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Signs and symptoms of primary HLH

How does primary HLH present?

Primary hemophagocytic lymphohistiocytosis (HLH) is a heterogeneous syndrome with a range of nonspecific signs and symptoms. This can make diagnosis a challenge, as many symptoms can overlap with more common conditions like infections, malignancy, and rheumatologic diseases.1,2

There are also a variety of laboratory abnormalities associated with primary HLH that should increase your suspicion in cases of severe hyperinflammation. Notable early signs of primary HLH include fevers of unknown origin (FUO), cytopenia, high ferritin, and increased liver enzymes.2  These features can share overlap with other cytokine storm syndromes.3

See below for more information about some of the commonly observed signs and symptoms of primary HLH.

Persistent fever
Hepatosplenomegaly
Rash
Infection
Seizures and CNS involvement
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Human body with HLH symptoms highlighted
Cytopenia
Hyperferritinemia
Hypofibrinogenemia
Hypertriglyceridemia
Elevated CXCL9
Elevated sCD25
Liver function impairment
Hemophagocytosis
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Human body with HLH symptoms
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Pathophysiology of primary HLH

Learn about the mechanisms of immune dysregulation in primary HLH.

What happens in primary HLH?
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Diagnosing primary HLH

Explore the diagnostic process for primary HLH.

How to diagnose primary HLH

References: 1. Jordan MB, Allen CE, Weitzman S, Filipovich AH, McClain KL. How I treat hemophagocytic lymphohistiocytosis. Blood. 2011;118(15):4041-4052. doi:10.1182/blood-2011-03-278127 2. George MR. Hemophagocytic lymphohistiocytosis: review of etiologies and management. J Blood Med. 2014;5:69-86. doi:10.2147/JBM.S46255 3. Cron RQ, Goyal G, Chatham WW. Cytokine Storm Syndrome. Annu Rev Med. 2023;74:321-337. doi:10.1146/annurev-med-042921-112837 4. Price B, Lines J, Lewis D, Holland N. Haemophagocytic lymphohistiocytosis: a fulminant syndrome associated with multiorgan failure and high mortality that frequently masquerades as sepsis and shock. S Afr Med J. 2014;104(6):401-406. doi:10.7196/samj.7810 5. Marsh RA, Haddad E. How I treat primary haemophagocytic lymphohistiocytosis. Br J Haematol. 2018;182(2):185-199. doi:10.1111/bjh.15274 6. Jordan MB, Allen CE, Greenberg J, et al. Challenges in the diagnosis of hemophagocytic lymphohistiocytosis: recommendations from the North American Consortium for Histiocytosis (NACHO). Pediatr Blood Cancer. 2019;66(11):e27929. doi:10.1002/pbc.27929 7. Machowicz R, Janka G, Wiktor-Jedrzejczak W. Similar but not the same: differential diagnosis of HLH and sepsis. Crit Rev Oncol Hematol. 2017;114:1-12. doi:10.1016/j.critrevonc.2017.03.023 8. Allen CE, Yu X, Kozinetz CA, McClain KL. Highly elevated ferritin levels and the diagnosis of hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2008;50(6):1227-1235. doi:10.1002/pbc.21423 9. Valade S, Joly BS, Veyradier A, et al. Coagulation disorders in patients with severe hemophagocytic lymphohistiocytosis. PLoS One. 2021;16(8):e0251216. doi:10.1371/journal.pone.0251216 10. Rocco JM, Oved JH, Patel RJ, et al. CXCL9 as a novel prognostic marker to identify high-risk adults with hemophagocytic lymphohistiocytosis. Blood. 2026;147(9):960-972. doi:10.1182/blood.2025030976