Table 5 2016 MAS, HLH-2004, HScore and MIS-A Criteria

•Ferritin > 684 mcg/L

and any 2 of following:

•Platelet count 181 × 10³/mm³

•Triglycerides > 156 mg/dl

•Fibrinogen ≤ 360 mg/dl

•AST > 48 IU/L

The diagnosis HLH can be established if one of either 1 or 2 below is fulfilled:

(1) A molecular diagnosis consistent with HLH

(2) Diagnostic criteria for HLH fulfilled (five out of the eight criteria below)

(A) Initial diagnostic criteria (to be evaluated in all patients with HLH)

•Fever

•Splenomegaly

•Cytopenias (affecting 2 of 3 lineages in the peripheral blood):

Hemoglobin < 9 g/dL (in infants < 4 weeks: hemoglobin < 10 g/dL) Platelets < 100 × 10^3/mm³

Neutrophils < 1 × 10^3/mm³

•Hypertriglyceridemia and/or hypofibrinogenemia: Fasting triglycerides ≥ 265 mg/dl

•Fibrinogen ≤ 150 mg/dL

•Hemophagocytosis in bone marrow or spleen or lymph nodes

•No evidence of malignancy

(B) New diagnostic criteria

•Low or absent NK-cell activity (according to local laboratory reference)

•Ferritin ≥ 500 mcg/L

•Soluble CD25 ≥ 2,400 U/ml

•Known underlying immunosuppression:

0 points (no) or 18 (yes)

•Temperature

0 (< 38.4), 33 (38.4–39.4), or 49 (> 39.4)

•Organomegaly

0 (no), 23 (hepatomegaly or splenomegaly) or 38 (hepatomegaly and splenomegaly)

•Cytopenia

0 (one lineage), 24 (two lineages) or 34 (three lineages)

•Ferritin (mcg/L)

0 (< 2000), 35 (2000–6000), or 50 (> 6000)

•Triglyceride (mg/dL)

0 (< 150), 44 (150–400), or 64 (> 400)

•Fibrinogen (mg/dL)

0 (> 250) or 30 (≤ 250)

•AST (IU/L)

0 (< 30) or 19 (≥ 30)

•Hemophagocytosis features on bone marrow aspirate

0 (no) or 35 (yes)

*The best cutoff value for HScore was 169, corresponding to a sensitivity of 93%, a specificity of 86%, and accurate classification of 90% of the patients

1. A severe illness requiring hospitalization in an individual aged ≥ 21 years;

2. Current or past infection with SARS-CoV-2;

3. Severe dysfunction in one or more extrapulmonary organ systems;

4. Laboratory evidence of elevated inflammatory markers (e.g., CRP, ferritin, D-dimer, interleukin [IL]-6);

5. Absence of severe respiratory illness;

6. Absence of an alternative unifying diagnosis