Hemophagocytic Lymphohistiocytosis

1. Disease Information

1.1 Overview (what is HLH?)

HLH is a life‑threatening hyperinflammatory syndrome characterized by ineffective termination of an immune response and uncontrolled activation of immune effector cells, resulting in systemic inflammation, tissue infiltration, and multi‑organ injury. Multiple recent reviews describe HLH as severe “dysregulated inflammation” driven by immune activation in response to a provoking trigger (lee2023diagnosisandmanagement pages 1-3, zoreflorenz2023inpatientrecognitionand pages 1-2).

Direct abstract‑quotable definitions: - HLH is “a life‑threatening syndrome of excessive, dysregulated inflammation in response to a provoking trigger.” (Lee & Logan, Cancers, 2023‑03; https://doi.org/10.3390/cancers15061839) (lee2023diagnosisandmanagement pages 1-3) - HLH is “a hyperinflammatory process that develops in patients with genetic abnormalities, hematologic malignancies, chronic inflammatory states, or infections.” (Zoref‑Lorenz et al., ASH Education Program, 2023‑12; https://doi.org/10.1182/hematology.2023000509) (zoreflorenz2023inpatientrecognitionand pages 1-2)

1.2 Classification (primary vs secondary)

Current clinical framing separates: - Primary (familial/genetic) HLH: due to congenital defects (typically in cytotoxic lymphocyte granule exocytosis/killing pathways), often presenting in infancy/early childhood. (lee2023diagnosisandmanagement pages 1-3, wimmer2024outcomeofadult pages 9-15) - Secondary (acquired) HLH: HLH syndrome arising in the context of triggers such as infection, malignancy, rheumatologic disease (macrophage activation syndrome, MAS), or iatrogenic immune perturbation. (lee2023diagnosisandmanagement pages 1-3, zoreflorenz2023inpatientrecognitionand pages 1-2)

1.3 Synonyms and alternative names

Commonly used near‑synonyms/related terms in recent sources include: - Hemophagocytic syndrome (used interchangeably in some clinical contexts) (zoreflorenz2023inpatientrecognitionand pages 1-2) - Macrophage activation syndrome (MAS) (a form of secondary HLH often in rheumatologic contexts) (lee2023diagnosisandmanagement pages 1-3) - Immune effector cell–associated HLH‑like syndrome (HLH‑like toxicities after CAR‑T therapy; overlaps with CRS) (concept referenced via HLH‑like toxicities) (zoreflorenz2023inpatientrecognitionand pages 1-2)

1.4 Disease identifiers (ontology/coding)

• MONDO / Orphanet / OMIM / ICD‑10/ICD‑11 / MeSH: not retrieved in this run; must be curated from the authoritative databases.

1.5 Evidence source types

The information summarized here is derived from: - Aggregated literature resources (reviews, consensus guideline) (lee2023diagnosisandmanagement pages 1-3, zoreflorenz2023inpatientrecognitionand pages 1-2, cox2024diagnosisandinvestigation pages 10-15) - Retrospective cohort/dissertation evidence for frequencies (adult HLH cohort) (wimmer2024outcomeofadult pages 55-56) - Scoping/systematic reviews for trigger‑specific epidemiology/outcomes (e.g., tick‑borne disease HLH; TB‑HLH) (jevtic2024hemophagocyticlymphohistiocytosis(hlh) pages 1-2) - Clinical trial registries (NCT entries) (NCT03312751 chunk 1, NCT03985423 chunk 1)

2. Etiology

2.1 Disease causal factors

Primary HLH (genetic causes)

Primary HLH is caused by inherited defects in lymphocyte cytotoxic machinery. Recent and supporting sources emphasize that congenital “defects in cytolytic pathway proteins” define primary HLH (pHLH) (lee2023diagnosisandmanagement pages 1-3), often involving granule exocytosis/killing genes (babolpokora2021moleculargeneticsdiversity pages 1-2, chinnici2023approachinghemophagocyticlymphohistiocytosis pages 1-2).

Secondary HLH (triggered hyperinflammation)

Secondary HLH is typically driven by a highly immunogenic trigger rather than a single monogenic cytotoxicity defect in adults (lee2023diagnosisandmanagement pages 1-3). Triggers include: - Infections: especially herpesviruses such as EBV, CMV, HSV, HIV (lee2023diagnosisandmanagement pages 1-3, zoreflorenz2023inpatientrecognitionand pages 1-2) - Malignancy: a major adult category, notably lymphomas (lee2023diagnosisandmanagement pages 1-3) - Rheumatologic/chronic inflammatory disease: MAS (lee2023diagnosisandmanagement pages 1-3) - Iatrogenic/drug‑related: CAR‑T, immune checkpoint blockade (ICB/ICI) (zoreflorenz2023inpatientrecognitionand pages 1-2)

2.2 Risk factors

Genetic risk factors

Even in clinically “secondary” HLH, genetic predisposition can be present. A cited retrospective Italian study reported monoallelic mutations in FHL‑related genes in 43/240 (18%) secondary HLH cases (wimmer2024outcomeofadult pages 19-23), suggesting partial cytotoxic pathway impairment may act as a susceptibility factor.

Environmental/infectious risk factors

• EBV is repeatedly highlighted as a leading infectious association in adults (papazachariou2024hemophagocyticlymphohistiocytosistriggered pages 1-2, lee2023diagnosisandmanagement pages 1-3, zoreflorenz2023inpatientrecognitionand pages 1-2) and a common trigger in pediatric secondary HLH in a Polish cohort (23/35; 65%) (babolpokora2021moleculargeneticsdiversity pages 1-2).
• Trigger‑specific reviews provide examples of infectious risk contexts:
• Tick‑borne illnesses: Ehrlichia spp. 45.9% of 98 tick‑borne HLH cases (jevtic2024hemophagocyticlymphohistiocytosis(hlh) pages 1-2)
• Tuberculosis‑associated HLH: systematic review with 39% mortality (lee2023diagnosisandmanagement pages 1-3)

2.3 Protective factors

No explicit genetic or environmental protective factors were identified in the retrieved evidence.

2.4 Gene–environment interactions

Evidence in this run supports a model where partial genetic impairment of cytotoxic pathways interacts with strong immune triggers (e.g., viral infections, malignancy) to precipitate HLH. This is consistent with the observed monoallelic FHL‑gene findings in secondary HLH (wimmer2024outcomeofadult pages 19-23) and the conceptual framing that adult HLH is often trigger‑driven (lee2023diagnosisandmanagement pages 1-3).

3. Phenotypes

3.1 Core phenotype spectrum (symptoms/signs/lab abnormalities)

Across recent reviews, common HLH features include fever, hepatosplenomegaly, cytopenias, hypertriglyceridemia, hypofibrinogenemia, elevated liver enzymes, hyperferritinemia, and elevated soluble CD25 (sCD25) (zoreflorenz2023inpatientrecognitionand pages 1-2, chinnici2023approachinghemophagocyticlymphohistiocytosis pages 1-2).

Direct quotable statement (phenotype set): HLH patients may present with “fever, central nervous system symptoms, cytopenias, or elevated liver enzymes” (zoreflorenz2023inpatientrecognitionand pages 1-2).

3.2 Frequencies from an adult cohort (real‑world phenotype distribution)

In a 62‑patient adult HLH cohort, high‑frequency findings included: - Ferritin ≥2000 µg/L: 97% (60/62) (wimmer2024outcomeofadult pages 55-56) - Temperature ≥38.4°C: 93% (56/60) (wimmer2024outcomeofadult pages 55-56) - Splenomegaly: 90% (54/60) (wimmer2024outcomeofadult pages 55-56) - AST ≥30 U/L: 90% (56/62) (wimmer2024outcomeofadult pages 55-56) - Triglycerides ≥132.7 mg/dL: 90% (55/61) (wimmer2024outcomeofadult pages 55-56) - sCD25 ≥2400 U/mL: 88% (53/60) (wimmer2024outcomeofadult pages 55-56) - Hemophagocytosis on pathology: 58% (33/57) (wimmer2024outcomeofadult pages 55-56) - Hepatomegaly: 62% (38/61) (wimmer2024outcomeofadult pages 55-56)

3.3 Age of onset and course

• Primary/familial HLH “usually manifests itself within the first two years of life” in classic descriptions (wimmer2024outcomeofadult pages 9-15).
• Secondary HLH is “the predominant form in older children and adults” (wimmer2024outcomeofadult pages 9-15).

3.4 Quality of life impact

No disease‑specific QOL instruments or quantitative QOL results were captured in the retrieved sources.

3.5 Suggested HPO terms (examples)

(Recommended for KB normalization; frequencies where available above) - Fever HP:0001945 - Splenomegaly HP:0001744 - Hepatomegaly HP:0002240 - Cytopenia HP:0001873 (and lineage‑specific terms) - Hyperferritinemia HP:0003281 - Hypertriglyceridemia HP:0002155 - Hypofibrinogenemia HP:0004348 - Elevated hepatic transaminases HP:0002910 - Encephalopathy / seizures (CNS involvement noted qualitatively) HP:0001298 / HP:0001250 (zoreflorenz2023inpatientrecognitionand pages 1-2, chinnici2023approachinghemophagocyticlymphohistiocytosis pages 1-2)

4. Genetic/Molecular Information

4.1 Causal genes (core familial HLH)

Core familial HLH genes emphasized across sources include PRF1, UNC13D, STX11, STXBP2 (babolpokora2021moleculargeneticsdiversity pages 1-2, gadourylevesque2020frequencyandspectrum pages 1-2, chinnici2023approachinghemophagocyticlymphohistiocytosis pages 1-2).

A structured gene summary is provided in Artifact 01.

Table: This table summarizes HLH genetic causes and related syndromes mentioned in the retrieved evidence, emphasizing the affected gene, pathway role, inheritance, and clinical associations. It is useful for distinguishing classic familial HLH degranulation defects from syndromic and inflammasome-related HLH predisposition genes.

4.2 Pathogenic variants (types, consequences)

The retrieved evidence emphasizes loss‑of‑function disruption of cytotoxic granule assembly/trafficking/exocytosis. A 2020 disease‑specific variant repository (FHLdb) (outside the 2023–2024 priority window but useful for variant-class distribution) reported variant classes in familial HLH genes (PRF1, UNC13D, STXBP2, STX11), including missense, frameshift, nonsense, splicing, in‑frame indels, deep intronic, and large rearrangements, and explicitly notes ACMG classification categories (lee2023diagnosisandmanagement pages 1-3).

4.3 Modifier genes / digenic inheritance

This run retrieved a dedicated review on digenic inheritance in HLH (Steen et al., 2021) but evidence text was not included in gatherable snippets; thus, digenic inheritance is noted as a concept but not expanded with quoted evidence here.

4.4 Epigenetic information

No HLH‑specific epigenetic mechanisms were captured in the retrieved evidence.

4.5 Chromosomal abnormalities

Not captured in the retrieved evidence.

5. Environmental Information

5.1 Infectious agents

Infections are a major trigger category: - Viral triggers frequently include EBV, CMV, VZV, HSV, HIV, and COVID‑19 (lee2023diagnosisandmanagement pages 1-3, zoreflorenz2023inpatientrecognitionand pages 1-2). - In a 2024 etiologic stratification study, cited adult proportions included herpesviruses accounting for 62% of viral HLH, with 43% EBV and 9% CMV (wu2024etiologicalstratificationand pages 1-2).

5.2 Environmental/lifestyle factors

No specific toxin, lifestyle, or occupational exposures were identified in the retrieved evidence.

6. Mechanism / Pathophysiology

6.1 Causal chain (trigger to clinical manifestations)

A consensus mechanistic chain from recent sources is: 1) Trigger (infection/malignancy/inflammation/iatrogenic immune activation) 2) Failure of cytotoxic control (due to inherited cytotoxic defects or functional exhaustion/overload) → inability to clear antigenic targets and terminate immune activation (lee2023diagnosisandmanagement pages 1-3, zoreflorenz2023inpatientrecognitionand pages 1-2) 3) Persistent activation/expansion of CD8+ T cells and NK cells with excessive cytokine production (lee2023diagnosisandmanagement pages 1-3) 4) IFN‑γ acts as a key driver, activating macrophages leading to hemophagocytosis and tissue infiltration (zoreflorenz2023inpatientrecognitionand pages 1-2) 5) Self‑amplifying inflammation (“cytokine storm”) → cytopenias, hepatic injury, coagulopathy, CNS dysfunction, multi‑organ failure (wimmer2024outcomeofadult pages 19-23, sousa2024prognosticimpactof pages 5-7)

Direct quotable mechanistic statement: IFN‑γ is described as “the main driver of the disease phenotype” in HLH and “activates macrophages associated with hemophagocytosis and tissue infiltration and damage.” (zoreflorenz2023inpatientrecognitionand pages 1-2)

6.2 Key cell types (suggested CL terms)

• Cytotoxic T cell (CD8+): CL:0000625 (lee2023diagnosisandmanagement pages 1-3, zoreflorenz2023inpatientrecognitionand pages 1-2)
• Natural killer cell: CL:0000623 (lee2023diagnosisandmanagement pages 1-3, zoreflorenz2023inpatientrecognitionand pages 1-2)
• Macrophage: CL:0000235 (lee2023diagnosisandmanagement pages 1-3, zoreflorenz2023inpatientrecognitionand pages 1-2)

6.3 Molecular pathways / processes (suggested GO terms)

• Cytolysis / granzyme‑mediated apoptosis: GO:0019835 / GO:0097194 (supported conceptually by perforin/granzyme pathway emphasis) (wimmer2024outcomeofadult pages 19-23)
• Exocytosis / secretory granule exocytosis: GO:0006887 / GO:0031629 (babolpokora2021moleculargeneticsdiversity pages 1-2, chinnici2023approachinghemophagocyticlymphohistiocytosis pages 1-2)
• Interferon‑gamma–mediated signaling pathway: GO:0060333 (zoreflorenz2023inpatientrecognitionand pages 1-2)
• Inflammatory response / cytokine‑mediated signaling: GO:0006954 / GO:0019221 (lee2023diagnosisandmanagement pages 1-3)

6.4 Molecular profiling and biomarkers (selected recent evidence)

• Ferritin and sCD25 are widely used screening/monitoring biomarkers in adult diagnostic workflow (cox2024diagnosisandinvestigation pages 10-15, cox2024diagnosisandinvestigation pages 39-46).
• The HiHASC guideline emphasizes “3Fs” screening: fever, falling blood counts, raised ferritin (cox2024diagnosisandinvestigation pages 10-15, cox2024diagnosisandinvestigation media 50579ca6).

6.5 Model organisms and translational mechanisms

While not extensively detailed in retrieved snippets, multiple sources reference classic cytotoxicity‑defect models (e.g., perforin deficiency) as the basis for IFN‑γ‑centric mechanistic understanding (wimmer2024outcomeofadult pages 19-23, zoreflorenz2023inpatientrecognitionand pages 1-2).

7. Anatomical Structures Affected

7.1 Organ level (UBERON suggestions)

Commonly affected organs and systems: - Spleen (splenomegaly): UBERON:0002106 (wimmer2024outcomeofadult pages 55-56) - Liver (hepatomegaly, transaminitis): UBERON:0002107 (wimmer2024outcomeofadult pages 55-56, zoreflorenz2023inpatientrecognitionand pages 1-2) - Bone marrow (hemophagocytosis, cytopenias): UBERON:0002371 (wimmer2024outcomeofadult pages 55-56) - Central nervous system involvement: UBERON:0001016 (qualitative CNS symptoms and diagnostic criteria) (zoreflorenz2023inpatientrecognitionand pages 1-2, chinnici2023approachinghemophagocyticlymphohistiocytosis pages 1-2)

7.2 Tissue/cell level

Reticuloendothelial system involvement with activated macrophages and infiltrating lymphocytes is emphasized (zoreflorenz2023inpatientrecognitionand pages 1-2, wimmer2024outcomeofadult pages 19-23).

7.3 Subcellular level

Not explicitly extracted in this run; implied involvement includes cytotoxic granules/secretory lysosome biology in NK/CD8 cells (babolpokora2021moleculargeneticsdiversity pages 1-2, chinnici2023approachinghemophagocyticlymphohistiocytosis pages 1-2).

8. Temporal Development

8.1 Onset pattern

HLH can have acute/subacute presentations with rapid progression; the adult inpatient review highlights the need for timely investigations and balancing workup with rapid treatment decisions (zoreflorenz2023inpatientrecognitionand pages 1-2).

8.2 Progression/course

Untreated or refractory disease may progress to “cytokine storm causing multi-organ failure and eventually death” (wimmer2024outcomeofadult pages 19-23).

9. Inheritance and Population

9.1 Epidemiology (selected quantitative findings)

Epidemiology varies by setting and trigger. Examples of quantitative disease burden in retrieved sources: - Country prevalence estimates: Japan 1:800,000, China 1.04:1,000,000, England 1–2:1,000,000 (Papazachariou & Ioannou 2024) (papazachariou2024hemophagocyticlymphohistiocytosistriggered pages 1-2). - Adult etiology distribution: In North America and Europe, “around 50% of adult HLH is due to an underlying malignancy” (lee2023diagnosisandmanagement pages 1-3).

A structured summary table is provided below.

Table: This table compiles key quantitative epidemiology and outcome data for HLH from recent reviews and cohorts, alongside major trigger categories. It is useful for quickly comparing disease burden, mortality, and common etiologic patterns across clinical contexts.

9.2 Inheritance (for genetic etiology)

• Classic familial HLH (FHL2–FHL5) genes are typically autosomal recessive (PRF1, UNC13D, STX11, STXBP2) (babolpokora2021moleculargeneticsdiversity pages 1-2).
• X‑linked predisposition syndromes include SH2D1A (XLP1) and XIAP/BIRC4 (XLP2) (babolpokora2021moleculargeneticsdiversity pages 1-2, wimmer2024outcomeofadult pages 19-23).

9.3 Population demographics

• Tick‑borne HLH scoping review: mean age 43.7, 64% male (jevtic2024hemophagocyticlymphohistiocytosis(hlh) pages 1-2).
• ICI‑associated HLH review: 18 males / 9 females, mean age 58 (range 26–86) (Xu et al., 2024) (paper retrieved but not in evidence ids; therefore not cited here; the abstract is included in paper_search output but no pqac id.)

10. Diagnostics

10.1 Clinical criteria

HLH is “commonly defined when a patient meets 5 or more of the 8 enrollment criteria from the HLH‑2004 study” (zoreflorenz2023inpatientrecognitionand pages 1-2). The tick‑borne HLH review reiterates HLH‑2004 criteria and includes numeric cutoffs for fever and cytopenias (jevtic2024hemophagocyticlymphohistiocytosis(hlh) pages 1-2).

10.2 Adult diagnostic workflow (recent guideline)

The 2024 HiHASC guideline emphasizes: - A 3‑step approach anchored in the “3Fs” screen: fever, falling blood counts, raised ferritin (cox2024diagnosisandinvestigation pages 10-15, cox2024diagnosisandinvestigation media 50579ca6) - Baseline quick‑screen labs available in 6–12 hours: full blood count, renal profile, ferritin, LFTs (including AST and LDH), triglycerides, fibrinogen (cox2024diagnosisandinvestigation pages 10-15, cox2024diagnosisandinvestigation pages 39-46). - Key caution: “There is no single diagnostic test or classification criteria with sufficient specificity and sensitivity to accurately diagnose HLH” (cox2024diagnosisandinvestigation pages 10-15).

Figure evidence (adult diagnostic algorithm): (cox2024diagnosisandinvestigation media 50579ca6)

10.3 Biomarkers and performance statistics (selected)

• Ferritin: pediatric data cited in HiHASC: ferritin >10,000 µg/L has 90% sensitivity and 98% specificity for HLH (cox2024diagnosisandinvestigation pages 10-15, cox2024diagnosisandinvestigation pages 39-46).
• Malignancy‑associated HLH enrichment: combined cutoff sCD25 >3900 U/mL + ferritin >1000 ng/mL had 84% sensitivity and 81% specificity (cox2024diagnosisandinvestigation pages 10-15, cox2024diagnosisandinvestigation pages 39-46).
• Differential diagnosis aid: adding CRP thresholds improved specificity when distinguishing HLH from AOSD and COVID cytokine storm (goubran2024theroleof pages 2-3).

10.4 Genetic testing strategy

A 2023 diagnostic review emphasizes that genetic analysis is mandatory to confirm familial HLH and that NGS is increasingly used to expand recognition of genetic predisposition, ideally in reference laboratories (chinnici2023approachinghemophagocyticlymphohistiocytosis pages 1-2).

10.5 Differential diagnosis

HLH is described as a “sepsis mimic,” and the diagnostic challenge is distinguishing aberrant from appropriate immune responses (zoreflorenz2023inpatientrecognitionand pages 1-2, sousa2024prognosticimpactof pages 5-7).

A compact diagnostic summary table is provided below.

Table: This table compiles the main quantitative diagnostic thresholds, biomarker performance data, standard regimens, salvage therapies, and key registered trials for HLH from the retrieved evidence. It is designed to support rapid comparison of diagnostic criteria and current treatment implementation.

11. Outcome/Prognosis

11.1 Survival and mortality (selected quantitative findings)

• Overall mortality in adults often exceeds 40% (wimmer2024outcomeofadult pages 9-15, wimmer2024outcomeofadult pages 19-23).
• Malignancy‑associated HLH has very poor outcomes, with “<20% survival at one year (median survival ~2 months)” (lee2023diagnosisandmanagement pages 1-3).
• Trigger‑specific examples:
• Tick‑borne infection‑associated HLH: mortality 16.3% across 98 cases (jevtic2024hemophagocyticlymphohistiocytosis(hlh) pages 1-2).
• Tuberculosis‑associated HLH systematic review: mortality 39% (lee2023diagnosisandmanagement pages 1-3).

11.2 Prognostic factors

• Elevated sCD25 is discussed as a potentially adverse prognostic parameter (adult cohort) (wimmer2024outcomeofadult pages 19-23).

12. Treatment

12.1 Standard regimens (real‑world implementation)

Adult management frequently extrapolates from pediatric HLH trials. The adult malignancy‑associated HLH review summarizes HLH‑94 induction: dexamethasone + etoposide, with intrathecal therapy for CNS disease (lee2023diagnosisandmanagement pages 6-8). A landmark cooperative pediatric study (HLH‑2004) confirms that most patients can be rescued by etoposide/dexamethasone, with 5‑year survival ~61% in 369 children (lee2023diagnosisandmanagement pages 6-8).

12.2 Targeted and emerging therapies (2023–2024 emphasis)

• Ruxolitinib (JAK1/2 inhibitor): A 2023 study of dose escalation in refractory HLH reported improved remission in 4/8 (50%), median time to best response 18.5 days, and estimated 2‑month OS 75%, with no grade ≥3 AEs (song2023doseescalatingruxolitinibfor pages 1-2).
• Emapalumab (anti‑IFN‑γ): pediatric efficacy is highlighted (ORR 65%; 70% to HCT) in a trial context summarized in the adult review (lee2023diagnosisandmanagement pages 8-9), and the adult emapalumab trial was terminated after enrolling 7 patients (NCT03985423 chunk 1).
• Anakinra (IL‑1 blockade): retrospective data suggest better outcomes in MAS than other sHLH contexts (lee2023diagnosisandmanagement pages 8-9).
• Alemtuzumab (anti‑CD52): salvage response reported as 64% in summarized evidence, but with high infection risk (lee2023diagnosisandmanagement pages 8-9).

12.3 HSCT

HSCT is curative intent for familial/relapsed/severe persistent HLH; the adult review notes substantial pre‑HSCT mortality (20–30%) and discusses reduced‑intensity conditioning approaches (lee2023diagnosisandmanagement pages 6-8, lee2023diagnosisandmanagement pages 8-9).

12.4 Clinical trials (recent and active)

Key HLH‑relevant trials in registry evidence include: - Pediatric primary HLH emapalumab Phase 3 completed: NCT03312751 (results posted 2024‑03‑12) (NCT03312751 chunk 1). - Adult HLH emapalumab Phase 2/3 terminated: NCT03985423 (NCT03985423 chunk 1). - Ruxolitinib salvage Phase 3: NCT04120090 (NCT04120090 chunk 1). - Combination emapalumab + ruxolitinib (planned): NCT06951971 (NCT06951971 chunk 1).

12.5 MAXO term suggestions (examples)

• Etoposide therapy: MAXO:0000747 (chemotherapy)
• Glucocorticoid therapy (dexamethasone): MAXO:0000201
• Hematopoietic stem cell transplantation: MAXO:0000748
• Janus kinase inhibitor therapy (ruxolitinib): MAXO:0001302 (JAK inhibitor therapy; placeholder—verify exact MAXO ID in KB)
• Anti‑interferon‑gamma antibody therapy (emapalumab): MAXO:000— (verify exact MAXO term)
• Interleukin‑1 receptor antagonist therapy (anakinra): MAXO:000— (verify exact MAXO term)

13. Prevention

13.1 Primary prevention

No established population‑level primary prevention exists for HLH as a syndrome.

13.2 Secondary/tertiary prevention

The most evidence‑supported “prevention” approach is early recognition and trigger control: - Rapid screening using the “3Fs” and early baseline labs to avoid diagnostic delay (cox2024diagnosisandinvestigation pages 10-15, cox2024diagnosisandinvestigation media 50579ca6). - Early identification and treatment of triggers (e.g., antimicrobials for infection triggers; malignancy‑directed therapy where appropriate) (lee2023diagnosisandmanagement pages 1-3, jevtic2024hemophagocyticlymphohistiocytosis(hlh) pages 1-2).

13.3 Genetic counseling

Because familial HLH is typically autosomal recessive (core FHL genes) or X‑linked (XLP syndromes), genetic confirmation enables family counseling and transplant planning (babolpokora2021moleculargeneticsdiversity pages 1-2, chinnici2023approachinghemophagocyticlymphohistiocytosis pages 1-2).

14. Other Species / Natural Disease

No naturally occurring veterinary HLH evidence was retrieved in this run.

15. Model Organisms

The retrieved evidence base did not provide a full model organism inventory. However, HLH mechanistic understanding is repeatedly grounded in cytotoxicity‑defect models (e.g., perforin deficiency) and IFN‑γ–driven inflammation paradigms (wimmer2024outcomeofadult pages 19-23, zoreflorenz2023inpatientrecognitionand pages 1-2). Additional model‑organism evidence should be curated from dedicated preclinical literature.

Visual evidence: Adult diagnostic algorithm (HiHASC)

The HiHASC guideline’s Figure 1 provides a practical diagnostic workflow (“3Fs” → quick screen labs → HScore/triggers) and is included here as visual evidence (cox2024diagnosisandinvestigation media 50579ca6).

Summary for knowledge base population (high‑confidence items)

• HLH is a syndrome of dysregulated hyperinflammation; classification into primary (genetic) vs secondary (trigger‑associated) remains clinically central (lee2023diagnosisandmanagement pages 1-3, zoreflorenz2023inpatientrecognitionand pages 1-2).
• Adult HLH is frequently malignancy‑associated (~50% in North America/Europe) with poor 1‑year survival (<20%) (lee2023diagnosisandmanagement pages 1-3).
• Diagnostic practice uses HLH‑2004 (5/8 criteria) and HScore (cutoff ~169) alongside rapid screening with ferritin and cytopenias (“3Fs”); ferritin >10,000 µg/L shows high sensitivity/specificity in pediatric data (zoreflorenz2023inpatientrecognitionand pages 1-2, cox2024diagnosisandinvestigation pages 10-15, cox2024diagnosisandinvestigation pages 39-46).
• Core familial genes: PRF1, UNC13D, STX11, STXBP2; syndromic predisposition genes include RAB27A, LYST, AP3B1; X‑linked predisposition includes SH2D1A and XIAP (babolpokora2021moleculargeneticsdiversity pages 1-2, chinnici2023approachinghemophagocyticlymphohistiocytosis pages 1-2).
• Standard therapy remains etoposide+dexamethasone (HLH‑94/HLH‑2004) with HSCT for familial/relapsed/severe persistent disease; newer agents (ruxolitinib, emapalumab, anakinra) are increasingly used in selected contexts, with ongoing trials (lee2023diagnosisandmanagement pages 6-8, song2023doseescalatingruxolitinibfor pages 1-2, NCT03312751 chunk 1, NCT03985423 chunk 1).

References

1. (cox2024diagnosisandinvestigation pages 10-15): Miriam F Cox, Strachan Mackenzie, Ryan Low, Michael Brown, Emilie Sanchez, Aisling Carr, Ben Carpenter, Mark Bishton, Andrew Duncombe, Akpabio Akpabio, Austin Kulasekararaj, Fang En Sin, Alexis Jones, Akhila Kavirayani, Ethan S Sen, Vanessa Quick, Gurdeep S Dulay, Sam Clark, Kris Bauchmuller, Rachel S Tattersall, and Jessica J Manson. Diagnosis and investigation of suspected haemophagocytic lymphohistiocytosis in adults: 2023 hyperinflammation and hlh across speciality collaboration (hihasc) consensus guideline. The Lancet Rheumatology, 6:e51-e62, Jan 2024. URL: https://doi.org/10.1016/s2665-9913(23)00273-4, doi:10.1016/s2665-9913(23)00273-4. This article has 52 citations.

2. (cox2024diagnosisandinvestigation pages 39-46): Miriam F Cox, Strachan Mackenzie, Ryan Low, Michael Brown, Emilie Sanchez, Aisling Carr, Ben Carpenter, Mark Bishton, Andrew Duncombe, Akpabio Akpabio, Austin Kulasekararaj, Fang En Sin, Alexis Jones, Akhila Kavirayani, Ethan S Sen, Vanessa Quick, Gurdeep S Dulay, Sam Clark, Kris Bauchmuller, Rachel S Tattersall, and Jessica J Manson. Diagnosis and investigation of suspected haemophagocytic lymphohistiocytosis in adults: 2023 hyperinflammation and hlh across speciality collaboration (hihasc) consensus guideline. The Lancet Rheumatology, 6:e51-e62, Jan 2024. URL: https://doi.org/10.1016/s2665-9913(23)00273-4, doi:10.1016/s2665-9913(23)00273-4. This article has 52 citations.

3. (zoreflorenz2023inpatientrecognitionand pages 1-2): Adi Zoref-Lorenz, Martin Ellis, and Michael B. Jordan. Inpatient recognition and management of hlh. Hematology. American Society of Hematology. Education Program, 2023 1:259-266, Dec 2023. URL: https://doi.org/10.1182/hematology.2023000509, doi:10.1182/hematology.2023000509. This article has 20 citations.

4. (lee2023diagnosisandmanagement pages 1-3): Jerry C. Lee and Aaron C. Logan. Diagnosis and management of adult malignancy-associated hemophagocytic lymphohistiocytosis. Cancers, 15:1839, Mar 2023. URL: https://doi.org/10.3390/cancers15061839, doi:10.3390/cancers15061839. This article has 45 citations.

5. (wimmer2024outcomeofadult pages 9-15): Thomas Wimmer. Outcome of adult patients with hemophagocytic lymphohistiocytosis: a retrospective analysis. Dissertation, Jan 2024. URL: https://doi.org/10.5282/edoc.33899, doi:10.5282/edoc.33899. This article has 0 citations.

6. (wimmer2024outcomeofadult pages 55-56): Thomas Wimmer. Outcome of adult patients with hemophagocytic lymphohistiocytosis: a retrospective analysis. Dissertation, Jan 2024. URL: https://doi.org/10.5282/edoc.33899, doi:10.5282/edoc.33899. This article has 0 citations.

7. (jevtic2024hemophagocyticlymphohistiocytosis(hlh) pages 1-2): Dorde Jevtic, Marilia Dagnon da Silva, Alberto Busmail Haylock, Charles W. Nordstrom, Stevan Oluic, Nikola Pantic, Milan Nikolajevic, Nikola Nikolajevic, Magdalena Kotseva, and Igor Dumic. Hemophagocytic lymphohistiocytosis (hlh) in patients with tick-borne illness: a scoping review of 98 cases. Infectious Disease Reports, 16:154-169, Feb 2024. URL: https://doi.org/10.3390/idr16020012, doi:10.3390/idr16020012. This article has 24 citations.

8. (NCT03312751 chunk 1): Study to Assess the Efficacy and Safety of Emapalumab in Primary Haemophagocytic Lymphohistiocytosis. Swedish Orphan Biovitrum. 2019. ClinicalTrials.gov Identifier: NCT03312751

9. (NCT03985423 chunk 1): A Study to Evaluate the Efficacy, Safety and Pharmacokinetics of Emapalumab in Adult Patients With HLH. Swedish Orphan Biovitrum. 2020. ClinicalTrials.gov Identifier: NCT03985423

10. (babolpokora2021moleculargeneticsdiversity pages 1-2): Katarzyna Bąbol-Pokora, Magdalena Wołowiec, Katarzyna Popko, Aleksandra Jaworowska, Yenan T. Bryceson, Bianca Tesi, Jan-Inge Henter, Wojciech Młynarski, Wanda Badowska, Walentyna Balwierz, Katarzyna Drabko, Krzysztof Kałwak, Lucyna Maciejka-Kembłowska, Anna Pieczonka, Grażyna Sobol-Milejska, Sylwia Kołtan, and Iwona Malinowska. Molecular genetics diversity of primary hemophagocytic lymphohistiocytosis among polish pediatric patients. Archivum Immunologiae et Therapiae Experimentalis, Oct 2021. URL: https://doi.org/10.1007/s00005-021-00635-4, doi:10.1007/s00005-021-00635-4. This article has 9 citations and is from a peer-reviewed journal.

11. (chinnici2023approachinghemophagocyticlymphohistiocytosis pages 1-2): Aurora Chinnici, Linda Beneforti, Francesco Pegoraro, Irene Trambusti, Annalisa Tondo, Claudio Favre, Maria Luisa Coniglio, and Elena Sieni. Approaching hemophagocytic lymphohistiocytosis. Frontiers in Immunology, Jun 2023. URL: https://doi.org/10.3389/fimmu.2023.1210041, doi:10.3389/fimmu.2023.1210041. This article has 98 citations and is from a peer-reviewed journal.

12. (wimmer2024outcomeofadult pages 19-23): Thomas Wimmer. Outcome of adult patients with hemophagocytic lymphohistiocytosis: a retrospective analysis. Dissertation, Jan 2024. URL: https://doi.org/10.5282/edoc.33899, doi:10.5282/edoc.33899. This article has 0 citations.

13. (papazachariou2024hemophagocyticlymphohistiocytosistriggered pages 1-2): Andria Papazachariou and Petros Ioannou. Hemophagocytic lymphohistiocytosis triggered by herpes simplex virus 1 and 2: a narrative review. Hematology Reports, 16:487-503, Jul 2024. URL: https://doi.org/10.3390/hematolrep16030047, doi:10.3390/hematolrep16030047. This article has 7 citations.

14. (gadourylevesque2020frequencyandspectrum pages 1-2): Vanessa Gadoury-Levesque, Lei Dong, Rui Su, Jianjun Chen, Kejian Zhang, Kimberly A. Risma, Rebecca A. Marsh, and Miao Sun. Frequency and spectrum of disease-causing variants in 1892 patients with suspected genetic hlh disorders. Blood advances, 4 12:2578-2594, Jun 2020. URL: https://doi.org/10.1182/bloodadvances.2020001605, doi:10.1182/bloodadvances.2020001605. This article has 76 citations and is from a peer-reviewed journal.

15. (simon2025anationwideanalysis pages 2-4): Dafna Brik Simon, Yarden Greental Ness, Orly Dgany, Sharon Noy-Lotan, Tanya Krasnov, Galit Berger, Tamar Feuerstein, Jerry Stein, Aviva Kraus, Asaf Yanir, Assaf Barg, Elad Jacoby, Noa Mandel-Shorer, Dan Harlev, Ehud Even-Or, Hannah Tamary, Oded Gilad, Orna Steinberg-Shemer, and Joanne Yacobovich. A nationwide analysis of the phenotype/genotype landscape of hemophagocytic lymphohistiocytosis: unc13d associates with poor prognosis. Genes, 16:1315, Nov 2025. URL: https://doi.org/10.3390/genes16111315, doi:10.3390/genes16111315. This article has 1 citations.

16. (almansi2024hemophagocyticlymphohistiocytosisan pages 2-4): Amjad Almansi, Shahd Alqato, Sami Bawardi, Tariq Sabobeh, Heba Al Madanat, Obadah Alquadan, and Eman Al-Antary. Hemophagocytic lymphohistiocytosis: an updated overview and management approach in the critical care setting. JAP Academy Journal, Mar 2024. URL: https://doi.org/10.58877/japaj.v2i1.119, doi:10.58877/japaj.v2i1.119. This article has 0 citations.

17. (wu2024etiologicalstratificationand pages 1-2): Lin Wu, Xuefang Cao, Jingshi Wang, Qi Kong, Junxia Hu, Lin Shi, Liurui Dou, Deli Song, Leilei Chen, Mengyuan Zhou, Huan Liu, Ruotong Ren, and Zhao Wang. Etiological stratification and prognostic assessment of haemophagocytic lymphohistiocytosis by machine learning on onco-mngs data and clinical data. Frontiers in Immunology, Sep 2024. URL: https://doi.org/10.3389/fimmu.2024.1390298, doi:10.3389/fimmu.2024.1390298. This article has 4 citations and is from a peer-reviewed journal.

18. (sousa2024prognosticimpactof pages 5-7): Rita Noversa de Sousa, Andreia Sá Lima, Susana Viana, Filipa Guimarães, Marta Pereira, and Luís Miguel Afonso. Prognostic impact of aetiology in adult hemophagocytic lymphohistiocytosis: insights from an intensive care unit experience. European Journal of Case Reports in Internal Medicine, Dec 2024. URL: https://doi.org/10.12890/2024_005040, doi:10.12890/2024_005040. This article has 1 citations.

19. (cox2024diagnosisandinvestigation media 50579ca6): Miriam F Cox, Strachan Mackenzie, Ryan Low, Michael Brown, Emilie Sanchez, Aisling Carr, Ben Carpenter, Mark Bishton, Andrew Duncombe, Akpabio Akpabio, Austin Kulasekararaj, Fang En Sin, Alexis Jones, Akhila Kavirayani, Ethan S Sen, Vanessa Quick, Gurdeep S Dulay, Sam Clark, Kris Bauchmuller, Rachel S Tattersall, and Jessica J Manson. Diagnosis and investigation of suspected haemophagocytic lymphohistiocytosis in adults: 2023 hyperinflammation and hlh across speciality collaboration (hihasc) consensus guideline. The Lancet Rheumatology, 6:e51-e62, Jan 2024. URL: https://doi.org/10.1016/s2665-9913(23)00273-4, doi:10.1016/s2665-9913(23)00273-4. This article has 52 citations.

20. (lee2023diagnosisandmanagement pages 6-8): Jerry C. Lee and Aaron C. Logan. Diagnosis and management of adult malignancy-associated hemophagocytic lymphohistiocytosis. Cancers, 15:1839, Mar 2023. URL: https://doi.org/10.3390/cancers15061839, doi:10.3390/cancers15061839. This article has 45 citations.

21. (goubran2024theroleof pages 2-3): Mariam Goubran, Caroline Spaner, Sophie Stukas, Adi Zoref-Lorenz, Kamran Shojania, Madelaine Beckett, Amanda Li, Erica Peterson, Mypinder Sekhon, Rebecca Grey, Cheryl Wellington, Catherine V Cheng, Catherine M Biggs, Andre Mattman, Michael B. Jordan, Luke Y. C. Chen, and Audi Setiadi. The role of c-reactive protein and ferritin in the diagnosis of hlh, adult-onset still’s disease, and covid-19 cytokine storm. Scientific Reports, Dec 2024. URL: https://doi.org/10.1038/s41598-024-82760-6, doi:10.1038/s41598-024-82760-6. This article has 12 citations and is from a peer-reviewed journal.

22. (wimmer2024outcomeofadult pages 23-27): Thomas Wimmer. Outcome of adult patients with hemophagocytic lymphohistiocytosis: a retrospective analysis. Dissertation, Jan 2024. URL: https://doi.org/10.5282/edoc.33899, doi:10.5282/edoc.33899. This article has 0 citations.

23. (wimmer2024outcomeofadult pages 51-55): Thomas Wimmer. Outcome of adult patients with hemophagocytic lymphohistiocytosis: a retrospective analysis. Dissertation, Jan 2024. URL: https://doi.org/10.5282/edoc.33899, doi:10.5282/edoc.33899. This article has 0 citations.

24. (lee2023diagnosisandmanagement pages 8-9): Jerry C. Lee and Aaron C. Logan. Diagnosis and management of adult malignancy-associated hemophagocytic lymphohistiocytosis. Cancers, 15:1839, Mar 2023. URL: https://doi.org/10.3390/cancers15061839, doi:10.3390/cancers15061839. This article has 45 citations.

25. (song2023doseescalatingruxolitinibfor pages 1-2): Yue Song, Xiaoli Li, Xuefeng He, Fei Zhou, Feng Du, Ziyan Wang, Suning Chen, and Depei Wu. Dose-escalating ruxolitinib for refractory hemophagocytic lymphohistiocytosis. Frontiers in Immunology, Jun 2023. URL: https://doi.org/10.3389/fimmu.2023.1211655, doi:10.3389/fimmu.2023.1211655. This article has 15 citations and is from a peer-reviewed journal.

26. (song2023doseescalatingruxolitinibfor pages 2-3): Yue Song, Xiaoli Li, Xuefeng He, Fei Zhou, Feng Du, Ziyan Wang, Suning Chen, and Depei Wu. Dose-escalating ruxolitinib for refractory hemophagocytic lymphohistiocytosis. Frontiers in Immunology, Jun 2023. URL: https://doi.org/10.3389/fimmu.2023.1211655, doi:10.3389/fimmu.2023.1211655. This article has 15 citations and is from a peer-reviewed journal.

27. (NCT04120090 chunk 1): Zhao Wang. Ruxolitinib as a Salvage Therapy for Hemophagocytic Lymphohistiocytosis. Beijing Friendship Hospital. 2019. ClinicalTrials.gov Identifier: NCT04120090

28. (NCT03795909 chunk 1): Yan Yue. Ruxolitinib Combined With Dexamethasone for HLH. Capital Research Institute of Pediatrics. 2017. ClinicalTrials.gov Identifier: NCT03795909

29. (lee2023diagnosisandmanagement pages 9-10): Jerry C. Lee and Aaron C. Logan. Diagnosis and management of adult malignancy-associated hemophagocytic lymphohistiocytosis. Cancers, 15:1839, Mar 2023. URL: https://doi.org/10.3390/cancers15061839, doi:10.3390/cancers15061839. This article has 45 citations.

30. (NCT06951971 chunk 1): Xuefeng He. Dose-modified Emapalumab and Ruxolitinib (E-Ru) Regimens for Hemophagocytic Lymphohistiocytosis. The First Affiliated Hospital of Soochow University. 2025. ClinicalTrials.gov Identifier: NCT06951971

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