Table 6.

Consensus recommendations for the treatment of special populations with HLH.

S. No.	Recommendation	Grade of evidence	Level of agreement (%)
23.	In infants and neonates from GCC populations where high consanguinity is associated with an increased burden of pathogenic variants, an HLH-94–based pediatric treatment approach should be considered the consensus mainstay of therapy, with individualized adjustment in neonates according to clinical severity and organ involvement.	Moderate	100% (13/13)*
24.	In MAS-HLH or autoimmune/inflammatory HLH, first-line therapy may include high-dose glucocorticoids with or without early biologic therapy (anakinra). For refractory disease, additional immunomodulatory therapies, including cyclosporine or IFN-γ blockade with emapalumab, may be considered. Ruxolitinib may also be considered in selected refractory MAS-HLH cases, particularly after failure of conventional or etoposide-based therapy.	Moderate	93% (13/14)*
25.	Systematic screening for CNS involvement, coupled with timely and tailored CNS-directed therapy, is of critical importance, particularly in GCC cohorts, where neurological disease occurs with disproportionate frequency and carries significant prognostic impact.	Low	100% (15/15)
26.	Infection-associated HLH, including EBV-HLH and CAEBV-HLH, should be recognized as a phenotype with unique therapeutic needs. In EBV-HLH, corticosteroids with or without IVIG and antiviral therapy may be used in less severe cases, while severe cases may require modified HLH-94; rituximab may be considered to target the EBV B-cell reservoir.	Low	100% (14/14)*
27.	In patients with CAEBV-HLH, chemotherapy followed by allo-SCT may be considered. Nivolumab may also be considered as a potential therapeutic option in selected relapsed or refractory EBV-associated HLH cases.	Low	100% (13/13)*
28.	Malignancy-associated HLH represents a high-risk phenotype that demands integrated cancer and HLH therapy. Corticosteroids may be started promptly, and etoposide may be considered early, including as pre-phase therapy when appropriate.	Low	93% (14/15)
29.	IEC-HS is a distinct HLH phenotype requiring specific diagnostic and management strategies. Treatment should be individualized according to severity grade**:  a) Grade 1: Corticosteroids, with or without anakinra, may be considered as first-line therapy,  together with intensive supportive care and close monitoring for organ dysfunction.  b) Grade 2: Anakinra and corticosteroids may be considered; ruxolitinib, emapalumab, or etoposide  may be considered in progressive disease.  c) Grade 3: Anakinra and corticosteroids may be considered; ruxolitinib or emapalumab may also  be added, with etoposide considered as an alternative.  d) Grade 4: Management as for grade 3 may be considered, with further escalation of therapy as  clinically indicated.	Low	100% (14/14)*
30.	In drug-induced HLH, the suspected offending agent should be discontinued immediately. Treatment may include IL-6 blockade, such as tocilizumab, and/or corticosteroids, adapted to the causative agent and disease severity. If there is insufficient response after 48 hours, escalation to etoposide may be considered.	Low	100% (14/14)*

*Abstention was recorded for this statement, as the expert indicated that it was outside their scope of practice.

**Grade 1: Asymptomatic or mild symptoms; requires observation and/or clinical and diagnostic evaluations. Intervention is not indicated; Grade 2: Mild to moderate symptoms, with intervention indicated. (e.g., immunosuppressive agents directed at IEC-HS, transfusions for asymptomatic hypofibrinogenemia); Grade 3: Severe or medically significant, but not immediately life-threatening (e.g., coagulopathy with bleeding requiring transfusion support, or hospitalization required for new-onset acute kidney injury, hypotension, or respiratory distress); Grade 4: Life-threatening consequences; urgent intervention indicated (e.g., life-threatening bleeding or hypotension, respiratory distress requiring intubation, dialysis indicated for acute kidney injury)

Level of agreement was calculated as the proportion of respondents selecting either “agree” or “somewhat agree.”

allo-SCT, allogeneic stem cell transplantation; CAEBV, chronic active Epstein-Barr virus; CNS, central nervous system; EBV, Epstein-Barr virus; GCC, Gulf Cooperation Council; HLH, hemophagocytic lymphohistiocytosis; HSCT, hematopoietic stem cell transplantation; IEC-HS, immune effector cell–associated HLH-like syndrome; IFN-γ, interferon gamma; IL, interleukin; IVIG, intravenous immunoglobulin; MAS, macrophage activation syndrome.