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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

Among these findings, 3 key features can help clinicians recognize a pattern that may raise suspicion for primary HLH.4

  • Fever
  • Ferritin
  • Falling blood counts

Consider these findings together and in the context of the patient’s clinical presentation when evaluating for primary HLH.4

What other conditions can present similarly to primary HLH?

Patients with HLH may initially present with clinical and laboratory features that can overlap with other conditions due to their nonspecific nature. Some examples of conditions that may share similar features can include5-8:

  • Active sJIA or AOSD flares
  • Drug hypersensitivity and other hyperinflammatory states
  • Liver failure and disseminated intravascular coagulation syndromes
  • Malignancy, especially hematologic malignancies
  • Sepsis
  • Severe infection-triggered inflammation
  • Reactions to CAR-T and bispecific antibody therapies
  • Tick-borne illnesses (Ehrlichia chaffeensis, Anaplasma phagocytophilum, Rickettsia rickettsii) in areas where they are more common

See below for more information about 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. Henter JI. Hemophagocytic lymphohistiocytosis. N Engl J Med. 2025;392(6):584-598. doi:10.1056/NEJMra2314005 5. Sen ES, Clarke SL, Ramanan AV. Macrophage activation syndrome. Indian J Pediatr. 2016;83(3):248-253. doi:10.1007/s12098-015-1877-1 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. Hines MR, Knight TE, McNerney KO, et al. Immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome. Transplant Cell Ther. 2023;29(7):438.e1-438.e16. doi:10.1016/j.jtct.2023.03.006 8. Jevtic D, da Silva MD, Haylock AB, et al. Hemophagocytic lymphohistiocytosis (HLH) in patients with tick-borne illness: a scoping review of 98 cases. Infect Dis Rep. 2024;16(2):154-169. doi:10.3390/idr16020012 9. 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 10. Marsh RA, Haddad E. How I treat primary haemophagocytic lymphohistiocytosis. Br J Haematol. 2018;182(2):185-199. doi:10.1111/bjh.15274 11. 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 12. 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 13. 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 14. 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