Giorgia Montrucchio1,2†
Riccardo Traversi1*†Gabriele Arrigo1Chiara Bonetto2Gabriele Sales1,2
Alessandro Busca3
Vito Fanelli1,2
Claudia Filippini1
Luca Brazzi1,2- 1Department of Surgical Sciences, University of Turin, Turin, Italy
- 2Department of Anesthesia, Intensive Care and Emergency, Anestesia e Rianimazione 1U, Città della Salute e della Scienza Hospital, Turin, Italy
- 3SSCVD Trapianto Cellule Staminali, Città della Salute e della Scienza Hospital, Turin, Italy
Background: Hemophagocytic Lymphohistiocytosis (HLH) is a rare life-threatening syndrome characterized by hyperinflammation caused by abnormally activated macrophages and cytotoxic T cells overlapping with sepsis and multi-organ disfunction (MOD). Its frequency is probably underestimated.
Methods: Patients’ data were extracted from a literature search performed on PubMed (MEDLINE) and EMBASE using the following search terms: “Hemophagocyitic Lymphohistiocytosis” OR “HLH” OR “MACROPHAGE ACTIVATING SYNDROME” OR “MAS” AND “Intensive Care Unit” OR “Critical Care” OR “ICU.” Search was limited to articles published after 2014, when HScore was proposed.
Results: We found 126 case reports and case series for a total of 148 patients with an overall mortality of 47.5%. Main triggers were infections (111 patients; 88.1%) followed by dysimmune disorders (29 patients; 19.7%) and hematological malignancies (20 patients; 13.6%). The following factors were associated with increased ICU mortality: viral infection (76 patients; 52.8%) p = 0.0071 and p = 0.0086 at multivariate analysis for SARS-CoV-2, hematological malignancies (p = 0.0035 at univariate analysis; p = 0.0083 at multivariate analysis), invasive mechanical ventilation (116 patients; 83.3%) p = 0.0060 at univariate analysis not confirmed in multivariate analysis (p = 0.0599). Corticosteroids were associated with reduced ICU mortality at univariate analysis (86 patients; 59.7% p = 0.0250) not confirmed at multivariate analysis (p = 0.7196).
Conclusion: Evidence from our analysis confirms the severity and rapid evolution of HLH, suggesting the importance of prompt clinical suspicion. Since HLH can be found in different hospital settings, including ICU, we believe that this syndrome should be considered in differential diagnosis for all patients presenting with MOD with unclear etiology. Development of specific diagnostic and therapeutic schemes should be considered a priority.
Background
Hemophagocytic Lymphohistiocytosis (HLH) is a syndromic disorder characterized by severe hyperinflammation and immune dysfunction with concomitant immune system activation (1).
Although rare, the exact frequency of HLH within the general and critical care population is unknown. However, HLH often requires supportive care management in ICUs (>60% in pediatric HLH cases) with high mortality rates (36–40% of pediatric cases and 41–68% of adult cases) (1).
Classically, HLH is categorized as primary (pHLH) and secondary (sHLH), although significant overlap exists (2). pHLH is caused by genetic mutations inherited in homozygous or compound heterozygous pattern, resulting in disruptive mutations that fully eliminate the function of cytotoxic T cells and NK cells. pHLH is also associated with various immunodeficiency disorders. Anyway, the diagnosis of pHLH cannot be excluded in patients older than 1 year.
Secondary or acquired HLH (sHLH) is induced by triggers such as infection, malignancy, rheumatologic disease, allogenic hematopoietic stem cell transplantation (HSCT), CAR-T therapy (3), drug hypersensitivity or other underlying causes. The immune dysfunction in sHLH is characterized by reversible natural killer (NK) or CD8 + T cell dysfunction, which occurs in some viral infections or rheumatologic disorders, or by NK-cell deficiency, which can occur after chemotherapy or during sepsis.
The diagnosis of HLH in the ICU may be challenging due to lack of specific laboratory, radiologic and histopathologic findings [bone marrow hemophagocytosis may be observed in the absence of proven hemophagocytic syndrome, in particular after blood transfusion or in sepsis (4)], and above all, due to the overlap of its clinical features with the Multi-Organ Disfunction syndrome (MOD) that characterizes the majority of ICU admission.
Scores considering clinical and laboratory finding have been developed for HLH diagnosis and their use is suggested in the ICU setting (4, 5).
Suggested treatment strategies are based on HLH-2004 protocols including high dose corticosteroids, etoposide and cyclosporine, followed by adjunctive/rescue therapy such as intravenous immunoglobulin, plasmapheresis and tocilizumab (1, 5). However, these therapeutic protocols are borrowed from pediatric and hematology guidelines and only scattered studies with data regarding ICU treatment have been reported. A growing interest and novel awareness about this syndrome are spreading among ICU physicians.
Previous observational studies and reviews have been realized in ICU patients in recent years. Table 1 provides an overview of major studies conducted in ICU settings with large cohorts of HLH patients, which offer important perspectives. However, case series and case reports were excluded from the considered literature, although they might have a complementary role in identifying knowledge gaps and generating hypotheses that can inform both clinical practice and future prospective research.
Table 1. Major studies on HLH conducted on large cohorts of ICU patients.
For this reason, here we present results from a literature search on case series and case reports, aimed at describing epidemiology, risk factors, diagnostics test, triggers, treatment modalities and outcomes of HLH patients treated in the ICU. Specifically, our narrative review highlights rare or atypical presentations, diagnostic delays, and treatment challenges that may not be fully captured in large databases or registry-based analyses.
Methods
Review search algorithm
Literature search in PubMed (MEDLINE) and EMBASE databases has been performed on June 22, 2024, using the following search terms: (“Hemophagocyitic Lymphohistiocytosis” OR “HLH” OR “Macrophaghe Activation Syndrome” or “MAS”) AND (“Intensive Care Unit” OR “Critical Care” OR “ICU”). Only articles published after 2014—the year of publication of HScore (4), suggested by the Society of Critical Care Medicine for the diagnosis of HLH in intensive care—were taken into consideration.
Given the narrative nature of our work, protocol registration was not undertaken.
Review study selection
All case reports and case series on patients ≥ 16 years old admitted to ICU for HLH published in English were evaluated (Figure 1). Eligible studies were those including patients with a positive diagnostic score, such as HScore or HLH-2004, for HLH or if HLH diagnosis was reported by paper’s author. In all cases where data regarding clinical course, treatment or outcome were not fully described, corresponding authors were contacted to obtain missing data. Screening of suitable articles was performed manually by two authors who independently reviewed titles and abstracts, with disagreements regarding inclusion in the review was resolved by discussion.
Figure 1. Review search algorithm.
HLH triggers were assigned to predefined categories: viral, bacterial or fungal infection, dysimmune disease, hematologic or solid malignancy, pregnancy related. Data regarding infectious triggers were then divided into sub-categories when the trigger was reported in more than five patients. Specific pharmacological and non-pharmacological treatment was grouped if such treatment was reported in more than five patients. Mortality was categorized into 7-day, 14-day and overall ICU mortality.
Statistical analysis
Values are presented as means and standard deviation or frequency and proportion. Comparison between groups was made using the t-test or Wilcoxon-Mann-Whitney for and Chi square or Fisher exact test was applied as appropriate. Possible independent risk factors of ICU mortality were tested performing a multivariable logistic model estimating the ODDS RATIO (OR) and the 95% confidence interval (CI 95%). All statistical tests were two-sided and p values of 0.05 or less were considered statistically significant. Statistical analyses were conducted using the SAS software package (SAS Institute, Cary, NC; version 9.4).
Results
Review and pooled analysis results
Literature search identified 391 papers: 260 were excluded not being conducted in ICU or including pediatric population, 2 not being written in English, 1 being withdrawn and 2 not reporting enough data, even after the investigation with Authors. Fifty-five articles came from North America (43.6%), 35 from Europe (27.8%), 27 from Asia (21.6%), 3 from South America (2.4%), 3 from Middle East (2.4%) and 2 from Africa (1.6%) (Table 2).
Table 2. Results from literature search.
Overall, data on suspected triggers, diagnostic workup, treatment and mortality were available for 146 patients with a mean age of 45 [±17] years.
Overall mortality was 47.5%: 25 (19.2%) and 30 (23.8%) patients died before 7 and 14 days from ICU admission, respectively. Age was significantly higher in non-survivors (p = 0.0251) at univariate analysis (Table 3) but not at multivariate analysis (Table 4).
Table 3. Results from univariate analysis of ICU mortality.
Table 4. Results of multivariable analysis of ICU mortality.
Diagnosis was performed using the composite score (HLH-2004, HScore) in 78 (52.70%) patients; clinical suspicion or direct hematology referral in 62 (41.9%) cases and was only autoptic in 6 (4.05%) cases.
Bone marrow biopsy (BMB) was performed on 108 (74.0%) patients and this subgroup was found to have a lower ICU mortality (p = 0.003).
Triggers
The most frequent suspected triggers were infections (106), followed by dysimmune disorders (30), malignancies (24), HIV (8) and pregnancy (7). Seventy-six patients had viral infection, 24 had bacterial infection and 6 fungal infections.
The most represented pathogens were Epstein–Barr virus (EBV, 29; 19.7%), SARS-CoV-2 (21; 14.3%) and Citomegalovirus (CMV, 8; 5.4%).
Viral infection was found to have a significant correlation with ICU mortality (p = 0.0377) at multivariate analysis.
The trigger factor was found to be hematologic malignancy in 20 (13.6%) patients and malignancy overall in 24 (16.3%).
All patients with human immunodeficiency virus (HIV) (8; 5.4%) had clinical and/or laboratory criteria defining acquired immunodeficiency syndrome (AIDS).
ICU mortality was found to be significantly correlated with viral infection (p = 0.0071) and SARS-CoV-2 (p = 0.0086) at univariate analysis. Hematologic malignancy was also statistically correlated with mortality at both univariate (p = 0.0035) and multivariate (p = 0.0083) analysis.
Treatment
One hundred and sixteen patients (82.3%) were treated with invasive mechanical ventilation, 52 required continuous renal replacement therapy (CRRT) (38.2%), 7 (5.2%) extracorporeal membrane oxygenator (ECMO) namely veno-venous ECMO in 6 patients and veno-arterial ECMO for cardiogenic shock in 1 patient.
Invasive mechanical ventilation was statistically associated with ICU mortality at univariate analysis (p = 0.0060) but not at multivariate analysis (p = 0.0599).
The most used pharmacological treatment were corticosteroids (86 cases; 59.7%), etoposide (35; 23.6%), intravenous immunoglobulin (IVIG) (24; 16.2%). Only corticosteroids use was associated with a reduction in ICU mortality (p = 0.0250) at univariate analysis but not at multivariate analysis (p = 0.7196).
Discussion
HLH is an under-recognized, life-threatening syndrome requiring prompt but challenging diagnosis and treatment, especially in the ICU context. Although limited data exist on critically ill adult with HLH, in recent years there has been a growing interest in understanding the epidemiology and outcomes of this condition (1, 6). A large retrospective study conducted in a French ICU and a German pooled analysis already showed clinical relevance of HLH in intensive care setting, highlighting most relevant triggers and clinical features of critically ill patients with HLH.
In this paper we reviewed the evidence from 126 case reports and case series that analyzed cases of HLH in the ICU.
Most of the articles included in our analysis come from North America and Europe and this geographical distribution could be explained by the poor availability of clinical and laboratory resources in low-and middle-income countries.
Included patients were mainly male, in line with data reported in the literature (1, 7).
The mortality we observed in this analysis is also in line with the values reported in other studies on severe patients with HLH without any significant differences being observed between the genders.
Although age at the univariate analysis seems to be correlated with mortality, the limited sample size probably did not allow us to confirm the data at the multivariate analysis. On the other hand, viral infections appear to explain a significant increase in mortality and among viral infections those induced by SARS-CoV-2 seem to be particularly important, probably due to the intense inflammatory pattern brought about by COVID-19. It should also be considered that the growing interest in HLH in recent years coincides with the pandemic period and the growing research activity related.
Viral infection, and particularly that induced by EBV, appears to have a more significant impact than reported by other works conducted both in ICU and outside (6, 7). However, it was not possible to identify a statistically higher mortality in the EBV group.
We observed a frequency of autoimmune disease in line with data reported in the literature. Hematologic malignancy accounted for a small share of triggers (12,2%) even in comparison with other studies on ICU and non-ICU population (6, 7), but strongly correlated with higher mortality. Hematologic patients requiring ICU admission are burdened with a constant increase in mortality regardless of diagnosis (8). In this context HLH in patients with hematologic malignancy can be seen as the progression of patients characterized by massive immunological dysregulation to multi-organ failure.
Almost two-third of patients underwent BMB or biopsy of other immune tissues and this cohort showed a significantly lower mortality. It can be assumed that this confirms the role of histopathology as a fundamental criterion used by clinicians to establish diagnosis and start a specific treatment for HLH. However, it should be noted that also composite scores (especially HScore) proved to be able to correctly guide clinical decision with sufficiently good sensitivity and specificity.
No treatment, except for high dose corticosteroids, has been shown to significantly reduce mortality and even this efficacy has not been confirmed by multivariate analysis or found in other studies.
This could be explained by at least two reasons: first, HLH treatments – both pharmacological and non-pharmacological – lack of standardization and the choice of their use is left to single centers expertise, second, all these therapies draw their efficacy from hematology setting and may not be as effective for critically ill patients. Aside from standard treatments suggested by available guidelines based on corticosteroids and etoposide as first-line therapy, Ruxolitinib, a Janus Kinase pathways inhibitor, represents a valid etoposide-sparing drug that showed association with favourable outcomes in association with steroids.
Although a previous review (9) highlighted the importance of this syndrome in critical area, specific and updated evidence supporting personalized diagnostic and therapeutic strategies for ICU is still lacking (1). For these reasons, we consider the results of the present work of particular interest in the context of intensive care, since HLH is a condition classically treated and studied by hematologist who developed a strong diagnostic awareness and standardized treatment protocols. Furthermore, the differential diagnosis of this condition in the critical care context is typically septic shock and/or MOD that accounts for a vast majority of ICU population.
Considering the overall review, our analysis appears to highlight a decidedly significant incidence of HLH, which is progressively increasing over time, in step with the diagnostic awareness of the treating physicians. Diagnostic score, such as HScore, can rapidly lead to HLH diagnosis with a more than acceptable level of certainty even in critically ill patients making HLH rule out easy and feasible when assessing most critical ICU patients.
The growing relevance of laboratory tests—triglycerides, ferritin, etc.—in new diagnostic protocols represents another great clinical clue. In fact, although invasive diagnostic methods are certainly difficult, particularly in critical patients, and require more time for reporting, the combination of clinical and laboratory diagnosis scores represents a feasible option that should be highlighted. Soluble IL2 receptor (CD25) is a simple and under-utilized biomarker for T cell activation in HLH and its use should be encouraged in HLH diagnostic work up. CD25 is also useful for differentiating catastrophic Still’s disease from HLH, as both condition could possibly need intensive care support. However, in our review, we found that these laboratory tests were explicitly reported only in a minority of cases, possibly suggesting how they still need to be implemented in clinical practice.
Data from this literature review show how diagnostic score, such as HScore, can rapidly lead to HLH diagnosis with a more than acceptable level of certainty even in critically ill patients (4, 10). A possible diagnostic and treatment approach for HLH, applicable in the ICU setting, is suggested in Figure 2.
Figure 2. Diagnostic approach and treatment strategies in critically ill patients with HLH. *Knaak et al. demonstrated that a ferritin level > 3,000 μg/L improved diagnostic power when associated with HLH-2004 score; Lachmann et al. suggest that a threshold of 9,000 μg/L is very sensible and specific for HLH diagnosis in ICU SIRS sistemic inflammatory response syndrome; MODs multi organ dysfunction; HSCT hematopoietic stem cell transplantation, CAR-T chimeric antigen receptor T-cell, BMB bone marrow biopsy, CSF cerebrospinal fluid.
Limitations
Our study has several limitations. First, the narrative (non-systematic) approach to data selection, the absence of formal bias assessment, and the inherent limitations of using uncontrolled observational data. In fact, all papers included in our analysis are case report or case series, with risk of survival bias even if overall ICU mortality is in line with other studies about HLH in critical care population.
Given the nature of the included studies, we did not apply formal risk of bias tools, which are typically designed for comparative or interventional studies.
Furthermore, we decided to include in this analysis only articles published after 2014 when HScore has been proposed for HLH diagnosis, to underline the importance of the proposed score and the impact on clinical diagnosis. However, this decision might limit the number of the included articles.
Finally, due to lack of standardized medical treatment for HLH in critical care population, we found strong differences in treatment strategies among different reports, for example in steroid use with different molecules and different regimens, limiting the strength of the treatment indications.
Conclusion
HLH is a syndrome characterized by immune dysregulation and hyperinflammation that can present with multi-organ disfunction. Prompt diagnosis in ICU is particularly challenging due to critical presentation, limited diagnostic options and clinical awareness.
Given that several HLH trigger are extremely frequent in critical patients, HLH should always be considered in patients with MOD or sepsis/septic shock-like clinical presentation without an established etiology and predisposing risk factors for HLH.
This narrative review is deliberately based on case reports and case series, with the aim of evaluating the available ICU-specific literature, limited, but of growing relevance. Despite the underlined limitations, some aspects of great clinical relevance emerge, in particular the association of SARS-CoV-2 and hematologic malignancies with mortality. Diagnostic scores such as HScore or HLH-2004 can help clinicians in identifying HLH especially with the combination of non-invasive laboratory tests, but the relevance of the role of bone marrow biopsy, remain pivotal. In the absence of effective treatment strategies, which continue to be mutuated from hematologic populations, further studies are needed to develop treatment protocols tailored on critical care population.
Data availability statement
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.
Author contributions
GM: Writing – original draft, Supervision, Investigation, Writing – review & editing, Conceptualization, Methodology. RT: Writing – review & editing, Investigation, Data curation, Visualization, Writing – original draft, Formal analysis. GA: Investigation, Writing – review & editing, Data curation. CB: Writing – review & editing, Data curation. GS: Writing – review & editing. AB: Data curation, Writing – review & editing. VF: Writing – review & editing. CF: Writing – review & editing, Formal analysis. LB: Writing – review & editing.
Funding
The author(s) declare that no financial support was received for the research and/or publication of this article.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Abbreviations
HLH, Hemophagocytic Lymphohistiocytosis; ICU, Intensive Care Unit; MOD, Multiorgan Disfunction; MOF, Multiorgan Failure; IMV, Invasive Mechanical Ventilation; CRRT, Continuous Renal Replacement Therapy; IVIG, Intravenous Immunoglobulin; BMB, Bone Marrow Biopsy; AKI, Acute Kidney Injury; ALF, Acute Liver Failure; ARF, Acute Respiratory Failure; URTI, Upper Respiratory Tract Syndrome; AIDS, Acquired Immunodeficency Syndrome; ECMO, Extracorporeal Membrane Oxygenator; CAR-T, Chimeric Antigen Receptor – T cell; CSF, Cerebrospinal Fluid.
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Keywords: septic shock, immune dysregulation, hematology critical care, hemophagocytic lymphohistiocytosis (HLH), hemophagocytic syndromes (HPS), HLH-2004 criteria, HScore
Citation: Montrucchio G, Traversi R, Arrigo G, Bonetto C, Sales G, Busca A, Fanelli V, Filippini C and Brazzi L (2025) Hemophagocytic Lymphohistiocytosis in the adult critically ill: a narrative review of case reports and case series. Front. Med. 12:1622770. doi: 10.3389/fmed.2025.1622770
Edited by:
Eizo Watanabe, Aichi Medical University, JapanReviewed by:
Luke Chen, University of British Columbia, CanadaKasumi Satoh, Akita University Hospital, Japan
Abhimanyu Chand, National Academy of Medical Sciences, Nepal
Copyright © 2025 Montrucchio, Traversi, Arrigo, Bonetto, Sales, Busca, Fanelli, Filippini and Brazzi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Riccardo Traversi, cmljY2FyZG8udHJhdmVyc2lAdW5pdG8uaXQ=
†These authors have contributed equally to this work and share first authorship