Diagnosing primary HLH
For patients with HLH, prompt diagnosis is crucial
Hemophagocytic lymphohistiocytosis (HLH) is heterogeneous, rapidly progressive, and can be fatal if untreated. It’s critical to ensure that patients are diagnosed as soon as possible.1
It’s also essential to identify any underlying triggers that can be associated with the development of HLH in patients.1
The presence or absence of certain triggers will influence the management strategies you will pursue.2
Diagnosing primary HLH
There are 3 recognized options for making a possible diagnosis of primary HLH. These options include3:
The fulfillment of 5 of the 8 HLH-2004 criteria in the absence of an underlying cause, such as malignancy.
A positive genetic test for mutations associated with primary HLH.
Family history consistent with primary HLH.
It can be challenging to navigate the diagnostic process while also trying to manage a patient’s condition. Explore the sections below for some guidance that you may find helpful.
What to consider when primary HLH is suspected
For patients with suspected primary HLH, it is critical to recognize the hyperinflammatory state as quickly as possible. Because primary HLH can present in newborns, adolescents, and adults, and often resembles infection, malignancy, or other inflammatory conditions, maintaining a high
index of suspicion is essential.4
Clinical trajectory matters
Disease progression and trends in laboratory and clinical findings are often more informative than isolated values. Persistent fever, worsening cytopenias, escalating inflammation, and evolving organ dysfunction may signal an underlying HLH state.4
Send genetic testing early when primary HLH is suspected
Genetic testing should be initiated promptly when primary HLH is being considered. Identifying pathogenic variants can help confirm the diagnosis, inform recurrence risk, and guide planning for definitive therapy.4
Evaluation and management occur simultaneously
Because HLH can progress rapidly, treatment decisions often begin while the diagnostic evaluation is still underway. Identifying the underlying cause should occur in parallel with assessment of disease severity and management of hyperinflammation.4
Early expert consultation is helpful
Specialist input from hematology, immunology, genetics, or HLH experts can help guide diagnostic evaluation, interpretation of genetic findings, and management decisions in complex cases.4
See below for more information about diagnostic criteria and biomarker testing that may be helpful for identifying primary HLH.
View this flash card for information about differential diagnosis between HLH and another condition that can mimic its presentation: sepsis.
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. Henter JI, Horne A, Aricó M, et al. HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48(2):124-131. doi:10.1002/pbc.21039 4. Shakoory B, Geerlinks A, Wilejto M, et al. The 2022 EULAR/ACR points to consider at the early stages of diagnosis and management of suspected haemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS). Arthritis Rheumatol. 2023;75(10):1714-1732. doi:10.1002/art.42636
