Distinguishing primary HLH from sepsis
Four signs that may suggest primary HLH
Despite distinct etiologies, primary hemophagocytic lymphohistiocytosis (HLH) and sepsis both involve a dysregulated immune response that results in hyperinflammation and multiorgan dysfunction. Because they can share similar signs and symptoms, it can be difficult to identify a patient with primary HLH before it’s too late.1
Primary HLH: A rare, rapidly progressive, life-threatening genetic condition2
Sepsis: A common, but extreme, life-threatening complication of infection3,4
Including primary HLH in your differential diagnosis when you suspect sepsis can help ensure timely and accurate identification
The signs are listed from most to least prevalent in patients with sepsis.
Prolonged fever:
Fever is common in both primary HLH and sepsis and tends to persist until inflammation is subdued. If a patient has sepsis, fever should subside with antibiotic treatment of the source of infection. Fever that persists despite antibiotic treatment may indicate primary HLH.1,3
Hyperferritinemia:
Ferritin may be elevated in patients with sepsis, but dramatically increased ferritin levels are characteristic of patients with primary HLH. While HLH-2004 diagnostic criteria include ferritin ≥500 μg/L, ferritin >10,000 μg/L is likely a better indicator of primary HLH.1,3
High sCD25:
Though uncommon in sepsis, elevated sCD25 (soluble interleukin-2 receptor) is a diagnostic indicator for patients with primary HLH. sCD25 activity ≥2400 U/mL may indicate primary HLH.1
Hypofibrinogenemia:
Also uncommon in sepsis, hypofibrinogenemia is often observed in patients with primary HLH. Fibrinogen levels ≤1.5 g/L may indicate primary HLH.1,3
Please note that this guidance may not apply to all cases since the signs and symptoms of primary HLH and sepsis present across a spectrum and may vary between patients.
If you suspect your patient may have primary HLH, consult a hematologist/oncologist who may be able to help.
HLH-2004 diagnostic criteria
Fulfillment of 5 of the 8 HLH-2004 criteria listed below can be used to suspect a diagnosis in the absence of an underlying cause, such as malignancies.5
Persistent fever
Low or absent NK-cell activity
High sCD25 ≥2400 U/mL
Splenomegaly
High ferritin ≥500 µg/L
Hemophagocytosis*
Cytopenia
(affecting ≥2 of 3 lineages in the peripheral blood)
- Hemoglobin <90 g/L (in infants <4 weeks: hemoglobin <100 g/L)
- Platelets <100 x 109/L
- Neutrophils <1.0 x 109/L
Hypertriglyceridemia and/or hypofibrinogenemia
- Fasting triglycerides ≥3.0 mmol/L (ie, ≥265 mg/dL)
- Fibrinogen ≤1.5 g/L
NK=natural killer; sCD25=soluble interleukin-2 receptor.
*Hemophagocytosis is not specific nor always present in early stages of the disease.6
If you suspect primary HLH, consult a hematologist/oncologist for further guidance.
Ask your local Sobi Health Systems Director how they can help connect you with an expert.
References: 1. Bursa D, Bednarska A, Pihowicz A, Paciorek M, Horban A. Analysis of the occurrence of hemophagocytic lymphohistiocytosis (HLH) features in patients with sepsis: a prospective study. Sci Rep. 2021;11(1):10529. Published online May 18, 2021. doi:10.1038/s41598-021-90046-4 2. 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-2011-03-278127v 3. 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 4. What is sepsis. Sepsis Alliance. Updated August 2, 2021. Accessed August 14, 2026. https://www.sepsis.org/sepsis-basics/what-is-sepsis 5. Henter J-I, Horne AC, Aricó M, et al; Histiocyte Society. HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48(2):124-131. doi:10.1002/pbc.21039 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
