Secondary hemophagocytic lymphohistiocytosis following blood transfusion in the absence of an identifiable trigger

Abstract

Hemophagocytic lymphohistiocytosis is a life-threatening inflammatory syndrome resulting from uncontrolled immune activation. Secondary hemophagocytic lymphohistiocytosis is typically triggered by infection, malignancy, or autoimmune disease, though diagnosis is often difficult due to nonspecific findings. We present the case of a 55-year-old man with pancytopenia and fever following a blood transfusion. There were no clear infectious, malignant, or autoimmune triggers identified. Bone marrow biopsy showed no hemophagocytosis, but laboratory workup revealed hypertriglyceridemia, hyperferritinemia, and elevated soluble IL-2 receptor. He met six hemophagocytic lymphohistiocytosis-2004 criteria and had a high H-score. He was treated with dexamethasone and etoposide, with rapid clinical improvement. This is a unique case of secondary hemophagocytic lymphohistiocytosis after a blood transfusion without other identifiable triggers, which has not yet been reported in the literature. This case underscores the importance of maintaining high clinical suspicion for hemophagocytic lymphohistiocytosis in adults with persistent fever and cytopenias, even in the absence of known triggers.

Introduction

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition characterized by the persistent activation of cytotoxic T lymphocytes and natural killer (NK) cells. ¹ The uncontrolled immune response leads to excessive release of inflammatory cytokines and macrophage activation, leading to widespread systemic inflammation and, often, multi-organ damage that may progress and present like a septic shock.^1,2 Familial HLH arises from mutations in cytotoxic T lymphocytes and NK cells, leading to widespread activation. Secondary HLH arises from external triggers such as infection, malignancy, rheumatologic disease, or drug hypersensitivity. ³ In adults, malignancy is the leading cause, accounting for up to 45% of cases and Epstein-Barr virus is the most common infectious trigger.^{2 –4}

Secondary HLH typically presents with a high, persistent fever, organomegaly, edema, coagulopathy, anemia, neurologic dysfunction, and liver dysfunction.^2,3,5 Laboratory findings often include cytopenias, hypertriglyceridemia, hypofibrinogenemia, hyperferritinemia, elevated soluble CD25, and low NK cell activity.^2,3,5 Most patients are critically ill, so prompt diagnosis of HLH is essential. Despite increasing incidence and awareness, secondary HLH carries a high mortality rate and remains underdiagnosed due to its variable presentation and nonspecific findings.^{5 –8}

We present a patient who developed fever after a blood transfusion without any identifiable trigger. Despite an atypical presentation, suspicion for HLH was high and the patient responded favorably to HLH-directed therapy.

Case

A 55-year-old male presented with pancytopenia and neutropenic fever. His history included deep vein thrombosis, chronic lymphedema, and treated hepatitis C. Two months prior, the patient was hospitalized for septic shock and acute hypoxic respiratory failure requiring intubation and pressor support. Wound cultures revealed methicillin-sensitive Staphylococcus aureus and streptococcus cellulitis of the left lower extremity. He developed acute kidney injury and rhabdomyolysis requiring hemodialysis. He developed an antibiotic-related rash and fever, which resolved on discontinuation of therapy.

Six weeks later, labs revealed pancytopenia: white blood cells 3.8 k/µL, hemoglobin 7.1 g/dL, mean corpuscular volume 93 fL, platelets 100 k/µL. Iron studies suggested anemia from inflammation. Bone marrow biopsy showed normocellular bone marrow with trilineage hematopoiesis and no evidence of acute lymphoma, leukemia, or myeloma. Although the core was aspirated, the aspirate smears were adequate, and no hemophagocytosis was seen.^2,9 Reticulocyte count was 66.1 × 10⁹/L, with a percentage of 3.8. Computed tomography imaging of the abdomen revealed splenomegaly as shown in Figure 1.

Figure 1.

CT abdomen and pelvis without contrast demonstrates splenomegaly measuring 185 mm.

CT: computed tomography.

Over 2 weeks, he received three units of packed red blood cells (pRBCs). Approximately 2 h after the third pRBC transfusion, he developed a fever of 102°F and remained febrile for approximately 48 h. Brown discharge was noted at his tunneled dialysis catheter, and he was empirically treated with antibiotics, though cultures were negative. Persistent pancytopenia, worsening neutrophil count (absolute neutrophil count 0.8 k/µL, hemoglobin 7.7 g/dL, platelets 103 k/µL) and persistent fever prompted transfer to our hospital.

On admission, infectious workup was negative, including sputum culture, hepatitis B and C serologies, HIV, blood cultures, urinalysis, and respiratory pathogen panel. Zinc and copper levels were within normal limits. He had no personal history of malignancy, hematologic, or autoimmune disease. HLH workup revealed triglycerides 332 mg/dL, ferritin 4677 ng/mL, fibrinogen 359 mg/dL, and soluble IL-2 receptor (sCD25) 2915.5 pg/mL. On examination, vitals were within normal limits. Chronic venous stasis dermatitis was noted on the bilateral lower extremities. Cardiovascular, respiratory, and abdominal examinations were normal.

He met six out of eight HLH-2004 criteria including fever, splenomegaly, cytopenias, hypertriglyceridemia, elevated ferritin, and elevated sCD25. H-score was greater than 169, the optimal cutoff, confirming a high probability of HLH. Treatment was initiated with dexamethasone and etoposide, resulting in rapid clinical and laboratory improvement (Table 1). He tolerated treatment and was discharged to complete the etoposide and steroid taper at an outside facility.

Table 1.

Laboratory values at the time of diagnosis and 5 days after the initiation of treatment for HLH.

Laboratory value	Pre-treatment	5 days post-treatment initiation
Hemoglobin	7.7 g/dL	8.6 g/dL
Neutrophil count	0.8 k/µL	3.6 k/µL
Triglycerides	332 mg/dL	187 mg/dL
Ferritin	4677 ng/mL	2696 ng/mL

HLH: hemophagocytic lymphohistiocytosis.

Discussion

HLH is a rare, life-threatening condition characterized by an uncontrolled immune response leading to widespread multi-organ dysfunction and failure. Secondary HLH is often triggered by infections, malignancy, or autoimmune diseases, but diagnosis may be difficult due to its nonspecific presentation and findings. Specifically, hyperferritinemia, hypertriglyceridemia, hypofibrinogenemia, and hemophagocytosis are common findings in sepsis, systemic inflammatory response syndrome, and disseminated cancer, making an HLH diagnosis difficult to determine, resulting in delays in treatment. ⁹

In this case, the patient presented with pancytopenia for several weeks, followed by a persistent high-grade fever after blood transfusion. The differential included HLH versus febrile nonhemolytic transfusion reaction (FNHTR). FNHTR typically resolves within hours and lacks significant laboratory changes, making this less likely. His bone marrow biopsy was reviewed with no evidence of hemophagocytosis, though this does not rule out HLH. Further, there were no identifiable infectious, autoimmune, or malignant triggers to suggest HLH, making the diagnosis challenging.

This case highlights the importance of early recognition and treatment once HLH is suspected, regardless of identifiable triggers. To our knowledge, there are no published reports describing secondary HLH triggered by a blood transfusion without other precipitating factors. While transfusion-related graft versus host disease in familial HLH and post-transfusion hemophagocytosis in the absence of HLH have been described, none have associated blood transfusion directly to secondary HLH.^10,11

Given that secondary HLH is an excessive immune and inflammatory response, it is biologically possible for a blood transfusion to introduce infectious agents or induce immune dysregulation, ultimately triggering HLH. Similarly, an underlying infection in the weeks prior to presentation may have contributed to the development of HLH via a subclinical inflammatory state. Secondary HLH typically presents within days to weeks of an inciting event, though some scenarios may have a longer latency period, such as rheumatologic disease or malignancy, as compared to infectious triggers that often have a shorter latency period.^5,12 This patient’s infection 2 months prior may have contributed to an inflammatory response, though the timeline of the blood transfusion and HLH onset supports this as the more likely inciting event.

Conclusion

This case illustrates that HLH can present without hemophagocytosis on bone marrow biopsy, emphasizing the importance of clinical history and laboratory findings. Though blood transfusion is not a known trigger of HLH, with a high clinical suspicion and early initiation of treatment, the patient responded favorably. This case broadens the clinical picture of secondary HLH diagnosis and triggering factors in adults presenting with nonspecific inflammatory findings with multiple organ involvement.