NIH Clinical Center Search the Studies: Study Number, Study Title

Protocol Details

Hemophagocytic Lymphohistiocytosis (HLH) Evaluation and Research of Clinical, ImmUnoLogic and TranscriptomE Study

This study is currently recruiting participants.

Summary | Eligibility | Citations | Contacts




Sponsoring Institute

National Institute of Allergy and Infectious Diseases (NIAID)

Recruitment Detail

Type: Participants currently recruited/enrolled
Gender: Male & Female
Min Age: 18 Years
Max Age: 120 Years

Referral Letter Required


Population Exclusion(s)

Adults who are or may become unable to consent


Hemophagocytic Lymphohistiocytosis;
Macrophage Activation Syndrome;
Cytokine Storm Syndrome;
Hyperinflammatory Syndrome;
Still's Disease;
Immune Dysregulation

Recruitment Keyword(s)



Lymphohistiocytosis, Hemophagocytic;
Secondary Hemophagocytic Lymphohistiocytosis;
Macrophage Activation Syndrome;
Hyperinflammatory Syndromes

Investigational Drug(s)


Investigational Device(s)




Supporting Site

National Institute of Allergy and Infectious Diseases


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.


To learn about sHLH and why some people get it and others do not.


Adults aged 18 years and older with sHLH.


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.

--Back to Top--



-Aged 18 years or older.

-Active 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.

-Able to provide informed consent.

-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)


-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


Known immunosuppression:

0 (no) or 18 (yes)

Temperature (degrees, Celsius):

0 (<38.4), 33 (38.4-39.4), 49 (>39.4)


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)


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.


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.

--Back to Top--


Rocco JM, Laidlaw E, Galindo F, Anderson M, Sortino O, Kuriakose S, Lisco A, Manion M, Sereti I. Mycobacterial Immune Reconstitution Inflammatory Syndrome in HIV is Associated With Protein-Altering Variants in Hemophagocytic Lymphohistiocytosis-Related Genes. J Infect Dis. 2023 Jul 14;228(2):111-115. doi: 10.1093/infdis/jiad059. PMID: 37040388; PMCID: PMC10345459.

Rocco JM, Laidlaw E, Galindo F, Anderson M, Rupert A, Higgins J, Sortino O, Ortega-Villa AM, Sheikh V, Roby G, Kuriakose S, Lisco A, Manion M, Sereti I. Severe Mycobacterial Immune Reconstitution Inflammatory Syndrome (IRIS) in Advanced Human Immunodeficiency Virus (HIV) Has Features of Hemophagocytic Lymphohistiocytosis and Requires Prolonged Immune Suppression. Clin Infect Dis. 2023 Feb 8;76(3):e561-e570. doi: 10.1093/cid/ciac717. PMID: 36048425; PMCID: PMC10169423.

Shakoory B, Geerlinks A, Wilejto M, Kernan K, Hines M, Romano M, Piskin D, Ravelli A, Sinha R, Aletaha D, Allen C, Bassiri H, Behrens EM, Carcillo J, Carl L, Chatham W, Cohen JI, Cron RQ, Drewniak E, Grom AA, Henderson LA, Horne A, Jordan MB, Nichols KE, Schulert G, Vastert S, Demirkaya E, Goldbach-Mansky R, de Benedetti F, Marsh RA, Canna SW; HLH/MAS task force. The 2022 EULAR/ACR points to consider at the early stages of diagnosis and management of suspected haemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS). Ann Rheum Dis. 2023 Oct;82(10):1271-1285. doi: 10.1136/ard-2023-224123. Epub 2023 Jul 24. PMID: 37487610.

Jordan MB, Allen CE, Greenberg J, Henry M, Hermiston ML, Kumar A, Hines M, Eckstein O, Ladisch S, Nichols KE, Rodriguez-Galindo C, Wistinghausen B, McClain KL. Challenges in the diagnosis of hemophagocytic lymphohistiocytosis: Recommendations from the North American Consortium for Histiocytosis (NACHO). Pediatr Blood Cancer. 2019 Nov;66(11):e27929. doi: 10.1002/pbc.27929. Epub 2019 Jul 24. PMID: 31339233; PMCID: PMC7340087.

--Back to Top--


Principal Investigator

Referral Contact

For more information:

Joseph M. Rocco, M.D.
National Institute of Allergy and Infectious Diseases (NIAID)
NIHBC 10 - CRC BG RM 4-1479NE
(301) 312-2858

Joseph M. Rocco, M.D.
National Institute of Allergy and Infectious Diseases (NIAID)
NIHBC 10 - CRC BG RM 4-1479NE
(301) 312-2858

Office of Patient Recruitment
National Institutes of Health Clinical Center (CC)
Building 61, 10 Cloister Court
Bethesda, Maryland 20892
Toll Free: 1-800-411-1222
Local Phone: 301-451-4383
TTY: TTY Users Dial 7-1-1

Clinical Trials Number:


--Back to Top--