An observational study in Lymphohistiocytosis, Hemophagocytic, Secondary Hemophagocytic Lymphohistiocytosis and Macrophage Activation Syndrome, sponsored by National Institute of Allergy and Infectious Diseases (NIAID). Recruiting at 2 sites in United States. Open to participants aged 18 Years to 120 Years. Per ClinicalTrials.gov, last updated 2026-11-05.
Sponsored by National Institute of Allergy and Infectious Diseases (NIAID) · Observational
Background:
Hemophagocytic lymphohistiocytosis (HLH) is a disease caused by disrupted immune function. People with HLH are prone to fevers and illnesses, which can be fatal. Some people develop a genetic form of this disease (pHLH), but researchers do not understand why some other people develop a nongenetic form (sHLH). They also do not have good ways to diagnose and treat sHLH.
Objective:
To learn about sHLH and why some people get it and others do not.
Eligibility:
Adults aged 18 years and older with sHLH.
Design:
Participants will be admitted to the study based on a review of their medical records. Those who join will have at least 3 clinical evaluations over 9 to 12 months. These may occur during an inpatient hospitalization if they require medical care or in the outpatient clinic.
Participants will also have a physical exam at each visit. Up to half a cup of blood will be drawn at each visit. Participants may also have their blood drawn by their own doctors, who will send the samples to the researchers. Researchers may also contact these participants by telephone or video calls.
The blood will be used for clinical tests as well as research. No new treatments will be administered as part of this study; however, standard medications and treatments may be recommended.
Participants may opt to continue their visits once a year for 3 more years. Participants may also opt for an extra clinial evaluation 1 week after starting a new treatment.
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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:
Primary Endpoint:
Identify immunologic mechanisms involved in the pathogenesis of sHLH from a variety of predisposing conditions.
Secondary Endpoints:
111 studies on the registry are indexed under Lymphohistiocytosis, Hemophagocytic; 41 are open to participants now.
This study's planned enrollment of 300 is above the median of 114 across 34 observational studies indexed under Lymphohistiocytosis, Hemophagocytic.
Browse Lymphohistiocytosis, Hemophagocytic studies →National Institute of Allergy and Infectious Diseases (NIAID) is the lead sponsor of 2,446 studies on the registry; 179 are open to participants now.
Of its 405 completed or terminated interventional studies of FDA-regulated products, 302 (75%) have results posted.
Counted across the registry records on this site, refreshed daily.
Adult participants with active secondary HLH by meeting any published criteria. 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.
Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
Established diagnosis of sHLH defined by meeting any published criteria, per Table 1:
Table 1: Published Criteria for HLH
HLH-2004 Criteria:
Molecular diagnosis of HLH OR At least 5 of 8 below criteria:
HScore:
Known :
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)
(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:
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:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
A biopsy takes a small piece of tissue to examine. “Archival tissue” is a sample already taken, for example at diagnosis, and kept by the hospital.
Whether a stored sample will do depends on when it was taken, how much there is and what the study needs. Ask whether the study accepts your stored sample or needs a new biopsy.
The protein in red blood cells that carries oxygen. A low level is anaemia, which can cause tiredness and breathlessness. Measured in g/dL or g/L (9 g/dL is 90 g/L).
Blood cells that help blood clot. Too few raises the risk of bleeding and bruising. A usual adult range is about 150–400 × 10⁹/L (150,000–400,000 per µL); each lab has its own reference range.
A weakened immune system. It can come from an illness, such as HIV or some blood cancers, or from medicines that turn the immune system down, for example after an organ transplant or for an autoimmune disease; steroids at higher doses count.
Read whether the line is about a condition or about medicines, and which medicines and doses it means.
Two enzymes measured in a routine blood test of the liver. Higher levels can mean the liver is under strain or damaged. SGPT and SGOT are older names for ALT and AST.
Criteria usually give a limit as a multiple of the upper limit of normal (ULN), often higher when cancer has spread to the liver.
Biopsy and archival tissue
A biopsy takes a small piece of tissue to examine. “Archival tissue” is a sample already taken, for example at diagnosis, and kept by the hospital.
Whether a stored sample will do depends on when it was taken, how much there is and what the study needs. Ask whether the study accepts your stored sample or needs a new biopsy.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Hemoglobin (Hb)
The protein in red blood cells that carries oxygen. A low level is anaemia, which can cause tiredness and breathlessness. Measured in g/dL or g/L (9 g/dL is 90 g/L).
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Platelets
Blood cells that help blood clot. Too few raises the risk of bleeding and bruising. A usual adult range is about 150–400 × 10⁹/L (150,000–400,000 per µL); each lab has its own reference range.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Immunosuppression
A weakened immune system. It can come from an illness, such as HIV or some blood cancers, or from medicines that turn the immune system down, for example after an organ transplant or for an autoimmune disease; steroids at higher doses count.
Read whether the line is about a condition or about medicines, and which medicines and doses it means.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
ALT and AST (liver enzymes)
Two enzymes measured in a routine blood test of the liver. Higher levels can mean the liver is under strain or damaged. SGPT and SGOT are older names for ALT and AST.
Criteria usually give a limit as a multiple of the upper limit of normal (ULN), often higher when cancer has spread to the liver.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
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.
Identify immunologic mechanisms involved in the pathogenesis of sHLH from a variety of predisposing conditions.
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.
Time frame: Through end of study.
Prospectively define acute and longitudinal clinical profiles that predict key clinical outcomes.
To prospectively and longitudinally characterize the predisposing conditions, clinical features, acute triggers, clinical labs, and outcomes of a cohort of individuals meeting sHLH criteria.
Time frame: Through end of study.
Compare clinical and immune profiles between the classically defined HLH subgroups.
To compare biomarkers and immune profiles between the classically defined sHLH subgroups (malignancy, autoimmune, immune-therapy, infectious-triggered, unknown etiology).
Time frame: Through end of study.
Improve the understanding of the pathogenesis of sHLH.
To evaluate for novel immunologic subsets of sHLH with unsupervised analyses using a multi-omic approach, including single-cell transcriptomics and proteomics.
Time frame: Through end of study.
Characterize risk factors to identify populations at risk for developing sHLH.
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.
Time frame: Through end of study.
Plan to share: Yes — Data dictionaries and anonymized individual participant data collected in this study that underlie results in a publication will be made available after the end of the study by request.
Supporting information: Clinical study report
Time frame: Upon completion of the protocol/upon publication.
Access criteria: Data will only be available upon request, the PI will review and approve requests for data.
Started Jul 2024 (actual). Primary completion is estimated for Oct 2030, 74 months after the start.
How these figures are worked out, and which studies are left out of them.
From the registry record's own update history. This site started tracking changes on Sep 25, 2026; for anything earlier, see the record history on ClinicalTrials.gov ↗
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