In a patient with normal platelet count, normal white blood cell count, and C‑reactive protein 27 mg/L, does this satisfy the HLH diagnostic criteria or point to a different inflammatory process?

Assessment of HLH Diagnostic Criteria with Normal Cell Counts and CRP 27 mg/L

This clinical picture does NOT satisfy HLH diagnostic criteria and strongly suggests a different inflammatory process. The normal platelet and WBC counts directly contradict the required cytopenia criteria, while the modestly elevated CRP is inconsistent with the hyperinflammatory state characteristic of HLH.

Why This Does Not Meet HLH-2004 Criteria

HLH diagnosis requires 5 of 8 specific criteria to be met, and this patient fails the critical cytopenia requirement 1:

• Cytopenias must affect ≥2 of 3 lineages: hemoglobin <90 g/L, platelets <100 × 10⁹/L, or neutrophils <1.0 × 10⁹/L 1, 2
• Your patient has normal platelets and normal WBC, meaning at most only 1 lineage could be affected (if hemoglobin is low, which you haven't specified) 1
• Without meeting the cytopenia criterion, the patient cannot have HLH unless there is a molecular diagnosis confirming genetic HLH 1, 2

The Ferritin Question Is Critical Here

The most important missing piece of information is the ferritin level 1:

• Ferritin ≥500 mg/L is one of the 8 HLH-2004 criteria, but this threshold is not specific for HLH 1
• Ferritin levels of 7,000-10,000 mg/L or higher are characteristic of HLH in adults, with values >10,000 mg/L being >90% sensitive and specific in children 1
• Hyperferritinemia should always prompt inclusion of HLH in the differential, but your patient's CRP of only 27 mg/L makes extreme hyperferritinemia unlikely 1

Why CRP 27 mg/L Argues Against HLH

A CRP of 27 mg/L represents mild-to-moderate inflammation, not the severe hyperinflammatory state of HLH 3, 4:

• HLH is characterized by excessive activation of the immune system with overproduction of inflammatory cytokines and a "cytokine storm" 5, 3, 4
• Patients typically present with hectic, persistent high fevers (often >39.4°C), hepatosplenomegaly, and profound systemic inflammation 6, 3, 7
• The modest CRP elevation suggests a controlled inflammatory response, not the uncontrolled hyperinflammation that defines HLH 3, 4

What Other Criteria Would Be Needed

Even if you wanted to pursue HLH diagnosis further, you would need to document 1, 2:

• Fever (one of the most consistent features) 6, 3
• Splenomegaly (present in majority of cases) 6, 3
• Hypertriglyceridemia (≥3.0 mmol/L or ≥265 mg/dL) and/or hypofibrinogenemia (≤1.5 g/L) 1
• Hemophagocytosis on bone marrow biopsy (though this can be absent initially and is neither sensitive nor specific) 1, 6
• Low or absent NK cell activity 1
• Soluble CD25 (sCD25) ≥2400 U/mL (reported as excellent diagnostic test with AUC 0.90) 1, 2

Clinical Pitfall to Avoid

Do not confuse any inflammatory condition with HLH simply because inflammatory markers are elevated 5, 7:

• Many diagnostic features of HLH are nonspecific and can overlap with sepsis, viral infections, or other inflammatory conditions 5, 7
• The key distinguishing feature is that HLH patients cannot control their hyperinflammatory response, leading to progressive multi-organ dysfunction if untreated 3, 4
• Normal blood counts essentially exclude active HLH, as cytopenias are a cardinal feature reflecting bone marrow dysfunction from the hyperinflammatory state 1, 3, 7

What This Clinical Picture Suggests Instead

With normal cell counts and CRP 27 mg/L, consider alternative diagnoses 5:

• Mild-to-moderate infection (viral or bacterial)
• Early autoimmune/inflammatory condition not yet meeting criteria for specific diagnosis
• Localized inflammatory process without systemic hyperinflammation
• Post-infectious inflammatory state with resolving inflammation

The normal platelets are particularly reassuring, as platelets rapidly reflect HLH activity and drop significantly during disease flares 1, 6.