Blood, Sweat and Smears: HLH, CXCL9 and Clinical Decision-Making

Podcast: Blood, Sweat and Smears – A Machaon Diagnostics Podcast
Episode: HLH, CXCL9 and Clinical Decision-Making with Dr. Joe Rocco
Host: Dr. Brad Lewis, Machaon Diagnostics
Guest: Dr. Joe Rocco, NIAID
Date: January 29, 2026

Episode Overview

This episode delves deep into the diagnosis and management of Hemophagocytic Lymphohistiocytosis (HLH), focusing on the utility of CXCL9 as a marker and its clinical relevance in acute decision-making. Dr. Brad Lewis interviews Dr. Joe Rocco—one of the few clinicians internationally who works exclusively with HLH patients—about best practices, new research on HLH phenotyping, and actionable insights for clinicians facing critically ill patients with hyperinflammatory syndromes.

Key Discussion Points & Insights

1. Dr. Rocco’s Background and Motivation (01:24 – 03:35)

• Dr. Rocco details his personal journey into HLH research, inspired by a memorable case during his medical training that spotlighted diagnostic and therapeutic uncertainty ("It is very rare that sort of people maybe remember the first case...I actually remember the first case of HLH I read about. This adult lady with a complex syndrome..." – Dr. Rocco, 01:39).
• NIH support allowed him to focus on HLH, running a natural history protocol that accepts referrals from across the U.S. and internationally (03:39).

2. Initial Recognition of HLH in the ICU & Real-Life Challenges (04:04 – 07:06)

• Early suspicion is critical: "The ideal time to start thinking about HLH is actually before the patient's in the ICU, if possible." (Dr. Rocco, 04:28)
• Hallmark features:
  • Unrelenting fevers versus fever patterns seen in typical sepsis cases
  • Cytopenias, notably low white count as highly specific
  • Ferritin: valuable for diagnosis, but high values don't always indicate more severe disease
• Ferritin can be misleading: “Some of the absolutely sickest lymphoma, lymphoproliferative disease, HLHs will have a ferritin of a couple thousand and they're extraordinarily difficult to treat.” (Dr. Rocco, 06:17)

3. Diagnostic Approach and Early Testing (07:06 – 12:02)

• HLH should be viewed as a syndrome or spectrum disease, not a standalone diagnosis.
• Key initial labs:
  • Liver function, triglycerides, fibrinogen
  • Imaging for hepatosplenomegaly (ordered pan scan)
  • Crucially: CXCL9 and soluble IL-2 receptor (sCD25)
    • CXCL9 serves as a surrogate for interferon-gamma activity, central in HLH pathogenesis.
    • These should be ordered immediately with fast turnaround, ideally within 24 hours.
• Dr. Lewis’ practical tip: "Having it next week or next month is good. For the death certificate, but less useful for the patient." (09:24)

4. Utility and Interpretation of CXCL9 (10:19 – 18:19)

• Send CXCL9 early—it’s highly dynamic, and a very high result can anticipate rapid clinical decline.
• "I don't get out of bed for a CXCL9 less than 10,000." (Dr. Rocco, 17:13)
  • 10,000–20,000: Worrisome, triggers strong clinical suspicion
  • 40,000–150,000+: Indicates very high mortality, demands urgent intervention
• Higher CXCL9 = higher short-term mortality. For every 10,000 increase, 90-day mortality odds rise by 6-7% (18:31–22:01).

5. Differentiating HLH Mimics and the Broader HLH Spectrum (12:02 – 15:32)

• Emphasis on searching for underlying drivers (malignancy, rheumatologic, infections).
• Distinction between HLH "mimics" (e.g., TMA, sickle cell crises) and true HLH, which is typically marked by pathologic interferon-gamma activation.
• Mention of IL-18 for ruling out Stills disease and broader genetic workups, with note on rapid NGS panels becoming available (Genetic testing via Machaon: approx. 2-day turnaround).

6. New Research: CXCL9 as a Prognostic and Decision-making Marker (18:21 – 24:07)

• Recent multi-center study (NIAID, Sloan Kettering, Pitt): In 170+ suspected HLH cases, only CXCL9 stood out as an acute prognostic marker.
• Mortality rises sharply above 16,000 CXCL9 (well above 50% at 60–90 days).
• CXCL9 elevation is similar regardless of HLH driver, in contrast to ferritin and sCD25, which vary by etiology.
  • Ferritin highest in rheumatologic and post-transplant HLH, but not always associated with high mortality.
  • sCD25 highest in malignancy-driven HLH; CXCL9 is the best acute marker for clinical deterioration.

7. Effects of Immunosuppression and Treatment Monitoring (24:07 – 26:38)

• Immunosuppressed patients may have higher CXCL9 (reflects severity rather than dampening of the marker).
• "CXCL9 is actually a little bit less likely to be prone to changes based on underlying immune suppression...It lends to its specificity for the interferon-gamma axis." (24:21)
• Response to HLH-directed therapy (e.g., steroids, imipalumab, ruxolitinib) is reflected in falling CXCL9. Poor response = higher risk of death.

8. HLH Management and Sequencing Therapy (26:38 – 38:38)

• Therapy should be escalated based on CXCL9:
  • Start with steroids, but if CXCL9 is high and patient refractory, escalate quickly to interferon-gamma targeting agents (imipalumab) or JAK inhibitors (ruxolitinib).
  • Dosing is correlated with CXCL9: higher numbers require higher doses.
  • Imipalumab: 6–10 mg/kg, possibly more in extreme cases ("If your CXCL9 is 100,000, the imipalumab doesn't make it out of your antecubital fossa...").
• Clinical Pearl: Treating HLH acutely buys time for diagnosis and therapy of the underlying driver (malignancy, infection, rheumatologic).

9. Genetics in Adult HLH & Under-recognition (33:34 – 36:24)

• Whole genome sequencing may reveal primary/genetic HLH in adults—traditionally assumed to be a pediatric disease, but likely underdiagnosed in adults.
• Panel-based next-gen sequencing now offers actionable results in ~2 days.

10. Difficult Cases, Long-term Strategy, and Future Research (40:40 – 45:37)

• In cases with no clear driver, monitoring and treating both interferon-gamma axis (imipalumab) and T-cell proliferation (ruxolitinib, etoposide) may be necessary.
• Novel targeted drugs are on the horizon (e.g., ELA026 targeting SIRP proteins).
• The future: Improved phenotyping (CXCL9-guided), tailored therapy, studies to address long-term outcomes now that acute mortality can be reduced.

Notable Quotes & Memorable Moments

• "Unrelenting fevers or B symptoms is certainly something to keep your ears up for."
  – Dr. Joe Rocco, 04:44

• "The higher [CXCL9] is, the worse it is and the more nervous you should get and the more aggressive you should be with initiating therapies."
  – Dr. Joe Rocco, 27:01

• "Mortality for these patients was extraordinary. Within the first 60 days, 90 days, it was well over 50%."
  – Dr. Joe Rocco, 21:10

• "I don't get out of bed for a CXCL9 less than 10,000."
  – Dr. Joe Rocco, 17:13

• "If your CXCL9 is 100,000, the imipalumab doesn't make it out of your antecubital fossa because it runs into all the gamma there that it binds to. The patient feels better for 10 minutes and then you know, it's gone."
  – Dr. Joe Rocco, 36:24

• "This is a population of patients that almost universally died. 50, 60, 70% of them died within 60 days. They're all going to live now, if we do this correctly."
  – Dr. Joe Rocco, 44:36

Key Timestamps

• 01:24 – Dr. Rocco’s HLH journey and NIH natural history protocol
• 04:28 – Recognizing HLH: fevers, cytopenias, and ferritin
• 07:21 – Lab evaluation and initial HLH spectrum workup
• 09:24 – Importance of rapid CXCL9/sCD25 turnaround
• 10:19 – Early sending/interpretation of CXCL9 in smoldering cases
• 17:13 – Practical CXCL9 thresholds: “I don't get out of bed for a CXCL9 less than 10,000.”
• 18:31 – Summary of recent multicenter study; CXCL9 as mortality marker
• 24:21 – Effect of immunosuppression on CXCL9’s reliability
• 27:01 – Sequencing and intensity of HLH therapies based on CXCL9
• 31:38 – Clinical case: imipalumab in acute ehrlichiosis HLH
• 33:34 – Genetic testing in adult HLH; new findings
• 36:24 – Dosing imipalumab by CXCL9 levels
• 38:38 – Broader utility of CXCL9—interferon gamma axis diseases beyond classic HLH
• 40:40 – Management when HLH driver is unknown; transitioning therapies
• 43:07 – Future directions and new therapies

Resources and Contact

• Clinicians interested in consulting or enrolling patients in the NIH HLH natural history study are encouraged to contact Dr. Joe Rocco at the NIAID (easy to find by email, as noted in the episode, 46:03).
• Rapid CXCL9, sCD25, and genetic panel testing is available through Machaon Diagnostics.

Summary

This episode offers a high-yield, modern framework for the recognition, diagnosis, and acute management of HLH, advocating for early and aggressive use of biomarkers like CXCL9 to guide therapeutic urgency and selection. Dr. Joe Rocco’s insights reflect a shift from rigid diagnostic criteria to dynamic, spectrum-based clinical reasoning—backed by new multicenter data—and provide a pragmatic “toolbox” for both hematologists and generalists faced with this rare but deadly syndrome. The conversation is energetic, collegial, and packed with actionable pearls for real-world practice.