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Primary hemophagocytic lymphohistiocytosis, a rare genetic immune disorder characterized by hyperinflammation, manifests in infancy and is associated with high mortality. In a study involving 34 children, an antibody to interferon-γ (emapalumab) produced responses in 65%; it served as a bridge to marrow transplantation in 70% of those who had received previous treatment.

Hemophagocytic lymphohistiocytosis (HLH) is a rapidly progressing, life-threatening syndrome characterized by excessive immune activation, often presenting as a complex cytokine storm. This hyperactive immune response can lead to multi-organ failure and systemic damage, resulting in an extremely short survival period if left untreated. Over the past decades, although HLH has garnered increasing attention from researchers, there have been few advancements in its treatment. The cytokine storm plays a crucial role in the treatment of HLH. Investigating the detailed mechanisms behind cytokine storms offers insights into targeted therapeutic approaches, potentially aiding in early intervention and improving the clinical outcome of HLH patients. To date, there is only one targeted therapy, emapalumab targeting interferon-γ, that has gained approval for primary HLH. This review aims to summarize the current treatment advances, emerging targeted therapeutics and underlying mechanisms of HLH, highlighting its newly discovered targets potentially involved in cytokine storms, which are expected to drive the development of novel treatments and offer fresh perspectives for future studies. Besides, multi-targeted combination therapy may be essential for disease control, but further trials are required to determine the optimal treatment mode for HLH.

Hemophagocytic lymphohistiocytosis (HLH) is a severe and life-threatening hyperinflammatory disorder characterized by dysregulated immune activation, primarily driven by excessive stimulation of cytotoxic lymphocytes (CTLs) and macrophages. This uncontrolled immune response leads to cytokine-induced tissue damage and multiorgan dysfunction. HLH presents a significant clinical challenge due to its rapid progression and high mortality rate. In adult patients, current first-line treatment strategies, adapted from pediatric protocols such as HLH-94 and HLH-2004, achieve complete disease resolution in only approximately 50% of cases. The urgent need for more effective therapeutic options is underscored by the lack of targeted treatments and the persistent high mortality associated with HLH. However, the pathophysiology of HLH remains complex and incompletely understood, involving multiple immune dysregulations, diverse etiologies, and variable clinical presentations, making drug development particularly challenging. Drawing from recent advancements, this review provides a translational perspective on the immunopathological mechanisms underlying HLH, highlighting emerging therapeutic targets and novel treatments currently under clinical investigation. By synthesizing these insights, we aim to identify key opportunities for the development of innovative therapies to improve patient outcomes.

Autoimmune polyglandular syndrome type 1 (APS-1) is a rare inborn error of immunity caused by mutations in the gene, typically associated with chronic mucocutaneous candidiasis, hypoparathyroidism, and adrenal insufficiency. We report the first known case of APS-1 complicated by a life-threatening combination of secondary hemophagocytic lymphohistiocytosis (sHLH) and atypical hemolytic uremic syndrome (aHUS), successfully treated with targeted and supportive therapies. A 16-year-old female with a diagnosis of APS-1 confirmed by the presence of the nonsense variant c.415C>T (R139X) in exon 3 and the Finnish major mutation c.769C>T (R257X) in exon 6 of the AIRE gene presented with fever, cytopenias, organomegaly, and hyperferritinemia, fulfilling criteria for sHLH. Despite immunosuppressive therapy, she developed acute kidney injury, thrombocytopenia, and microangiopathic hemolytic anemia, consistent with aHUS. Treatment with the IL - 1 receptor antagonist anakinra and the complement inhibitor eculizumab led to rapid resolution of systemic inflammation and progressive renal and hematological recovery. sHLH is an exceptionally rare complication in APS-1 and has so far been reported in only one patient with a combined EBV and SARS-CoV-2 infection. aHUS has never been described in patients with APS-1. This case highlights the potential for hyperinflammatory and complement-mediated complications in APS-1, supporting the hypothesis of a cytokine storm syndrome that bridges features of sHLH and aHUS. It broadens the known spectrum of immune dysregulation in APS-1 and underscores the importance of early recognition and combined immunomodulatory treatment in similar clinical scenarios.

Improved awareness of hemophagocytic lymphohistiocytosis (HLH) among clinicians has led to an increase in its diagnosis. Often diagnosis is made based on the HLH- 2004 criteria. While these criteria have considerable strengths, they lack specificity and may be fulfilled in the setting of many pro-inflammatory disorders. Genetic defects affecting cellular cytotoxicity cause familial (primary) HLH. On the other hand, secondary HLH is more a pathophysiologic process common to many conditions, rather than a singular disease entity. Improved genetic, immunologic, and functional testing have changed not only the way we diagnose HLH, but also how we treat it. In 2004, there were few active agents and regimens. In 2024, there are multiple safe and effective targeted therapies. We have begun to understand that routine and immediate use of etoposide-based therapy in secondary HLH is likely not appropriate, and emerging cytokine-directed therapies may be more rational interventions. Moreover, it is recognized that identifying and treating the driver of secondary HLH is at least as important as treating the cytokine storm and immune dysregulation. Unfortunately, over-reliance on, and narrow interpretation of, the HLH- 2004 criteria can lead to overdiagnosis, misdiagnosis, and unneeded exposure to drugs that can be harmful. It is important that clinicians understand the limitations of the current diagnostic paradigms for secondary HLH, and the shortcomings of reflexive use of etoposide-based therapy. Herein we will discuss the pros and cons of the current paradigm for the recognition, diagnosis, and treatment of secondary HLH.

Background Epstein–Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) is the most frequent subtype of secondary HLH triggered by infections. Previous studies have shown that ~30 % or more of patients with EBV-HLH do not respond to standard therapy. This study investigated the efficacy and safety profile of a modified DEP regimen in combination with PEG-aspargase (L-DEP) as a salvage therapy for refractory EBV-HLH. Methods In this study from October 2014 to October 2015, 28 patients with refractory EBV-HLH received a L-DEP regimen at the Beijing Friendship Hospital, Capital Medical University. Treatment efficacy and adverse events were evaluated at 2 and 4 weeks after L-DEP treatment. Results Median EBV-DNA concentrations before and 2 weeks after receiving the L-DEP regimen were 9.6 × 10 5 (1.5 × 10 4  − 1 × 10 9 ) copies/mL and 2.2 × 10 5 (3.8 × 10 2  − 1.2 × 10 7 ) copies/mL, respectively; the post-treatment values were significantly lower than that of the pretreatment ( P  = 0.048). Nine of the 28 study patients achieved complete response (CR) and 15 partial response (PR), resulting in an overall response rate of 85.7 % (CR+PR). Four patients who did not achieve response died within 4 weeks of receiving L-DEP. Thirteen of the 24 patients who achieved partial or complete response received subsequent allogenic hematopoietic stem cell transplantation (allo-HSCT). Ten of these 13 patients survived until 1 March 2016. The major adverse effects of the L-DEP regimen were high serum amylase concentrations, abnormal liver function, and coagulation disorders. Conclusions This study suggests that L-DEP is a safe and effective salvage therapy prior to allo-HSCT for refractory EBV-HLH and increases the possibility of such patients receiving allo-HSCT. A prospective multicenter large-scale clinical trial that aims to validate the L-DEP regimen for refractory EBV-HLH is currently underway (ClinicalTrails.gov Identifier: NCT02631109).

Background The BRAF V600E mutation is a rare genetic alteration in cholangiocarcinoma for which sequential therapy with immune checkpoint inhibitors (ICIs) and BRAF/MEK inhibitors may be effective. However, the full spectrum of adverse events associated with the sequential use of these agents remains unclear. Hemophagocytic lymphohistiocytosis (HLH) is a fatal cytokine release syndrome that can be triggered by a cytokine storm. Case A 49‐year‐old man underwent left lateral hepatectomy and adjuvant chemotherapy for cholangiocarcinoma and subsequently developed lymph node recurrence. The patient initially received systemic chemotherapy with gemcitabine, cisplatin, and S‐1; however, due to disease progression, the regimen was switched to gemcitabine, cisplatin, and durvalumab. After these treatments, a BRAF V600E mutation was identified through comprehensive gene panel testing, leading to the initiation of BRAF and MEK inhibitors. However, 3 months later, the patient presented to the emergency department of Steel Memorial Muroran Hospital with fever and fatigue in June 2024. He was initially diagnosed with septic shock but was unresponsive to broad‐spectrum antibiotics. Laboratory tests revealed elevated ferritin levels, elevated soluble interleukin‐2 receptor levels, and Epstein–Barr Virus (EBV)‐DNA. HLH was diagnosed, and multidisciplinary treatment, including steroid pulse therapy, was initiated. The patient's condition improved dramatically, and he survived. Conclusion We report a rare case of cholangiocarcinoma with suspected EBV‐associated HLH that developed after sequential therapy with an ICI and BRAF/MEK inhibitors. Clinicians should consider HLH as a differential diagnosis in patients with a history of ICI therapy who present with severe unexplained inflammation or shock. Prompt diagnosis and multidisciplinary management are crucial to prevent death.

Background. Aggressive natural killer cell leukemia (ANKL) is rare and difficult to diagnose in early stages, with no standard treatment and a poor prognosis. Case presentation. Two adolescents with ANKL presented with hemophagocytic lymphohistiocytosis (HLH), with Case-1 presenting as refractory HLH and Case-2 with lung involvement. The morphology of bone marrow showed an increase in unidentified cells, which mainly expressed CD56. Cytogenetic analysis showed complex karyotypes. Both patients received intensive combined chemotherapy based on pegaspargase and anthracyclines. Case-1 died of tumor lysis syndrome. Case-2 underwent hematopoietic stem cell transplantation and is currently alive and disease-free. Conclusions. HLH can serve as the initial manifestation of ANKL. Leukemia cells of ANKL have significant variations in the morphology and mainly express CD56. Intensive combination chemotherapy based on pegaspargase and anthracyclines may be considered for ANKL.

COVID-19 infection has a heterogenous disease course; it may be asymptomatic or causes only mild symptoms in the majority of the cases, while immunologic complications such as macrophage activation syndrome also known as secondary hemophagocytic lymphohistiocytosis, resulting in cytokine storm syndrome and acute respiratory distress syndrome, may also occur in some patients. According to current literature, impairment of SARS-CoV-2 clearance due to genetic and viral features, lower levels of interferons, increased neutrophil extracellular traps, and increased pyroptosis and probable other unknown mechanisms create a background for severe disease course complicated by macrophage activation syndrome and cytokine storm. Various genetic mutations may also constitute a risk factor for severe disease course and occurrence of cytokine storm in COVID-19. Once, immunologic complications like cytokine storm occur, anti-viral treatment alone is not enough and should be combined with appropriate anti-inflammatory treatment. Anti-rheumatic drugs, which are tried for managing immunologic complications of COVID-19 infection, will also be discussed including chloroquine, hydroxychloroquine, JAK inhibitors, IL-6 inhibitors, IL-1 inhibitors, anti-TNF-α agents, corticosteroids, intravenous immunoglobulin (IVIG), and colchicine. Early recognition and appropriate treatment of immunologic complications will decrease the morbidity and mortality in COVID-19 infection, which requires the collaboration of infectious disease, lung, and intensive care unit specialists with other experts such as immunologists, rheumatologists, and hematologists.

ObjectiveHaemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are life-threatening systemic hyperinflammatory syndromes that can develop in most inflammatory contexts. They can progress rapidly, and early identification and management are critical for preventing organ failure and mortality. This effort aimed to develop evidence-based and consensus-based points to consider to assist clinicians in optimising decision-making in the early stages of diagnosis, treatment and monitoring of HLH/MAS.MethodsA multinational, multidisciplinary task force of physician experts, including adult and paediatric rheumatologists, haematologist/oncologists, immunologists, infectious disease specialists, intensivists, allied healthcare professionals and patients/parents, formulated relevant research questions and conducted a systematic literature review (SLR). Delphi methodology, informed by SLR results and questionnaires of experts, was used to generate statements aimed at assisting early decision-making and optimising the initial care of patients with HLH/MAS.ResultsThe task force developed 6 overarching statements and 24 specific points to consider relevant to early recognition of HLH/MAS, diagnostic approaches, initial management and monitoring of HLH/MAS. Major themes included the simultaneous need for prompt syndrome recognition, systematic evaluation of underlying contributors, early intervention targeting both hyperinflammation and likely contributors, careful monitoring for progression/complications and expert multidisciplinary assistance.ConclusionThese 2022 EULAR/American College of Rheumatology points to consider provide up-to-date guidance, based on the best available published data and expert opinion. They are meant to help guide the initial evaluation, management and monitoring of patients with HLH/MAS in order to halt disease progression and prevent life-threatening immunopathology.