What's the Take Home?

A 28-Year-Old Man Presents with a Steadily Worsening Multiorgan Illness, Fever, and Profound Malaise

Ronald N. Rubin, MD
Volume 66 - Issue 1 - January 2026

  • Correct answer: C. Underlying malignancy is a common trigger and is usually lymphomatous cancer.

    Discussion. The presented patient is manifesting an uncommon, but not rare, complex, diffuse multiorgan syndrome known as hemophagocytic lymphohistiocytosis (HLH).

    Unknown in the literature until the mid-20th century, HLH is a condition in which the immune and inflammatory processes become logarithmically and catastrophically overactivated, escape the normal control and shutoff mechanisms, and leads to multiorgan failure and even death. Although an HLH diagnosis was essentially a terminal one in the past, a better understanding of the pathophysiology, earlier and more accurate diagnosis, and ongoing therapeutic advancement have improved its prognosis. Still, HLH remains a very dangerous diagnosis usually requiring intensive care.

    The demographics and epidemiology of HLH are bimodal. In the pediatric and adolescent population (incidence roughly 1 per million), HLH is almost always due to defective genes, which regulate the normal ability to terminate appropriate immune responses.1 In this patient population, hyperinflammation with overactivation of inflammatory cells and hyper-cytokininemia ensue to the point of organ damage/failure and death. The genes behave as autosomal recessives genetically.2 The effected genes are known such that in addition to the HLH clinical criteria schemes for diagnosis, current genetic gene probes are used to confirm the diagnosis in the demographic.2

    The adult secondary form of HLH has an incidence of 4.2-6.1 per million and, in a vast majority of cases, is not associated with genetic abnormalities.2 Rather, incidence of HLH is due to an otherwise normal immune system response becoming so intense and uncontrolled that it exceeds a yet unknown biological threshold again with overactivation of inflammatory cells and cytokines that cause multiorgan damage and death.1 The precise reason and biomechanisms for the adult, acquired form are not as elegantly elucidated as in the genetic defects. But somehow there is loss of "turn off" biochemistry.1 What is known from clinical studies, however, is that there are certain "triggering events" found in an overwhelming majority of adult cases. The most common are associated infections, especially viruses like Epstein-Barr and HIV (50%), malignancy-associated disorders, especially lymphoproliferative cancers, such as lymphoma and Hodgkin's disease (28%); and autoimmune/inflammatory diseases as with rheumatoid arthritis and SLE (12%). These data make Answer C the most accurate answer offered. Searching for and identifying such triggering conditions early in the evaluation is vital since addressing these conditions is required to reverse the hyperinflammation of HLH and effect a response to therapy overall.

    Clinical presentation and diagnosis. HLH is a clinically defined syndrome. Generally, patients with HLH become very ill with multiorgan clinical involvement as well as diffuse laboratory abnormalities. Patients with HLH will often be quickly placed into an ICU setting with a "sepsis" diagnosis. In fact, one of the important issues with HLH is thinking about it as a potential diagnosis in a critically ill patient labeled as sepsis, particularly when early, aggressive therapeutics (broad-spectrum antibiotics and fluids) are not having much impact.

    Currently, a standard set of 7 clinical and laboratory criteria are used for determining a diagnosis. At least 5 criteria need to be present to establish a working diagnosis of HLH.1,3 The HLH-2024 Diagnostic Criteria are as follows:3 

    1. Fever above 38.5 Cº
    2. Splenomegaly (often by examination or with imaging)
    3. Cytopenias of more than 2 cell lines (hemoglobin less than 9.0 gm/dL; platelets less than 100K, neutrophils less than 1,000)
    4. Fibrinogen less than 150 g/dL or profound triglycerides over 500 ug/dL
    5. The presence of hemophagocytosis, which requires bone marrow biopsy
    6. Ferritin above 500 ng/dL
    7. Elevated soluble CD 25 above 2400 u/mL1,3

    The latter is a marker of T-cell activation, an important part of the pathophysiology of HLH, and of the 7 criteria is the one that will be a "send out" to a reference laboratory and thus time delay. Note that the remaining 6 are relatively easy studies that most full-service hospitals can perform locally within 24-48 hours. As a consultant treating the patient at the bedside, one can ascertain the fever, spleen size, and cell counts, order the fibrinogen and triglyceride, and go from there. If there is a good shortcut to the presence of HLH, it is the presence of an ultra-high ferritin, not merely above 500 ugm/dL, but often above 5000 ugm/dL or even higher.4 Other less specific findings will also light up the laboratory profiles and include elevated transaminases, elevated bilirubin and LDH, elevated D-dimers, and a history of some sort of immunosuppression in the patient.5

    Therapy considerations. Therapy for HLH is comprised of 2 major strategic objectives. The first objective involves maneuvers to dampen the uncontrolled hyper-inflammatory state, which needs to be accomplished such that the patient does not die of the resultant multiorgan damage and failure. The second objective (remember, adults do not commonly have genetic defect causation, so Answer B is incorrect) is to simultaneously, efficiently, and aggressively search for the "trigger" underlying condition for the HLH response and address it. Failure to address the trigger underlying condition can lead to poor outcomes and mortality despite anti-inflammatory therapeutics.2,5 Recall that secondary, adult HLH has trigger causation as follows:

    • Infections, 50%
    • Cancers, often occult and predominantly hematologic and lymphatic, 28%
    • Autoimmune diseases, 12%1,3,6

    Thus, the playbook is bacteriology, virology, imaging with tissue biopsy as appropriate, and evaluations for juvenile rheumatoid arthritis (JRA), systemic lupus erythematosus (SLE), and antiphospholipid antibodies.

    Specific anti-inflammatory therapeutics for adult, secondary HLH are complex and in the domain of ICU medicine. But in the simplest terms, the backbone therapy for all three commonly inciting conditions (infection, malignancy, and auto-immune) consist of corticosteroids (usually dexamethasone in high dosage) and polyvalent immunoglobulins with the addition of specific anti-neoplastic agents for malignancy-induced and cyclosporin-related autoimmune conditions.1,3,6 Once the initiating trigger has been identified, specific regimens should be immediately added. Examples include anti-virals against Epstein-Barr or HIV as appropriate, chemotherapy regimens for cancers, and a menu of ever-expanding anti-inflammatory biologicals for auto-immune cases. An interesting medication that has both anti-inflammatory and anti-neoplastic properties is etoposide, which has shown to have a beneficial value in essentially all forms of secondary HLH and is now part of most regimens, both in the acute and chronic phases of therapy.5,7

    With ongoing improvements in more rapid diagnosis of an evolving HLH syndrome, prompt discovery of the inciting causation and the expert placement of the therapy described above there has been very significant improvement in the prognosis of adult HLH. Several decades ago, HLH had a near 100% fatality rate. Now, current studies demonstrate reductions in mortality rate to 50% in benign causation cases and 80% in the difficult cancer-caused cases.8 The worst prognoses are the malignancy-associated form, where most cases are due to highly aggressive lymphomas. The 20% 2-year survival in this group is as much cancer caused death as HLH caused.1,3,8 Alternatively, properly diagnosed and treated HLH of the auto-immune variety now has a 2+ year survival rate of 85-90% in adults. 1,3,8

    What’s the Take Home? HLH is a severe, life-threatening syndrome involving profound abnormal activation of the body's immune system-lymphocytes, cytokines, and other effector cells and biologic pathways, which overwhelms the normal controlling mechanisms and proceeds to multiple organ damage or failure and death. The pediatric variant is an autosomal recessive disorder in which specific defects in immune regulation pathways and biochemistry have been identified. The adult variant is usually not genetically caused but rather results from excessive immune stimulation and overwhelming of the normal regulation pathways. The most common causes or triggers are infections (especially viral-EBV, HIV, dengue), malignancy (most often occult at presentation and lymphomatous in nature), and autoimmune disorders (JRA and SLE).

    HLH shares many findings with the sepsis syndrome and there is no specific diagnostic imaging or laboratory findings. Well-validated HLH scoring schemes exist using 7 markers, and when 5 or more are present, indicate HLH. One easily available study with a somewhat higher sensitivity/specificity is an ultra-high ferritin level. Other easily obtained criteria include high fevers, splenomegaly, and cytopenias.

    Importantly, when one encounters a patient severely ill with multisystem organ finding, clinicians should consider HLH and initiate a prompt evaluation using the HLH criteria as well as probe for an in initiating cause. Once diagnosed, there are continually evolving therapeutic regimens, the specifics of which are in the realm of intensive care medicine, infectious disease, and hematology/oncology. But early suspicion and diagnosis are very important for improving outcomes. Therapy has made a difference in HLH, which not long ago was essentially 100% fatal. Today, HLH, triggered by benign causation, now has survivals well surpassing 50%. Malignancy-associated forms show a 2-year survival rate of 20%, mostly related to the underlying cancers.

    Patient follow-up. The profound cytopenias prompted a rapid and urgent hematology consultation. The systemic presentations suggested something more than a bone marrow failure syndrome, so imaging was performed, which confirmed significant splenomegaly and the additional finding of a large mediastinal mass. Additional laboratory findings showed ferritin of greater than 7500 ugm/dL and triglycerides of 4.1 mmol/L. A bone marrow biopsy was positive for erythrophagocytosis. Thus, 6 of 7 criteria for HLH were present and the clinical syndrome was diagnosed. For completeness. a soluble CD25 assay was sent to a referral laboratory. During this time, aggressive anti-inflammatory therapy (dexamethasone and etoposide) was initiated. There was a degree of calming of the hyper-inflammatory state and markers. Meanwhile, biopsy of the mediastinal mass revealed a high-grade T-cell lymphoma and a classic CHOP-E (cytoxan, doxorubicin, oncovin, steroid) and etoposide chemotherapy was initiated. After 2 cycles of therapy, there has been improvement in all HLH markers and significant shrinkage in the mediastinal mass. Still, the long-term prognosis is extremely guarded. When the CD25 assay returned, it was positive.

    AUTHOR
    Ronald N. Rubin MD1,2

    AFFILIATIONS
    1Lewis Katz School of Medicine at Temple University, Philadelphia, PA
    2Department of Medicine, Temple University Hospital, Philadelphia, PA

    CITATION
    Rubin RN. A 28-year-old man man presents with a steadily worsening multiorgan illness, fever, and profound malaise. Consultant. 2026;66(1):DOI:10.25270/con.2026.01.000008

    DISCLOSURES
    The author reports no relevant financial relationships.

    CORRESPONDENCE:
    Ronald N. Rubin, MD, Temple University Hospital, 3401 N. Broad Street, Philadelphia, PA 19140 (blooddocrnr@yahoo.com)

    References

    1. Henter J. Hemophagocytic lymphohistiocytosis. N Eng J Med 2025;392:584-598
    2. Henter j, Seini F, Eriksson J et al. Diagnostic guidelines for familial hemophagocytic lymphohistiocytosis revisited. Blood. 2024;144:3308-3318
    3. La Rosee P, Home A, Himes M, et al. Recommendations for the management of hemophagocytic lymphohistiocytosis in adults. Blood 2019;132:2465-2477
    4. Machowicz R, Kroger N, Kreiger T et al. Hyperferritinemia in adult HLH is best what we have so far. Blood. 2015;125:1548-1552
    5. Manchowicz R, Janka G, Wiktor-Jedrzejczak W. Your critical care patient may have HLH (hemophagocytic lymphohistiocytosis). Crit Care. 2106;20:215
    6. Bohm S, Wustua K, Pachiopnik Schmid J et al. Survival in primary hemophagocytic lymphohistiocytosis 2016-2021: etoposide is better than its reputation. Blood. 2024;143:872-881
    7. Lofstedt A, Jaderstem N, Meeths M. Malignancy associated hemophagocytic lymphohistiocytosis in Sweden: incidence clinical characteristics and survival. Blood. 2024;143:233-242
    8. La Rosee P, Horne A, Himes M et al. Recommendations for the management of hemophagocytic lymphohistiocytosis. Blood. 2019;133:2465-2477

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