Hemophagocytic lymphohistiocytosis (HLH): a narrative review of the pathogenesis, clinical presentation, diagnosis, treatment, and prognosis

Introduction

Background

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disease characterized by excessive, dysregulated activation of the immune system (1). Clinically, the disease often presents with a variety of symptoms including fever, hepatosplenomegaly, and cytopenias (2). HLH is often conceptualized as primary and secondary forms, with primary HLH referring to patients with genetic defects in the molecular pathways involved in the immunologic synapse or the genes that play a role in the clearance of Epstein-Barr virus (EBV), and secondary HLH referring to a hyperinflammatory response most often due to an external trigger without known genetic predisposition (3). Patients with HLH are often critically ill due to multi-organ dysfunction, and diagnosing the disease remains a challenge. This clinical entity remains difficult to diagnose, as it can overlap with several states of increased inflammation.

Here, we present a concise, targeted review of the pathogenesis, clinical presentation, diagnosis, treatment, and prognosis of HLH.

Rationale and knowledge gap

HLH is associated with a high mortality rate, therefore recognizing the disease early is crucial. There are no absolute diagnostic criteria for HLH, therefore it is imperative that clinicians recognize certain clinical markers and presentations that are consistent with this diagnosis. This diagnostic uncertainty is a common gap in the medical knowledge of clinical providers, therefore in this review we attempt to distill information about HLH in a way that will equip clinicians with the ability to differentiate HLH from other states of increased inflammation in the setting of multiorgan dysfunction. The literature on HLH continues to evolve, with an increased scientific understanding of the disease and how subsets of patients respond to certain treatments. Therefore, this narrative review attempts to uniquely provide readers with contemporary, pragmatic information about HLH in order to aid clinicians with timely diagnosis and treatment.

Objectives

In this narrative review, we aim to address the following questions that are relevant to recognizing and managing HLH:

• What is the underlying mechanism of development of HLH, and what are the most common genetic defects found in this condition?
• What are some diagnostic clues that can be helpful in recognizing HLH?
• What are some clinical tools that can aid in prognosticating patients with HLH?
• What are the most up-to-date guidelines for the treatment of HLH, and how do these treatment options differ based on the underlying cause of HLH?
• What is the general prognosis and follow-up for patients with HLH?

We present this article in accordance with the Narrative Review reporting checklist (available at https://aob.amegroups.com/article/view/10.21037/aob-25-3/rc).

Methods

We conducted a comprehensive search to find relevant literature on HLH in the PubMed and Embase via the Wolters Kluwer Ovid interface, dating from 1983 to 2025. A medical librarian developed and deployed the search strategy, in consultation with the research team. The search strategy was written using syntax, controlled vocabulary, and search fields. Emtree and MeSH thesauri terms and text words were employed for search concepts related to HLH, pathogenesis, immunogenesis, presentation, diagnosis, and treatment (Table 1).

Discussion

Pathogenesis of HLH: primary and secondary

Primary hemophagocytic lymphohistiocytosis (pHLH)

HLH can be divided conceptually into primary and secondary forms. pHLH, also known as familial HLH, occurs when there are germline genetic defects in the molecular pathways involved in the immunologic synapse (4). These genes can also be involved in clearance of EBV (3). The immune effector cells subsequently have impaired cellular cytotoxicity function, leading to dysregulated macrophage activity and increased inflammatory cytokines (5).

Under physiologic conditions, cytotoxic T cells and natural killer (NK) cells will form an immunologic synapse and then release granules containing granzymes and perforins into a target cell that contains the antigen (e.g., viral infection or malignancy). This response leads to apoptosis of the cells, abrogating further immunogenic stimuli and responses (Figure 1). In cases of pHLH, unsuccessful formation of the immune synapse and thus lack of apoptosis leads to chronic activation of effector cells and abnormal upregulation of immune activity. There can be downregulation of CD-47 on hematopoietic cells, promoting phagocytosis. Calreticulin (calregulin) can be upregulated, also promoting the phagocytosis of mature blood cells (4).

Figure 1 Immunologic synapse and selected proteins involved in effector cell functions. Created with Biorender.com. FHL, familial hemophagocytic lymphohistiocytosis.

pHLH predominantly affects the pediatric population but can manifest in adulthood as well. Familial HLH can be in the setting of genetic defects such as those in genes PRF1, MUNC13-4, STX1, STXBP2, as well as other genes that are currently unknown (4,6) (Table 2). It can also be seen in immune deficiency syndromes such as Chediak-Higashi syndrome, Griscelli syndrome, and X-linked lymphoproliferative syndrome (7).

Secondary hemophagocytic lymphohistiocytosis (sHLH)

sHLH, also known as acquired HLH, is more common than pHLH, occurring in both pediatric and adult patients (8). In sHLH, patients can have escalating CD8⁺ T-cell responses against infections, malignancy, autoimmune disease, and other inflammatory states (3). These stimuli to the immune system lead to uncontrolled inflammation and macrophage activation, which can result in the engulfment of normal hematopoietic cells in the bone marrow, liver, and spleen (5). Macrophage activating syndrome (MAS) is a term used for HLH driven by a rheumatologic or autoimmune disorder, including systemic lupus erythematosus and systemic onset juvenile idiopathic arthritis (5,9). There have also been cases of sHLH reported in the setting of vaccination (10). Currently, approximately 36% of sHLH cases are found to be idiopathic, with no specific underlying trigger identified (11). While severe cases of COVID-19 infection can present similar to HLH, it often fails to meet all of the clinical HLH criteria (12).

Infectious triggers

EBV is one of the most recognized infectious triggers of HLH and is often in the context of EBV reactivation during periods of immunocompromise. Less commonly, HLH can be triggered by bacterial, parasitic, and fungal infections. Intracellular pathogens such as Mycobacterium tuberculosis, Pneumocystis jirovecii, and Plasmodium have been reported in the literature as triggers of HLH; the intracellular nature of these organisms supports the pathogenic mechanism of HLH wherein the inability to clear intracellular infections leads to continued antigenic stimulation of T cells (13). Following the COVID-19 pandemic, sHLH was observed in the setting of hyperinflammation and cytokine storm induced by a common viral agent (11).

Malignancy

Studies have reported sHLH in approximately 1% of hematological disorders, with large B-cell and T-cell lymphomas reported to have the highest incidence. There are some solid cancers that have been found to be associated with HLH, including renal cell, colorectal, hepatocellular, and lung cancer (3). sHLH can occur in the setting of malignancy presentation, relapse, or following treatment with either chemotherapy and/or cellular therapies including hematopoietic cell transplantation (11).

Autoimmune

MAS is a term used for HLH driven by a rheumatologic or autoimmune disorder. It can be associated with adult-onset Still’s disease, systemic lupus erythematosus, systemic vasculitis, Sjögren syndrome, and systemic sclerosis (14). Infections are frequently identified as a contributory trigger to the onset of MAS, but it can also be seen with immunosuppression used to treat rheumatologic disorders (11).

Additional triggers of HLH

Other triggers of HLH have been reported, including drug-induced HLH. Chemotherapy agents such as fludarabine and cyclophosphamide, as well as immunotherapy agents such as pembrolizumab and nivolumab, have been implicated in drug-induced HLH. HLH can also be seen post-transplant (both solid organ and hematopoietic cell), treatment with cellular therapies such as chimeric antigen receptor T cells (CAR-T), and in the setting of pregnancy (3). HLH-like symptoms following CAR-T cell therapy are often referred to as immune effector cell-associated HLH-like syndrome (IEC-HS), a distinct yet related entity from cytokine release syndrome (CRS) (15).

Clinical presentation

There is a myriad of symptoms that can be present at the time of HLH onset. Fever is the most common symptom, present in close to 100% cases of HLH. Other presenting symptoms include organomegaly (e.g., lymphadenopathy, hepatomegaly, splenomegaly), liver dysfunction, coagulopathy, and skin changes (2). Hepatomegaly is observed in approximately 95% of children but is seen in less frequently in adults, with reports ranging from 18–67%. Splenomegaly is observed in approximately 50–83% of adults. The median age of presentation of children is 8 months, whereas adults typically present with a median age of 49 years (1). Laboratory investigations usually demonstrate bi/tricytopenia, hypertriglyceridemia, hypofibrinogenemia, hyperferritinemia, elevated soluble CD25 (IL-2r) levels, abnormal liver tests, and/or hemophagocytosis in the bone marrow or elsewhere (2).

CNS involvement can be the first site of clinical presentation in HLH, and between 10 and 70% of adults with HLH have been cited to have neurological involvement. Clinically, this can present as seizures, ataxia, cranial nerve palsies, and/or encephalitis (16). Performing a lumbar puncture and measuring neopterin levels when suspecting CNS HLH should be pursued, as it can help delineate CNS involvement in the setting of HLH from similarly presenting conditions such as demyelinating syndromes, infections, malignancy, and CNS vasculitis (17). Neopterin can be elevated in the cerebrospinal fluid in those with HLH (18).

Diagnosis

HLH remains a difficult entity to accurately diagnose given its overlap with other systemic disorders such as sepsis, multiple organ dysfunction syndrome, and other syndromes associated with elevated cytokines.

The HLH-2004 criteria were initially created to include patients with suspected pHLH in clinical trials (HLH-94 criteria) but are often extrapolated to the adult population to help diagnose sHLH (19). In the HLH-2004 trial, five of the eight following criteria had to be met to diagnose a patient with HLH: (I) fever (>38.5 ℃), (II) splenomegaly (more than 2 cm below the costal margin), (III) bicytopenia (hemoglobin <90 g/L, platelets <100×10⁹/L, neutrophils <1.0×10⁹/L), (IV) hypertriglyceridemia or hypofibrinogenemia (fasting triglycerides >3.0 mmol/L; fibrinogen <1.5 g/L), (V) hemophagocytosis, (VI) hyperferritinemia (ferritin >500 micrograms/L), (VII) low/absent NK-cell activity, and 8) elevated soluble CD25 (IL-2r) levels (>2,400 U/mL). In the revised HLH-2004 criteria, also known as the HLH-2024 diagnostic criteria, the Histiocyte Society has suggested utilizing genetic and lymphocyte cytotoxicity assays as two distinct diagnostic strategies, in addition to five of the seven original (NK-cell activity omitted) clinical criteria in the HLH-2004 trial (20). It is important to note that the HLH-2004 criteria have never been fully validated in adults and serve as a guide and prediction tool rather than a complete, validated diagnostic tool (21).

The HScore is used as a risk stratification model that generates a probability for the presence of sHLH. The HScore was published in 2014 by Fardet et al. (22) and utilizes nine criteria to predict the probability of a patient having HLH. The nine criteria included are (I) known underlying immunosuppression, (II) elevated temperature, (III) organomegaly (spleen and/or liver), (IV) number of cytopenias (1, 2, or 3 cell lines), (V) ferritin level, (VI) triglyceride levels, (VII) fibrinogen levels, (VIII) aspartate aminotransferase (AST) level, and (IX) hemophagocytosis present in bone marrow aspirate. The scoring system ranges from 0 to 337, with a higher score corresponding to an increased probability of HLH (1,19). The HScore has been compared to the HLH-2004 criteria and was found to be more sensitive and specific than the HLH-2004 criteria on initial presentation of the patient but has similar diagnostic accuracy as the patient becomes more critically ill (1).

In patients with HLH in the setting of hematological malignancies, Zoref-Lorenz et al. have suggested the utilization of the optimized HLH inflammatory (OHI) index, which takes into account combined elevations of ferritin and soluble CD25 to help predict HLH and mortality in the setting of hematological malignancies (23).

There are several shortcomings of the HLH-2004 diagnostic criteria, despite the widespread use. For instance, although fever is a common manifestation of HLH, it can also be a manifestation of many inflammatory conditions making it non-specific. Similarly, cytopenias are common in profound states of inflammation; many patients who are hospitalized in the intensive care unit will have a cytopenia in one or more cell lines. Hypofibrinogenemia and hypertriglyceridemia are grouped in the HLH-2004 criteria, and again, elevation is non-specific (19).

Some institutions routinely check ferritin levels in critically ill patients, given that the degree of serum ferritin elevation does not increase in other diseases to the same extent as HLH (24). When the ferritin level is extremely elevated, the sample may require dilution for diagnostic accuracy (21). While ferritin elevation >500 ng/mL as proposed by the HLH-2004 criteria is sensitive for HLH, it lacks specificity. Ferritin elevation can also be seen in sepsis, malignancy, rheumatologic disease, liver injury, and kidney failure (19).

Hemophagocytosis is not necessary for the diagnosis of HLH as it is observed in the bone marrow in only 25% of patients with HLH (25). It can also be seen in the bone marrow of patients with hematological diseases and sepsis without clinical HLH (16). Even in cases of sHLH, there are possible genetic polymorphisms that predispose patients and make them more susceptible to uncontrolled immune system activation (26).

When HLH is suspected clinically, a broad work up for multiple differential diagnoses is typically obtained. Common components of the diagnostic work up include a complete blood count, triglycerides, a bone marrow biopsy, abdominal imaging to assess liver and spleen size, liver chemistry, soluble CD25 (IL-2r), lactate dehydrogenase (LDH), C-reactive protein (CRP), and limited coagulation studies. For suspected cases of sHLH, additional work up is primarily directed at elucidating the underlying etiology (e.g., autoimmune etiologies, infections, etc.). For suspected cases of pHLH, additional genetic testing is obtained to assess for pathogenic genetic variants such as PRF1, UNC13D, STXBP2, STX11, and RAB27A. Unfortunately, this genetic testing is only performed by a small number of laboratories and may have long turnaround times that should not delay care (21).

The identification of pathogenic mutations in primary HLH can take weeks to months to result, therefore some screening tests can be performed; including chromium release natural killer cytotoxicity test (NK-cell function test), flow cytometry testing of cytotoxic lymphocyte perforin expression, and evaluation of NK-cell degranulation utilizing flow cytometric measurement of CD107a upregulation. Compared to the perforin and CD107a expression, the NK function test has been found to be less sensitive and no more specific (27). Other tests that have been implicated in diagnosis of HLH include HLA-DR expression, a marker of T cell activation. A study that looked at utilization HLA-DR expression in CD8⁺ T cells reported positivity in HLH patients that ranged from 21% to 64%, with higher values in pHLH. Additionally, the chemokine CXCL9 can be used to monitor IFN-γ activity in HLH in the setting of rheumatologic conditions, with 83% sensitivity and 94% specificity (28).

Distinguishing HLH from isolated sepsis can be challenging, but there may be clues on presentation that favor HLH. For instance, hepatosplenomegaly is more often seen in HLH, but not usually in sepsis. Additionally, patients with HLH tend to have more significant cytopenias requiring frequent transfusions and are usually persistently febrile despite being on antibiotics intended for sepsis treatment. Hypofibrinogemia is often associated with HLH, although sepsis complicated by disseminated intravascular coagulation (DIC) can also have low fibrinogen levels. A leukocytosis is not very typical of HLH, unless in the setting of rheumatologic associated HLH (29). HLH also tends to have higher ferritin levels, but lower CRP and procalcitonin levels when compared to sepsis without HLH (30).

Soluble CD25 (IL-2r) levels have been shown to correspond to disease activity, as well as to clinical response to therapy. Interleukin-2 (IL-2) was the first human interleukin to be characterized, and has three subunits (α, β, and γ). The α subunit is expressed after cellular activation, and activation of the IL-2 receptor serves as a surrogate marker for T cell activation. Some data also suggest that higher baseline soluble IL-2r levels are correlated to worse clinical outcome and higher mortality. Other cytokines commonly elevated in HLH include IL-6, interferon-γ, IL-1β, and TNF-α. These cytokines can also be elevated in other conditions, and more work is needed to address the sensitivity of these markers and their relative changes when diagnosing HLH (31).

Genetic testing remains the mainstay method of diagnosing pHLH. Next generation sequencing is an accurate method of identifying point mutations, small deletions, and insertions in genes that have been implicated in pHLH. Whole exome sequencing allows for a comprehensive genetic investigation given its ability to sequence all protein-coding genes in the genome, possibly identifying previously unknown genes that predispose to HLH (28).

Treatment

Prompt recognition and timely treatment initiation of HLH is critical. Untreated pHLH is almost always fatal within weeks, while sHLH without treatment has a 50–75% mortality rate (32,33).

The approach to HLH treatment varies depending on whether pHLH or sHLH is suspected (Figure 2). In clinically stable patients with an identifiable trigger, treating the underlying condition may be sufficient for HLH resolution (e.g., antimicrobials for infection, chemotherapy for malignancy) (34,35). In contrast, all patients with pHLH, severe HLH, idiopathic HLH, relapsing HLH, or HLH that do not respond to disease-targeted therapy should be treated with more aggressive immunosuppressive therapies targeted at blunting the immune response (e.g., HLH-94 or modified HLH-94 protocol) (33-35). The goal of HLH treatment is to abrogate the secretion of inflammatory cytokines and resulting systemic, dysregulated immune activation (17). Below, we outline several treatment approaches for HLH, including emerging therapies.

Figure 2 Overview of treatment considerations for hemophagocytic lymphohistiocytosis. Created with Biorender.com. EBV, Epstein-Barr virus; HLH, hemophagocytic lymphohistiocytosis; HSCT, hematopoietic stem cell transplant; IVIG, intravenous immunoglobulin; L-DEP, PEG-asparaginase, liposomal doxorubicin, etoposide and high-dose methylprednisolone; MAS, macrophage activating syndrome.

The treatment of HLH can be broadly conceptualized as containing three main components: dampening the excessive inflammation, identifying and treating the triggering factor if applicable, and considering the need for allogeneic hematopoietic stem cell transplantation (HSCT) (36).

In order to abrogate the dysregulated hyperinflammation, the most established protocols containing cytotoxic chemotherapy are the HLH-94 protocol and subsequent HLH-2004 protocols (36). The original HLH-94 protocol for HLH treatment includes an initial eight week course of etoposide (150 mg/m² for adults, and 5 mg/kg for children <10 kg, twice weekly for the first two weeks, then weekly until week eight, with dose adjustments for liver or renal dysfunction), dexamethasone (starting at 10 mg/m²/day for two weeks, then tapered), intrathecal methotrexate in cases of CNS involvement, and cyclosporine (dose-adjusted to reach therapeutic levels) (33,36). Some advocate for the use of tacrolimus instead of cyclosporine due to lower nephrotoxicity (1). The primary mechanism of action for etoposide is to inhibit topoisomerase II, and its role in treating HLH is in part due to depleting activated T cells and therefore decreasing further cytokine production (17).

In the HLH-2004 trial, adding cyclosporine did not help with controlling acute inflammation. A notable adverse effect of regimens containing etoposide is bone marrow suppression, placing patients at higher risk of invasive infections (17).

HSCT is usually pursued as a potentially curative approach in those who achieve remission following chemotherapy, although complete remission is not an absolute requirement (17,20). The HLH-94 protocol and consideration of HSCT continue to remain as treatment options, especially for those patients with pHLH (20).

Secondary HLH treatment

The treatment of sHLH in the setting of an identified trigger usually attempts to address the underlying driving etiology, and there are several emerging targeted therapies.

Management of HLH in the setting of infection

The approach to treating HLH in the setting of infection is largely dependent on the infectious trigger. Though most infectious causes of HLH are not managed with an etoposide-based regimen, patients with EBV-HLH can be treated with an etoposide and glucocorticoid containing approach. B-cell depletion with rituximab has also been shown to be of benefit in EBV-HLH, reducing viral load and ferritin levels (37,38). Refractory HLH driven by EBV may also be treated with PEG-asparaginase combined with liposomal doxorubicin, etoposide, and methylprednisolone (L-DEP regimen) as a bridge to HSCT (39). In the setting of intracellular infections such as tuberculosis, targeting the specific infection is typically most effective (20).

Management of malignancy-associated HLH

In the case of HLH due to malignancy that requires urgent intervention, treatment with etoposide, glucocorticoids, and/or possibly IVIG can be considered initially. Ultimately, the underlying malignancy should be treated with the appropriate therapy (17,20,40). Lymphoma represents the most common malignant trigger of HLH, and patients typically carry the poorest prognosis. In the cases of certain malignancies such as lymphoma, patients can then be bridged to autologous or allogenic SCT (41).

Management of HLH secondary to rheumatological disease (MAS)

Although etoposide-based regimens (e.g., HLH-94 protocol) are the mainstay of treatment in many patients with HLH, they have not been shown to be as effective in patients with MAS (42,43). Patients with MAS predominantly benefit from disease-specific treatment in combination with glucocorticoids and/or other adjunctive therapies (34,44,45). For instance, those with MAS in the setting of adult-onset Still’s disease (AOSD) and often characterized by elevated IL-18 levels may ultimately benefit from disease control with canakinumab (anti-IL1beta). In those with severe disease, Janus kinase (JAK) inhibitors, IL-1 inhibitors (e.g., anakinra), IL-6 inhibitors, and emapalumab (anti-IFN-γ) can also be considered (20).

Management of IEC-HS secondary to CAR-T cell therapy

Treatment of CRS (cytokine release syndrome) secondary to CAR-T cell therapy includes corticosteroids and IL-6 antagonism (e.g., tocilizumab) as per American Society of Clinical Oncology (ASCO) guidelines (34,46). This strategy targets IL-6, a key mediator in the inflammatory cascade of CAR-T associated CRS, to control the exaggerated immune response. In contrast, IEC-HS (immune effector cell-associated HLH-like syndrome) is typically treated in the first line setting with anakinra (anti-IL1R) +/− corticosteroids. With increasing disease severity, IEC-HS may warrant increased doses of anakinra, ruxolitinib (JAK inhibitor), low dose etoposide, and/or emapalumab (15,31,43).

Other targeted therapies for HLH

There have been many other targeted drugs proposed in the treatment of HLH. Antibodies against IFN-γ such as emapalumab may play a role in treating both pHLH and sHLH, though it is currently only approved for pHLH (17). The initial phase II/III trial in pediatric patients demonstrated high overall response rates to emapalumab in combination with dexamethasone (47). Emapalumab has also shown effectiveness in inducing remission of MAS secondary to systemic juvenile idiopathic arthritis (sJIA) or AOSD in patients who failed high-dose steroid treatment (48). Ruxolitinib has been shown in studies to dampen hyperinflammation, but may not work to eradicate the underlying cause of HLH. IL-6, a mainstay participant in the inflammatory response, is a target that is currently being studied by using IL-6 antagonists, such as tocilizumab. The addition of anti-CD52, anti-CD20, and IL-18 blockade are also currently being studied (17).

Prognosis

If left untreated, HLH is often fatal. The prognosis is often very poor for those with sHLH from a malignancy, with estimated survival of 20–30% at 2 years (20). Additional factors associated with a poor prognosis include age greater than 45 years, hyperferritinemia, and thrombocytopenia (4).

Death in the setting of HLH is most commonly due to multi-organ failure. This multi-organ failure can occur as a complication of the disease itself (e.g., bleeding from thrombocytopenia), the underlying disorder that was complicated by HLH, or from treatment complications (49). It is difficult to compare mortality between adult and pediatric patients, but overall mortality appears to be higher in adults with HLH, with mortality reportedly ranging 42–75%, and 29–46% in the pediatric population. The increased prevalence of malignancy-associated HLH in the adult population likely contributes to the decreased overall survival in adults compared to pediatric patients (4,7,49).

A study looking at National Inpatient Sample (NIS) data from 2006 to 2019 that included 16,136 adult patients with HLH who were hospitalized investigated patient characteristics and their effect on mortality. This study found that those with HLH in the setting of congenital immunodeficiency syndromes and secondary to malignancy had the highest mortality rates. Interestingly, males were also found to have worse outcomes compared to their female counterparts (50). While there is not a specific biomarker predictive of outcomes, some studies have found decreased platelet counts (below 40×10⁹/L) to be predictors of poor overall survival, which could be due to the overall hyperinflammatory response. Survival of EBV-associated HLH has been found to be significantly improved when etoposide is added within four weeks of diagnosis (51). The lack of availability at some institutions of tests such as soluble CD25 levels can also contribute to a delay in the diagnosis, further increasing mortality rates (51).

Relapse following initial HLH diagnosis is highest within the first year following disease remission; thus, close outpatient surveillance is routinely practiced for a variety of clinical scenarios, often with laboratory monitoring including ferritin levels. A high index of suspicion for relapse should be present for those patients who start to develop fevers and new cytopenias (24).

Limitations of this narrative review/future directions

Limitations to note in this narrative review include some selection bias in studies chosen to be captured in the review, although this was mitigated with the assistance of a professional librarian. Additionally, there are few randomized controlled trials in patients with HLH, making primary literature evidence relatively scarce at this time compared to other hematologic disorders.

There is an imminent need for additional research in this rare but fatal disease, necessitating cross-disciplinary collaborations. Given the clinical heterogeneity of HLH, it is of great importance to develop more sensitive and specific diagnostic approaches, prognostication schema, and targeted therapies that are informed by patient-specific factors.

Conclusions

Here we provide a narrative review of the presentation, workup, and treatment approach to HLH, a clinical entity characterized by elevated, dysregulated inflammation. This entity can be conceptually divided into primary (or familial) and secondary HLH. Common triggers of secondary HLH include infections, malignancy, and rheumatologic conditions. It remains a diagnostically challenging disease, with cytokine evaluation, pathogenic mutation testing, and inflammatory markers playing a role in supporting the diagnostic workup. The treatment approach is nuanced and largely dependent on the underlying cause of HLH. The high mortality rate of the disease requires prompt recognition of clinical manifestations and appropriate workup, with involvement of multidisciplinary specialists to facilitate optimal clinical care.

Acknowledgments

The authors thank the Mayo Clinic librarians for their assistance.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://aob.amegroups.com/article/view/10.21037/aob-25-3/rc

Peer Review File: Available at https://aob.amegroups.com/article/view/10.21037/aob-25-3/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://aob.amegroups.com/article/view/10.21037/aob-25-3/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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