A Race Against Time: Illustrating the Importance of Prompt Recognition and Diagnosis of Hemophagocytic Lymphohistiocytosis (HLH)

Introduction

Hemophagocytic lymphohistiocytosis (HLH) is a rapidly progressive lymphoproliferative disorder that results in excessive immune activation. Epstein-Barr virus (EBV) is associated with lymphoproliferative disorders that can range from relatively benign illnesses to aggressive lymphoproliferative states such as those seen in HLH and some T-cell lymphomas. Our case illustrates a diagnosis of HLH for a patient who initially did not meet the HLH-2004 diagnostic criteria, but had a high pre-test probability of having the condition necessitating prompt treatment.

Case Description:

This is a case of a 22-year-old female with a history of chronic EBV viremia and hydroa vacciniforme (HV) - a rare, chronic, photosensitivity disorder frequently associated with EBV infection - on chronic low dose steroids and recent thalidomide initiation for HV. She was previously admitted to the medical intensive care unit (MICU) for adrenal insufficiency in the setting of long-term steroid use and then returned 2 weeks later with subjective fevers, dyspnea and nasal discharge. She again required admission to the MICU due to severe sepsis, where she received antibiotic treatment for pneumonia and a suspected nasal abscess. Over the course of 24 hours, she had an acute decline in her clinical condition and developed disseminated intravascular coagulation (DIC), pancytopenia, hemoptysis requiring intubation, acute liver failure, and renal failure requiring hemodialysis.

Hematology was consulted; possible differentials for the patient's current presentation included HLH due to her underlying EBV associated lymphoproliferative disorder and DIC due to severe infection. Given the patient's rapidly deteriorating clinical status, a joint decision was made with her family to initiate treatment for presumed HLH despite her meeting 4 out of 8 criteria for diagnosis of HLH (5 of 8 are required), as any delay in treatment would increase her mortality risk. Bone marrow biopsy was deferred due to critical illness and molecular testing was pending at this time. Likely due to long term steroid use, the patient never mounted a fever during her admission, which is an atypical presentation for HLH as patients are usually persistently febrile. However, she met certain HLH diagnostic criteria: low fibrinogen (152 mg/dL), hypertriglyceridemia (563 mg/dL), pancytopenia (hemoglobin 10.2 g/dL, platelet count 8000/UL), elevated ferritin (926.4 ng/mL), and hepatosplenomegaly. She was started on the HLH-94 protocol with dexamethasone and etoposide; rituximab was added due to her EBV status. In the days following the administration of HLH treatment, she had steady improvement in organ function, was extubated, and taken off dialysis. Subsequently, her sIL-2/CD-25 receptor was elevated at 8,600 pg/mL, confirming the diagnosis of HLH. She was referred for genetics counseling and allogenic-stem cell transplant evaluation.

Discussion

HLH leads to multi-organ failure and is rapidly fatal if left untreated. Clinicians must maintain a high index of suspicion in patients who have a high pre-test probability of developing this condition. Our patient had no documented fevers in the setting of immunosuppression from chronic steroid use, and she did present with the degree of ferritin elevation that is typical of HLH. However, a diagnosis of HLH was suspected with empiric treatment initiated as the patient had a history of chronic EBV and HV, likely predisposing her to developing a T-cell lymphoproliferative disorder such as HLH.

References

1. Chen CC, Chang KC, Medeiros, LJ, et al. Hydroa Vacciniforme and Hydroa Vacciniforme-Like Lymphoproliferative Disorder: A Spectrum of Disease Phenotypes Associated with Ultraviolet Irradiation and Chronic Epstein-Barr Virus Infection. International Journal of Molecular Sciences 2020;21(23), 9314.

2. Henter JI, Aricò M, Egeler, RM, et al. HLH-94: a treatment protocol for hemophagocytic lymphohistiocytosis. HLH study Group of the Histiocyte Society. Medical and Pediatric Oncology 1997;28(5), 342-347.

3. Henter, JI, Samuelsson-Horne, A., Aricò, M., et al. Treatment of hemophagocytic lymphohistiocytosis with HLH-94 immunochemotherapy and bone marrow transplantation. Blood 2002;100(7), 2367-2373.

4. La Rosée P, Horne A, Hines M, et al. Recommendations for the management of hemophagocytic lymphohistiocytosis in adults. Blood 2019;133(23), 2465-2477.

No relevant conflicts of interest to declare.