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  INCLUSION CRITERIA:

  - Aged 18 years or older.

• - Established diagnosis of sHLH defined by meeting any published criteria, per Table 1: - Meeting the HLH-2004 criteria.

• - HScore of >168.

For those without a bone marrow biopsy to evaluate for hemophagocytosis (worth 35 points in the criteria), HScore>134 will be used.

• - For those with underlying rheumatologic disease: meeting the 2016 American College of Rheumatology criteria for macrophage activation syndrome.

• - Agree to storage and sharing of study data and biospecimens for future research use.

Table 1: Published Criteria for HLH.HLH-2004 Criteria: Molecular diagnosis of HLH OR At least 5 of 8 below criteria:

• - Fever (>38.4 Degrees Celcius) - Splenomegaly.

• - Cytopenias affecting >=2 of 3 lineages: Hgb <9 g/dL, platelets <10^5/microliter, neutrophils <10^6/microliter.

• - Hypertriglyceridemia (>256 mg/dL) and/or fibrinogen <1.5 g/L.

• - Hemophagocytosis on biopsy.

• - Serum ferritin >=500 ng/mL.

• - Increased serum sCD25 (>2400 U/mL) - Low or absent NK cell activity.

HScore: Known immunosuppression: 0 (no) or 18 (yes) Temperature (degrees, Celsius): 0 (<38.4), 33 (38.4-39.4), 49 (>39.4) Organomegaly: 0 (no), 23 (liver/spleen), 38 (both) Number of cytopenias: 0 (1 lines), 24 (2 lines), 34 (3 lines) Ferritin (ng/mL): 0 (<2000), 35 (2000-6000), 50 (>6000) Triglycerides (mg/dL): 0 (<1.5), 44 (1.5-4), 66 (>4) Fibrinogen (g/L): 0 (>2.5), 30 (<2.5) AST (IU/mL): 0 (<30), 19 (>30) Hemophagocytosis: 0 (no) or 35 (yes) Cutoff value=169.ACR 2016-MAS Criteria: A febrile patient with known or suspected sJIA is classified as having macrophage activation syndrome if the following criteria are met: Ferritin >684 ng/mL.AND any 2 of the following:

• - Platelets <=181,000/microliter.

• - AST >48 IU/mL.

• - Triglycerides >156 mg/dL.

• - Fibrinogen <=3.6 g/L.

Abbreviations: ACR, American College of Rheumatology; AST, aspartate transaminase; Hgb, hemoglobin; HLH, hemophagocytic lymphohistiocytosis; MAS, macrophage activation syndrome; NK, natural killer, sJIA, systemic juvenile idiopathic arthritis.

EXCLUSION CRITERIA:

An individual who meets any of the following criteria will be excluded from participation in this study:

• - Currently pregnant.

• - Any condition that, in the judgment of the investigator, may put the participant at undue risk or make them unsuitable for participation in the study.

Study Description: The purpose of this multisite natural history study is to study the immunopathogenesis of secondary hemophagocytic lymphohistiocytosis (sHLH). This will include detailed longitudinal clinical and immunologic characterization of sHLH, as well as mechanistic studies evaluating inflammasome activation, cytotoxicity, and JAK-STAT signaling. Participants with sHLH will undergo clinical assessment and management along with three research blood draws with the option for additional blood draws at time points such as post-immunosuppressive treatment or treatment escalation and during longer-term follow-up. Participation may be in person or remote, with blood collected and processed locally then shipped to the NIH. Longitudinal clinical information will be recorded, and standard of care will be offered as needed. Primary Objective: To study the immunopathogenesis of sHLH from various etiologies including biomarkers, cellular phenotypes, and gene expression to determine mechanistic pathways that may be amenable to host-directed therapies. Secondary Objectives:

• - To prospectively and longitudinally characterize the predisposing conditions, clinical features, acute triggers, clinical labs, and outcomes of a cohort of individuals meeting sHLH criteria.

• - To compare biomarkers and immune profiles between the classically defined sHLH subgroups (malignancy, autoimmune, immune-therapy, infectious-triggered, unknown etiology).

• - To evaluate for novel immunologic subsets of sHLH with unsupervised analyses using a multi-omic approach, including single-cell transcriptomics and proteomics.

• - To evaluate for rare, protein-altering variants in genes associated with cytotoxicity, inflammasome activation, or immunoregulation via (optional) co-enrollment in NIAID Centralized Sequencing protocol.

Primary Endpoint: Identify immunologic mechanisms involved in the pathogenesis of sHLH from a variety of predisposing conditions. Secondary Endpoints:

• - Characterize the longitudinal clinical course of sHLH, including relapse rates and predictors of key clinical outcomes at one year after diagnosis.

• - Identify differences in clinical and/or immunologic profiles between sHLH subgroups (malignancy, autoimmune, immune-therapy, infectious-triggered, unknown etiology).

• - To evaluate for novel immunologic profiles in sHLH using multi-omic unsupervised analyses.

• - Identify new genetic determinants of susceptibility to sHLH in the setting of different predisposing conditions.

Arms

: sHLH

Hemophagocytic lymphohistiocytosis (HLH) represents a clinical condition of persistent, dysregulated immune activation with unrelenting fevers, hyperferritinemia, and cytopenias, which lead to multiorgan failure and death.

Interventions