Nedel W. Hemophagocytic lymphohistiocytosis in critically ill patients: A guide for clinicians. World J Crit Care Med 2026; 15(3): 120840 [DOI: 10.5492/wjccm.120840]
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Wagner Nedel, MD, PhD, Assistant Professor, Department of Intensive Care Unit, Conceição Hospital Group, Francisco Trein 596, Segundo Andar, Porto Alegre 91350200, Brazil. wagnernedel@gmail.com
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Nedel W. Hemophagocytic lymphohistiocytosis in critically ill patients: A guide for clinicians. World J Crit Care Med 2026; 15(3): 120840 [DOI: 10.5492/wjccm.120840]
Author contributions: Nedel W contributed to conceptualization and manuscript writing.
Conflict-of-interest statement: The author reports no relevant conflicts of interest for this article.
Corresponding author: Wagner Nedel, MD, PhD, Assistant Professor, Department of Intensive Care Unit, Conceição Hospital Group, Francisco Trein 596, Segundo Andar, Porto Alegre 91350200, Brazil. wagnernedel@gmail.com
Received: March 10, 2026 Revised: April 12, 2026 Accepted: June 1, 2026 Published online: September 9, 2026 Processing time: 171 Days and 5.4 Hours
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a critical syndrome of immune dysregulation, marked by a hyperinflammatory cytokine storm and multiorgan failure. While primary forms are genetic, secondary HLH in adults is more prevalent and frequently precipitated by infections (notably viral), malignancies, or autoimmune diseases. Distinguishing secondary HLH from sepsis and multiorgan failure presents a significant clinical challenge due to overlapping clinical features, such as persistent fever and cytopenias. Diagnosis relies on clinical judgment and predictive frameworks like the HLH-2004 criteria or the HScore. Although elevated ferritin levels are a hallmark biomarker, isolated values lack sufficient specificity, necessitating a multifaceted diagnostic approach. Treatment strategies focus on controlling hyperinflammation while addressing the underlying trigger. Initial therapies often include corticosteroids, intravenous immunoglobulin, or the interleukin-1 receptor antagonist anakinra, with etoposide reserved for severe or refractory cases. Despite advances in management, mortality rates in the intensive care unit remain high, particularly when invasive organ support is required. Early recognition and multidisciplinary collaboration are essential to improve outcomes in this heterogeneous patient population. Further research is necessary to refine diagnostic cutoffs and identify personalized, phenotype-specific therapeutic interventions.
Core Tip: Secondary hemophagocytic lymphohistiocytosis is a severe hyperinflammatory condition that frequently resembles or complicates sepsis in patients who are critically ill. A high level of clinical suspicion is necessary when patients present with ongoing fever, unexplained reductions in blood cell counts, and extremely high levels of ferritin. Employing the HScore or hemophagocytic lymphohistiocytosis-2004 criteria aids in making an earlier diagnosis. Swift, multidisciplinary management that emphasizes identifying triggers and applying customized immunosuppression is crucial to lowering the high mortality rates linked to multiorgan failure.
Citation: Nedel W. Hemophagocytic lymphohistiocytosis in critically ill patients: A guide for clinicians. World J Crit Care Med 2026; 15(3): 120840
Hemophagocytic lymphohistiocytosis (HLH) is a syndrome characterized by exacerbated inflammation associated with immune dysfunction and immune system activation[1-3]. HLH can either remain slow-progressing or escalate into a self-sustaining, intense inflammatory cytokine storm leading to failure of multiple organs (MOF)[1]. HLH typically has a “sepsis-like” presentation, sometimes accompanied by acute organ injury[2].
Secondary HLH (sHLH) is more frequently observed in adults, where the immune system’s dysregulation is more intricate and varies based on the etiology. However, the hyperinflammatory response also includes the excessive activation of lymphocytes and/or macrophages[2], characterized by reversible natural killer (NK) or CD8+ T-lymphocyte dysfunction[3]. Various factors triggering HLH initiate a positive feedback cycle characterized by extremely elevated levels of proinflammatory cytokines, known as a “cytokine storm”, ultimately resulting in MOF and fatality[4,5].
HLH is often underrecognized or misdiagnosed, at least partially, because of the lack of validated diagnostic criteria. Thus, the true prevalence of HLH in critically ill patients remains unknown. Sepsis shares many clinical characteristics and pathophysiological aspects with HLH. This article offers a summary of adult-onset HLH for general intensive care practitioners and presents practical diagnostic and treatment strategies based on the latest evidence.
TERMINOLOGY
HLH is a heterogeneous group of disorders. Traditionally, HLH has been divided into familial HLH, primary HLH (a genetic condition that primarily affects children), and secondary (or acquired) HLH, which is an immune response occurring during adolescence or adulthood[6,7]. The existing terminology for sHLH is confusing, requiring a unified nomenclature[1]. HLH due to autoimmune disease is commonly referred to as macrophage activation syndrome (MAS)[3], although this nomenclature may not apply to all cases of HLH. However, multiple terms have been used. These include MAS-like syndrome, MAS-HLH[3], hyperferritinemic syndrome, viral-associated hemophagocytic syndrome, and sepsis-HLH overlap syndrome[1]. Some studies have used broad definitions, such as “sepsis with hepatobiliary dysfunction and disseminated intravascular coagulation (DIC)”[1].
TRIGGERS FOR SHLH
HLH susceptibility appears to have a genetic basis for both primary and secondary forms; however, the genetic contribution in the latter is less well understood. In a systematic review evaluating critically ill patients with HLH, infections were the most frequent trigger (50%), followed by malignancies (28%), and autoimmune diseases (12%)[8]. Table 1 describes the most important triggers for sHLH.
Table 1 Triggers for secondary haemophagocytic lymphohistiocytosis.
The most prevalent trigger for sHLH is infection, especially viral infections. Among viral infections, Epstein-Barr virus (EBV) is the predominant agent recognized[1]. EBV can independently initiate HLH or trigger sHLH in conjunction with related malignancies, such as EBV-driven lymphoproliferative disorders[6]. Among viral infections, it is also remarkable that severe acute respiratory distress syndrome corona virus-2 (SARS-CoV-2) infection is a significant trigger for sHLH. In critically ill patients with SARS-CoV-2 infection[9], sHLH represents an important etiology of persistent liver injury after viral infection[10]. Other herpes viruses, such as cytomegalovirus, and non-herpes viruses, such as parvovirus B19, influenza, dengue, and hepatitis A, are also causes of sHLH[6,11]. Bacterial infections have been reported in approximately 9% of sHLH cases[1], mainly in tuberculosis[6]. Although fungal and parasitic infections are not commonly seen, they should be taken into account for patients who are immunocompromised or have a pertinent travel history[1]. Visceral leishmaniasis holds significant importance because it can be effectively treated with liposomal amphotericin, even when sHLH is present[12].
sHLH can occur due to chemotherapy, hematopoietic stem cell transplantation, and immune therapies. It is most commonly associated with hematological malignancies, particularly lymphomas[3,13]. sHLH affects approximately 1% of adult patients with hematological cancer; however, its prevalence increases to until 20% in patients with certain types of B-cell and T-cell lymphoma[6]. sHLH has also been reported in solid neoplasms. Recently, sHLH have been described in patients receiving targeted immunotherapy, and intensivists are likely to see an increasing number of patients with these unique side effects[12]. Therapies that might induce HLH encompass monoclonal antibodies, dendritic vaccines, combinations of checkpoint inhibitors, and chimeric-antigen receptor T-cell (CAR-T) therapies. CAR-T therapy is associated with an overproduction of cytokines, leading to widespread inflammation and organ dysfunction[14]. This condition is initially known as cytokine release syndrome (CRS) but can develop into sHLH[15]. Although the occurrence of CRS is believed to be quite high, ranging from 74% to 100% in the anti-CD19 context, the likelihood of sHLH developing in this scenario is not as well-defined. The reported incidence rates fluctuate between 1%-3% and 35%, influenced by factors such as the underlying disease, the patient group, and the specific CAR-T product used[14].
In adult patients, sHLH is most closely associated with adult-onset Still’s disease and systemic lupus erythematosus[16,17]. In addition, sHLH has been described to complicate rheumatoid arthritis, systemic vasculitis, and other conditions, with infection and drug therapy as the main suspected triggers[1]. Inflammatory bowel disease is also associated with sHLH, especially in those patients using thiopurines. The most common triggers are viral infections, followed by lymphoma[18].
It is important to recognize that sepsis can present with a range of immune responses, from a hyperinflammatory reaction to weakened immune function, or even a mix of both[19], and sHLH could be implicated in the hyperinflammatory subset of septic patients. The exact frequency of sHLH in sepsis is still uncertain. In a study by Kyriazopoulou et al[20], it was estimated to occur in about 4% of a large group of sepsis patients. The definition of sHLH included a modified HScore (details provided below), liver and bile duct dysfunction, and DIC, or a combination of these factors, and it was linked to higher mortality rates[20].
Distinguishing sHLH from sepsis can be difficult. sHLH might occur without an infection but can lead to symptoms that are indistinguishable from those of septic shock, acting as a “sepsis mimic”. Hyperinflammation is a phenotype commonly observed in patients with sepsis[3,21]. Both conditions may occur simultaneously when there is an underlying illness, such as cancer or an autoimmune disorder. A reasonable trigger for HLH investigation is a patient who does not respond to initial treatment for sepsis and develops bicytopenia during the course of disease[22].
Some isolated factors that can act as triggers include vaccines, undergoing surgeries such as splenectomy, cardiac procedures, colectomy, hepatic resection, and postpartum, as well as the use of certain medications[8], and severe burns[6].
DIAGNOSIS
Familiarity with HLH is important because of its nonspecific symptoms and laboratory findings, as well as the fact that the hyperinflammatory state of HLH can be observed in other conditions (sepsis, MOF, and other cytokine storm syndromes)[3,13,23]. Fever is the cardinal sign of sHLH, present in 96% of the cases[7], and is induced by overproduction of interleukin (IL)-1. Classically, fever is persistent and typically unresponsive to antibiotics. Lymphadenopathy is not consistently observed in adults, as well as in hepato-and splenomegaly, which are most associated with lymphoma or EBV infection. Splenomegaly is present in 69% of HLH cases[7]. Approximately half of the patients have pulmonary manifestations, and acute respiratory distress syndrome is the hallmark of lung damage. Pulmonary arterial hypertension, interstitial lung disease, and pulmonary alveolar proteinosis are also associated with sHLH, and lung damage is associated with poor prognosis[3,24]. Cardiovascular dysfunction is variable, ranging from mild hypotension to shock, and vasopressors are frequently required. Skin manifestations are present in up to 25% of patients, with a varied clinical presentation, ranging from rashes to erythroderma, petechiae, and purpura. Anemia and thrombocytopenia are more prevalent than neutropenia in patients with HLH, and they usually develop early in the disease course. Anemia and thrombocytopenia are identified in approximately 67% and 78% of adult HLH cases, respectively, at any time during the disease course[7]. Cytopenias are usually related to severe cytokine-related inflammation that suppresses hemopoiesis.
The combination of cytopenia and increased levels of aspartate aminotransferase and alanine aminotransferase in a patient with persistent fever should trigger investigation for possible HLH[1]. Other characteristics that suggest an HLH diagnosis in this scenario include hyperbilirubinemia, hepatomegaly, hypertriglyceridemia[7], and elevated lactate dehydrogenase and D-dimer levels. D-dimer are usually elevated even when the international normalized ratio, partial thromboplastin time, and fibrinogen are normal[13]. The majority of critically ill HLH patients present with coagulation disorders (low fibrinogen, DIC, and low prothrombin time), and these patients have MOF of greater severity[25]. Hypertriglyceridemia and hypofibrinogenemia, however, are less prevalent in adult HLH patients than in pediatric patients[7].
Ferritin
Ferritin is an inflammatory biomarker and is released in response to hypercitokinemia[20]. It is also associated with increased lymphocyte cytotoxicity, a marker of hyperinflammatory responses in sepsis[26]. Very high ferritin values are more commonly observed in patients with renal failure and hepatocellular injury than in those with HLH[5]. Some infections, such as varicella-zoster virus infection, hepatitis, and malaria, are also associated with increased ferritin levels (1500-1900 mg/L)[23].
The existence of an accurate cutoff for ferritin levels in the diagnosis of HLH in critically ill patients remains a subject of debate. In a recent study, 2623 out of 6340 intensive care unit (ICU) patients (41.4%) had elevated ferritin levels over 500 μg/L, but only 40 of those patients (< 1%) had HLH[27]. It was observed that a 10-fold higher ferritin level was present in patients with HLH when compared with those without, and a ferritin cutoff of 9083 μg/L is correlated with high specificity (91.9%) and sensitivity (92.5%) for HLH in the ICU, at least in one study[28]. Higher ferritin levels (> 10000 mg/L) could increase the specificity for HLH, but with a limited positive predictive value, due to the low prevalence of HLH in the entire population of critically ill patients[1,29] and must be used in combination with other criteria for HLH diagnosis. In another retrospective cohort study, Saeed et al[30] found that a ferritin level > 10000 mg/L was associated with a specificity of 92%, a positive likelihood ratio of 7.76, and a negative likelihood ratio of 0.48[30]. Isolated ferritin values should not be used as the only diagnostic criteria of HLH. Even in patients with very high values (> 50000 mg/L), the diagnosis of HLH is present in a minority of patients (19 of 113), as evidenced in one cohort study[31]. Other diagnoses in this scenario include infections, acute hepatitis, and CRSs[29]. Another role of ferritin is that it can be an important marker of disease severity. A cohort of patients who had significant hemophagocytosis on bone marrow examination found that ferritin significantly predicted death related to hemophagocytosis. In this study, a serum ferritin level > 2000 mg/L predicted death with a sensitivity of 71% and a specificity of 76%[32]. Trends in serum ferritin levels are useful in predict clinical outcomes and identifying rebound hyperinflammation[1].
Hemophagocytosis
Hemophagocytosis is characterized by the phagocytosis of hematopoietic elements at various stages of maturation by activated macrophages within the bone marrow or reticuloendothelial system. While this histological hallmark provides the nomenclature for HLH, it is notably neither pathognomonic nor a mandatory diagnostic criterion. Consequently, the identification of hemophagocytosis in marrow or tissue remains the most inconsistent and least reliable clinical finding, despite its eponymous association with the syndrome[5], not being a finding that is either sensitive or specific to HLH, and it is often absent early in the disease. The detection of hemophagocytosis through invasive procedures may delay early life-saving treatment for HLH[33], and should not delay the start of treatment. Notably, hemophagocytes may be systematically misclassified using the histological method[7]. In addition, by removing hemophagocytosis from the HLH-2004 criteria and HScore, the prediction accuracy for HLH diagnosis is only marginally decreased compared to the original scores[33]. Hemophagocytosis is a frequent finding, especially in patients in the ICU with sepsis or hematologic diseases[7]; it was observed in up to 64% of critically ill patients with sepsis and thrombocytopenia and in 65% of those who died[4], and critically ill patients can have a higher incidence of hemophagocytosis even without HLH[34].
Several potential markers for specific immunological responses in sHLH have been identified, including soluble IL-2 receptor (or sCD25), soluble CD163, NK cell activity, and cytokine profiling[1,7]. Both IL-18 and chemokine (C-X-C motif) ligand (CXCL)9 are promising tools in differentiate HLH and other inflammatory disorders[35,36], as well as different HLH subtypes[37]. These biomarkers may, in the future, promote personalized treatment strategies[38]. Extended turnaround times and limited routine availability preclude the use of these specialized immunological assays for rapid diagnosis in the critically ill population. These are very specific tests, which should not be a limiting factor in the management of HLH, especially in resource-limited settings.
Predictive scores for HLH
The HLH-2004 score establishes the diagnostic framework for familial HLH, necessitating the fulfillment of at least five out of eight clinical and laboratory criteria. Despite its common application in adult sHLH - largely due to a paucity of validated alternatives - the framework incorporates specialized investigations that are often unfeasible in routine intensive care settings. Furthermore, delayed processing times for these assays may impede timely diagnosis, often resulting in positive scores only during advanced disease stages. While individual parameters within the HLH-2004 set lack specificity, the collective fulfillment of five criteria in critically ill patients strongly correlates with dysregulated, uncontrolled inflammation[3]. However, this cutoff is a subject of debate. Meeting just four of the HLH-2004 criteria proved to be highly effective, with a sensitivity of 95% and a specificity of 93%, for diagnosing HLH in adults admitted to intensive care units[39]. The presence of two or more HLH diagnostic criteria, even if it does not meet the diagnostic criteria for HLH, is associated with increased mortality in patients with sepsis[40] and may be a useful signal of an inadequate host response to the initial injury.
The HScore is an uncomplicated scoring method designed for use at the bedside, specifically for sHLH. in adult patients in a multicenter study and subjected to external validation[41]. This scoring system integrates nine clinical and laboratory variables, facilitating bedside calculation via digital platforms to estimate the likelihood of sHLH. However, it is important to note that the primary cohort utilized for the HScore’s validation consisted largely of individuals with infectious or neoplastic etiologies. Consequently, the generalizability of this tool may be restricted when evaluating patients whose HLH is secondary to autoimmune or autoinflammatory conditions[42]. While it has yet to be fully validated as a diagnostic tool for sHLH in critically ill patients, Kyriazopoulou et al[20] found that a modified HScore is associated with the presence of MAS and, indirectly, with patient outcomes in cases of sepsis. For example, a cutoff of 168 points had a high sensitivity (100%) and specificity (94%)[39]. In a case-control study comparing HLH-positive and HLH-negative patients, the median HScore was 235 in HLH+ and 42 in HLH- patients (P < 0.001), and the number of HLH-2004 criteria was four in HLH+ and one in HLH- patients (P < 0.001). The area under the receiver operating characteristic curve (AUROC) was 0.99 for both criteria[43].
In a recent observational study, Lachmann et al[42] validated different diagnostic criteria in 13 cohorts of sHLH. The best-performing criteria were the original HLH-2004 criteria with a decreased cutoff (cutoff 4 - sensitivity 86%, specificity 86%), followed by the revised HLH-2004 criteria without NK cell activity (cutoff 4 - sensitivity 83%, specificity 87%), and the HScore (cutoff 169 - sensitivity 82%, specificity 87%).
It is important to emphasize that none of these predictive scores were designed for critically ill patients. Clinical scenarios characteristic of critically ill patients, such as sepsis, are not adequately considered in their particularities. Therefore, the evaluation of multiple diagnostic tools is fundamental for understanding sHLH. Currently, no laboratory tests or physical findings specific for sHLH are available. In a study evaluating sHLH due to sepsis, serum ferritin was the most discriminating parameter for the early diagnosis, with a sensitivity of 85% and 84% of specificity, and an AUROC of 0.939. The addition of IL-18 to the HScore was identified as a highly potential diagnostic tool, increasing the accuracy to the original score (AUROC 0.984 vs 0.967)[36]. In addition, owing to the physiopathological nature of HLH, its clinical presentation can have considerable overlap with other inflammatory conditions, such as complement-mediated thrombotic microangiopathy. In such cases, therapy aimed at attacking both processes seems reasonable[44].
A diagnostic approach
sHLH should be considered in critically ill patients with persistent fever, unresponsiveness to vasopressors, inexplicable cytopenias, and organ failure that does not respond to appropriate therapy[13]. Consequently, there should be a heightened suspicion for HLH in situations where MOF progresses rapidly and there is a lack of adequate response to suitable empiric treatment or increased supportive care[3]. When encountering a critically ill patient being treated for an acute condition, such as sepsis, who fails to respond initially to adequate antibiotic therapy and focus control, and who develops persistent fever, cytopenias, and worsening organ damage (particularly liver damage) without a better explanation for their clinical decline, we should initiate an investigation and consider treating for HLH. In such cases, it is crucial to measure serum ferritin levels, and elevated levels should prompt initial treatment and further investigation. In septic patients, ferritin levels > 4000 mg/L increase the likelihood of concomitant sHLH, while levels > 10000 mg/L may indicate the immediate need for treatment in cases in which there is no other evident cause for an increase in ferritin levels. Ferritin levels should also be used for treatment monitoring[45].
Conducting a comprehensive diagnostic evaluation, which involves clinical assessments, laboratory analyses, and radiographic imaging, is crucial for determining the probability of sHLH and uncovering its underlying causes. While the HScore serves as a valuable adjunct in corroborating clinical suspicion, the initiation of time-sensitive therapeutic interventions must not be deferred due to a low HScore or failure to meet the complete HLH-2004 diagnostic threshold[1]. Even with only four HLH-2004 criteria, immediate therapy should be considered, particularly if worsening of organ dysfunction is evident[3]. Even a “negative” HLH score should not limit the investigation. Sequential assessments of one of the predictive scores may be necessary, especially in a context of clinical deterioration. The definitive diagnosis of sHLH relies fundamentally on clinical acumen and the recognition of complex physiological patterns. Given that advanced sHLH is associated with exceedingly high mortality rates, clinicians must carefully weigh the risk of diagnostic omission against the potential morbidity of aggressive immunosuppressive regimens. Consequently, the initiation of early therapeutic intervention is warranted in the presence of reasonable clinical suspicion. Figure 1 describes a suggested diagnostic strategy for sHLH.
Figure 1 A proposed structured investigation for secondary hemophagocytic lymphohistiocytosis diagnosis.
ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; ATB: Antibiotic; HLH: Hemophagocytic lymphohistiocytosis; sHLH: Secondary hemophagocytic lymphohistiocytosis; HS: H score.
Although elevated liver enzymes are found in virtually all patients with HLH, little is known about the hepatic aspects of HLH in adults. Acute hepatitis may dominate the clinical presentation. In addition, liver biopsy can reveal activated macrophages with sinusoidal hemophagocytosis. These forms of predominant hepatic HLH are associated with some features typically associated with HLH[46]. Patients with septic shock who have hepatobiliary dysfunction and DIC phenotype had increased levels of the majority of biomarkers related to macrophage activation, as well as increased mortality, when compared with septic patients without this phenotype[47]. This phenotype is defined as a total bilirubin level ≥ 1.2 mg/dL, platelet count ≤ 100 × 109 /L, and an international normalized ratio ≥ 1.5 IU.
Computed tomography of the chest, abdomen, and pelvis is important to elucidate primary triggers and exclude differential diagnosis. Furthermore, a multidisciplinary approach involving other specialities should be integrated as clinically warranted to optimize diagnostic precision[3]. In order to uncover underlying malignancies, such as lymphoma that might be identified during steroid treatment, or to detect hidden infections from rare pathogens, it may be necessary to repeat laboratory examinations or conduct biopsies. A bone marrow analysis, additional tissue sampling, positron emission tomography scans, and other diagnostic techniques, including cell-free DNA testing for lymphoma, could be advantageous[1].
TREATMENT
Most treatment regimens have been developed based on the intensive immunosuppressive protocols used for familial HLH. Consequently, the initiation of therapy and the selection of therapeutic agents are predominantly guided by expert opinion and clinical experience. The physiopathological mechanisms of the disease involve the unchecked activation of CD8+ T cells and NK cells, leading to a cytokine storm characterized by excessive IL-6 production, as well as uncontrolled hemophagocytosis[45]. Therefore, treatments that suppress the hyperexpression of the inflammatory response may have a potential role in treatment. It is fundamental to provide support for organ injuries and secondary complications, such as antibiotics, vasoactive drugs, renal and respiratory support, as well as blood product replacement.
The clinical presentation of adult patients hospitalized in the ICU for HLH is characterized by a high incidence of de novo episodes where the underlying cause is not immediately apparent. Despite the urgency of targeted management, diagnostic latency - particularly regarding histopathology - complicates early intervention. Pre-therapeutic tissue sampling should be restricted to stable cohorts; however, empirical treatment must be prioritized in the presence of acute illness or progressive deterioration[2].
The complexity involved in diagnosing sHLH, along with the potential for multiple underlying pathophysiological processes to occur at once, underscores the need for a treatment strategy overseen by a multidisciplinary team of specialists. In a systematic review with a pooled analysis of observational studies and case series, Lachmann et al[28] found an association between IV immunoglobulin treatment and improved survival, whereas treatment with cyclosporine was associated with an increased risk of death. Steroids are usually the mainstay of initial immunosuppression. Hydrocortisone doses for sepsis is not adequate for HLH treatment, and is not and it is not suitable when increased immunosuppression is required. If there is a suspicion of central nervous system involvement, dexamethasone is a logical option and might offer superior benefits. Concerns have been raised regarding the primary administration of steroids in cases where the HLH-driver has not yet been identified[1]. Due to the initial high sensitivity of certain lymphomas to steroids, initiating treatment with high-dose steroids before obtaining all necessary biopsies or conducting a positron emission tomography scan may obscure the diagnosis of lymphoma. Furthermore, the use of high doses of corticosteroids may be a risk factor for the development of infections. The clinical impact of a delay in treatment must be weighed against the delay in identifying the causative agent.
Anakinra may be regarded as a primary treatment option in situations of diagnostic uncertainty. Anakinra is a recombinant interleukin-1 receptor antagonist that effectively manages the initial cytokine storm associated with sHLH[48]. It is well tolerated and possesses a favorable side effect profile; consequently, it is increasingly being considered as an early treatment modality for sHLH[49]. In clinical situations characterized by significant diagnostic uncertainty and where infection has not been definitively ruled out, approaches utilizing anakinra may be considered advantageous. In a post-hoc analysis of the effectiveness of anakinra in sepsis with HLH characteristics (hepatobiliary dysfunction or DIC), IL-1 receptor blockade was associated with an improved 28-day survival[50]. Recently, a precision immunotherapy approach based on anakinra administration in patients with sepsis and macrophage activation-like syndrome (ferritin > 4420 mg/mL) was proposed. When compared with placebo, anakinra was associated with a greater sepsis-related organ failure assessment (SOFA) score decrease during the sepsis course; however, 28-day mortality was not significantly different between the groups[51]. The financial cost of anakinra may be prohibitive in middle- and low-income countries; therefore, local availability for emergency use in critical care may be limited.
Intravenous immunoglobulin (IVIG) is a recognized treatment for HLH. It is suggested in the management of sHLH patients without severe, persistent, or relapsing cases[3]. Given the limited half-life, it is advisable to consider administering a repeat dose after two weeks. Additionally, plasma exchange serves as an alternative method for cytokine removal[52]; however, there is little evidence supporting its use in adults.
Etoposide is a cytotoxic agent that exhibits specific activity against macrophages and cytotoxic T cells, effectively mitigating the cytokine storm[45]. Etoposide infusion is associated with significant improvement in hemodynamic parameters and shock reversal[53]. It should be considered a treatment for nonresponsive sHLH severe sHLH, or worsening HLH-triggered organ dysfunction[3] particularly in EBV-driven diseases and malignancies. Tocilizumab, an anti-IL-6 drug active in CRS, may have a potential role in inducing remission of HLH, generally with other concomitant treatments (dexamethasone, cyclophosphamide, and immunoglobulins)[45].
A proposed therapeutic algorithm is described in Figure 2. Combination therapy for sHLH has also been studied. In an observational pilot study comprising nine patients, Scholz et al[54] found a 6-month survival rate of 86% using triple therapy: Polyvalent IVIG, high-dose dexamethasone, and ruxolitinib, a Janus kinase inhibitor. Despite these promising results, this therapeutic strategy requires further elucidation. This aligns with a post-hoc analysis conducted by Shakoory et al[50] on a randomized controlled trial from the 1990s, which indicated a potential mortality benefit associated with the use of anakinra in septic ICU patients exhibiting hepatobiliary dysfunction and DIC, but not in patients presenting with either condition in isolation. This study, however, should be regarded as hypothesis-generating only at present[50]. Combined therapy with anakinra, high-dose corticosteroids, and/or IVIG has also been associated with improvement in the SOFA score in sHLH[55]. In a double-blind, randomized clinical trial, 36 patients with sepsis were randomized to the administration of personalized immunotherapy (n = 15) or placebo (n = 21). Anakinra was administered if ferritin > 4420 mg/L, in the personalized arm. There was no difference in 28-day and 90-day survival between the arms; however, the low number of patients included limits definitive conclusions[56]. Emapalumab, an anti-interferon γ, is an alternative in refractory HLH, when used in combination with ruxolitinib and dexamethasone[57]. It is also used as an alternative for etoposide, especially due to the risk of bone marrow suppression[58], or as a steroid-sparing agent[59]. The use of mixed or personalized immunotherapies, as well as its ideal administration, remains a subject of debate, and it is not possible to define an appropriate management approach at present.
Figure 2 Suggested therapeutic algorithm for hemophagocytic lymphohistiocytosis.
SC: Subcutaneous.
It is imperative to sustain targeted therapies for intracellular diseases, including leishmaniasis, tuberculosis, human immunodeficiency virus infection, rickettsial disease, and cytomegalovirus infection. Furthermore, additional conditions, such as herpes virus type 8-associated lymphoproliferative disorder, warrant consideration, as they may benefit from prompt IL-6 inhibition and rituximab administration. Rituximab is also pivotal in managing EBV-driven lymphoproliferative disorders.
PROGNOSIS
In critically ill patients, hospital mortality rates range from 50% to 68%[53]. The need for invasive organ support (vasopressors, mechanical ventilation, and dialysis) is associated with an increased mortality[2,53]. Notably, there is a direct correlation between the maximum elevation of serum ferritin concentration and an increased risk of mortality[27]. A rapid reduction in serum ferritin levels following treatment is associated with a more favorable short-term prognosis[20]. In a French cohort, there was no difference in ICU mortality regarding HLH etiology (septic, intracellular infection-related, malignancy-associated, and idiopathic); however, the low number of patients included may limit definitive conclusions. Nonetheless, in a larger cohort of critically ill patients with sHLH, malignancy-associated HLH patients had the highest mortality[27]. Age, SOFA score at ICU admission, increase in SOFA until HLH diagnosis, and the presence of bone marrow hemophagocytosis are associated with worse prognosis[60], as well as HLH secondary to SARS-CoV-2 infection[61]. Mortality is strongly associated with the number of organ failures[53,60].
CONCLUSION
HLH is a potentially fatal complication, and immediate treatment is potentially associated with better outcomes. In critically ill adult patients, HLH is secondary to a wide range of primary injuries. There is no gold standard for its diagnosis, and its identification can be achieved through various diagnostic criteria or clinical phenotypes. sHLH is a rare condition, therefore, systematic translational work has been difficult to perform, resulting in an unclear pattern of immune marker association with clinical outcomes. The identification of implicated immune markers in secondary disease can further support targeted therapies. The choice of the ideal therapy, coupled with the precise identification of a phenotype associated with increased mortality, remains an open question. Therefore, further studies are needed to identify the ideal treatment for the ideal patient to achieve the best outcome.
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P-Reviewer: Juneja D, Director, MD, India; Kumar R, FACG, Head, MD, Professor, India; Soldera J, Associate Professor, MD, PhD, Brazil S-Editor: Bai Y L-Editor: A P-Editor: Zhang L
