of needed therapy.

Meta Tag

Content Type Presentation

Knowledge Area Immunology

Knowledge Level Intermediate

Knowledge Level Advanced

Membership Level Select

Tag Autoimmune Diseases

Year 2022

Keywords

Hemophagocytic lymphohistiocytosis

T lymphocytes

macrophages

cytokine storm

secondary HLH

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