Macrophage Activation Syndrome-Associated Hemophagocytic Lymphohistiocytosis Triggered by Myasthenia Gravis: A Rare Hyperinflammatory Complication in a Young Adult

Abstract

Macrophage activation syndrome-associated hemophagocytic lymphohistiocytosis (MAS-HLH) is a rare adult hyperinflammatory syndrome, and its occurrence in myasthenia gravis (MG) is exceptionally uncommon. We describe a 25-year-old woman with acetylcholine receptor antibody-positive MG and antiphospholipid antibody positivity who presented with acute hypoxic respiratory failure, encephalopathy, and polyserositis. Despite antimicrobials and MG-directed therapy, she developed persistent fevers, leukocytosis, and worsening neurologic dysfunction. Laboratory evaluation revealed ferritin >7500 ng/mL, fibrinogen of 151 mg/dL, triglycerides of 339 mg/dL, and soluble interleukin-2 (IL-2) receptor of 5551 pg/mL, yielding an HScore of 238 and a >90% predicted probability of HLH. Bone marrow biopsy demonstrated very rare hemophagocytic histiocytes. Extensive infectious, autoimmune, and paraneoplastic evaluation including cerebrospinal fluid cytology, flow cytometry, multiplex meningoencephalitis polymerase chain reaction, and brain magnetic resonance imaging was unrevealing, supporting a diagnosis of secondary MAS-HLH triggered by MG-associated immune dysregulation. Given progressive hyperinflammation and concern for central nervous system (CNS) involvement, the patient received high-dose corticosteroids followed by etoposide, resulting in rapid clinical improvement, declining ferritin, and normalization of IL-2 receptor. She subsequently completed 4 weekly postdischarge etoposide doses with sustained remission. This case underscores the importance of considering HLH in disorders of autoimmunity and immune dysregulation like MG, in patients who develop disproportionate systemic inflammation or neurologic decline and highlights the critical role of early recognition, multidisciplinary evaluation, and timely cytokine-directed immunosuppression in improving outcomes in adult MAS-HLH.

Introduction

Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory disorder driven by uncontrolled immune activation, cytokine storm, and end-organ dysfunction. Although well described in pediatrics and in association with malignancy, infections, and rheumatologic disease, secondary HLH in adults remains underrecognized and diagnostically challenging.^1,2 Macrophage activation syndrome (MAS), a rheumatologic variant of HLH, is most commonly associated with systemic juvenile idiopathic arthritis and adult-onset Still’s disease, but has been reported in diverse autoimmune conditions when systemic inflammation becomes dysregulated.^3,4

Myasthenia gravis (MG), an autoimmune disorder of the neuromuscular junction, is not typically linked to HLH; however, MG crises are often accompanied by systemic inflammation, immune dysregulation, and iatrogenic triggers that can theoretically precipitate MAS-HLH in susceptible individuals.^5,6 Distinguishing HLH from severe MG exacerbation, infection, or immune-mediated encephalitis is particularly difficult given overlapping features including fever, cytopenias, neurologic changes, and multiorgan involvement.

Hyperferritinemia, elevated soluble interleukin-2 (IL-2) receptor (sCD25), persistent fevers, and hemophagocytosis on bone marrow biopsy are key diagnostic clues but may manifest late or incompletely in MAS.^2,4 Etoposide-based regimens remain the backbone of treatment in severe secondary HLH, while high-dose corticosteroids are used early in MAS variants with variable success.^2,7-9

We report a young adult with MG who developed a hyperinflammatory syndrome consistent with MAS-HLH. This case highlights the diagnostic difficulty of identifying HLH in patients with autoimmune neurologic disease and emphasizes the importance of prompt immunosuppressive escalation.

Case Presentation

A 25-year-old woman with anticardiolipin/lupus anticoagulant positivity, biopsy-proven neurogenic myopathy, and acetylcholine receptor antibody-positive MG presented with severe progressive fatigue and dyspnea.

On hospital day 1, she was admitted to the intensive care unit with acute hypoxic respiratory failure, fever, and tachycardia. Initial laboratory evaluation (Table 1) demonstrated leukocytosis of 35.7 K/µL (reference range: 3.8-10.8 K/µL), anemia of 8.6 g/dL (reference range: 12-16 g/dL), platelet count of 303 K/µL (reference range: 150-450 K/µL), hyponatremia of 121 mmol/L (reference range: 136-145 mmol/L), elevated aspartate aminotransferase of 111 U/L (reference range: 13-39 U/L), and hypoalbuminemia of 2.9 g/dL (reference range: 3.5-5.7 g/dL). Computed tomography chest without contrast showed a small left pleural effusion with adjacent atelectasis, mild dependent right lower lobe atelectasis, cardiomegaly with a mild-to-moderate pericardial effusion, and partial visualization of hepatosplenomegaly. Thoracentesis yielded 150 mL of amber exudative fluid based on Light’s criteria. Bacterial cultures and an extended respiratory viral panel were negative. Empiric treatment for community-acquired pneumonia with ceftriaxone and doxycycline was initiated. Neurology was consulted and recommended pyridostigmine 60 mg 3 times daily and prednisone 10 mg daily.

Table 1.

Key Initial Laboratory Values.

Parameter	Result	Reference range
Albumin	2.9 g/dL	3.5-5.7 g/dL
AST	111 U/L	13-39 U/L
Ferritin	>7500 ng/mL	11-307 ng/mL
Fibrinogen	151 mg/dL	246-451 mg/dL
Hemoglobin	8.6 g/dL	12-16 g/dL
Platelets	303 K/µL	150-450 K/µL
sCD25	5551 pg/mL	532-1891 pg/mL
Sodium	121 mmol/L	136-145 mmol/L
Triglycerides	339 mg/dL	<150 mg/dL
WBC	35.7 K/µL	3.8-10.8 K/µL

Abbreviations: AST, aspartate aminotransferase; IL-2, interleukin-2; sCD25, soluble IL-2 receptor; WBC, white blood cell.

Values shown represent the earliest available measurements for each parameter during the initial evaluation period and may not all correspond to the same time point or the first laboratory draw upon hospital arrival. Reference ranges reflect institutional standards.

Hematology/oncology was consulted on hospital day 2 to assist with the decision between plasmapheresis and intravenous immunoglobulin (IVIG). Persistent fever, leukocytosis, polyserositis, organomegaly, and new onset lethargy with intermittent confusion raised concern for HLH, particularly MAS triggered by MG. Work-up revealed ferritin >7500 ng/mL (reference range: 11-306.8 ng/mL), fibrinogen of 151 mg/dL (reference range: 246-451 mg/dL), triglycerides of 339 mg/dL (reference range: <150 mg/dL), and sCD25 of 5551 pg/mL (reference range: 532-1891 pg/mL; Table 2). The calculated HScore was 238, corresponding to a >90% probability of HLH. Bone marrow biopsy was pursued. Due to her elevated thromboembolic risk from antiphospholipid antibodies, plasmapheresis was favored over IVIG.

Table 2.

HLH Diagnostic Criteria.

HLH-2004 criterion	Criterion threshold	Patient result	Met?
Fever	≥38.5 °C	Persistent fever
Splenomegaly	Present on exam or imaging	Hepatosplenomegaly on CT
Cytopenias (≥2 lineages)	• Hemoglobin <9 g/dL • Platelet count <100 K/µL • Absolute neutrophil count <1.0 K/µL	• Anemia only (8.6 g/dL) • Normal WBC • Normal platelets
Hypertriglyceridemia and/or hypofibrinogenemia	• Triglycerides ≥265 mg/dL and/or • Fibrinogen ≤150 mg/dL	• Triglycerides: 339 mg/dL • Fibrinogen: 151 mg/dL
Hemophagocytosis	Bone marrow, spleen, or lymph node	Very rare hemophagocytic histiocytes in marrow
Hyperferritinemia	Ferritin ≥500 ng/mL	Ferritin: >7500 ng/mL
Elevated sCD25	Above upper limit of normal (reference range: 532-1891 pg/mL)	sCD25: 5551 pg/mL
Low/absent NK cell activity	Reduced or absent	Not assessed

Abbreviations: CT, computed tomography; HLH, hemophagocytic lymphohistiocytosis; IL-2, interleukin-2; NK, natural killer; sCD25, soluble IL-2 receptor; WBC, white blood cell.

HLH diagnostic thresholds are based on HLH-2004, with interpretation aligned to contemporary 2024 guidance, which permits omission of NK-cell function testing when unavailable. Cytopenias require involvement of at least 2 hematologic lineages. Patient values represent the earliest verified results relevant to each criterion.

She underwent plasmapheresis on hospital days 2, 3, 5, and 6. Lumbar puncture on hospital day 6 showed mild protein elevation and lymphocytic pleocytosis; cerebrospinal fluid (CSF) cytology, flow cytometry, multiplex meningoencephalitis polymerase chain reaction, and paraneoplastic antibody testing were negative. Brain magnetic resonance imaging revealed no mass lesion, inflammation, or leptomeningeal enhancement. In parallel, an extensive infectious evaluation (including human immunodeficiency virus, hepatitis B virus, hepatitis C virus, cytomegalovirus, human herpesvirus 6, herpes simplex virus types 1 and 2, Epstein–Barr virus, and fungal studies), was obtained but resulted negative. High-dose corticosteroids (prednisone 1 mg/kg) were started for suspected immune-mediated encephalitis.

Bone marrow evaluation on hospital day 7 revealed very rare hemophagocytic histiocytes. Given markedly elevated sCD25 and ferritin with worsening symptoms, secondary HLH, most consistent with MAS was favored. Attempts to obtain a primary HLH genomic panel were unsuccessful due to technical difficulties.

On hospital day 8, etoposide (50 mg/m²) was initiated. By hospital day 9, ferritin had decreased to 4865 ng/mL with clinical improvement, and she was downgraded to the medical floor. Fluctuating ferritin levels during hospital days 10 to 14 prompted a second etoposide dose on hospital day 15. By hospital day 16, sCD25 improved to 1711 pg/mL, and given her overall clinical improvement the patient was discharged with a prednisone taper and hematology follow-up.

After discharge, she completed 4 weekly outpatient etoposide doses on postdischarge days 12, 19, 26, and 33. She remained clinically improved with normalized sCD25 and down-trending ferritin. Patient referred to a tertiary HLH center for further evaluation.

The full clinical course, including therapeutic interventions and response, is summarized in Figure 1.

Figure 1.

Clinical timeline of events. Timeline summarizing the patient’s clinical presentation, diagnosis, management, and outcomes.

Discussion

This case illustrates a rare but compelling presentation of MAS-HLH arising in the setting of acetylcholine receptor antibody-positive MG. The patient’s persistent deterioration from an MG exacerbation to fulminant hyperinflammation underscores the challenge of distinguishing severe autoimmune activation from evolving HLH, particularly when early features overlap. However, the patient’s biochemical, clinical, and immunopathologic profile was far more consistent with secondary HLH than with MG crisis or infection, aligning with established HLH diagnostic frameworks.^1,2

Several key features strongly supported MAS-HLH. The degree of hyperferritinemia (>7500 ng/mL) and markedly elevated sCD25 (>5500 pg/mL) exceeded what is typically observed in MG exacerbations, sepsis, or cytokine-driven encephalopathy, and is characteristic of HLH physiology.^1-4 Hypofibrinogenemia, hypertriglyceridemia, hepatosplenomegaly, encephalopathy, and polyserositis represented classic HLH-associated organ involvement, that is, not explained by MG or isolated infection.^1-3 Persistent fever, rising sCD25, and worsening neurologic status despite empiric antibiotics and MG-directed therapy further supported uncontrolled cytokine activation rather than infection or neuromuscular decompensation. Comprehensive infectious evaluation remained negative, helping exclude infectious mimickers.^2,3

Although MG is not widely recognized as a trigger of MAS-HLH, its underlying immunobiology provides a plausible mechanistic substrate. MG is characterized by autoreactive T-cell activation, impaired regulatory T-cell function, complement-mediated injury, and cytokine upregulation, which may predispose to macrophage dysregulation under systemic immune stress.^4,5 MAS, a subtype of HLH associated with autoimmune disease, arises from overwhelming IL-1, IL-6, interferon-γ, and tumor necrosis factor-α production that results in uncontrolled macrophage and T-cell activation. ⁴ In this patient, antiphospholipid antibody positivity and an active MG flare likely contributed to a heightened inflammatory milieu capable of precipitating MAS-HLH.

The patient’s HScore of 238 corresponded to a >90% probability of HLH and integrated clinical, biochemical, and laboratory parameters predictive of adult HLH. ¹ Importantly, the minimal hemophagocytosis seen on bone marrow biopsy did not weaken the diagnosis. Bone marrow hemophagocytosis has limited diagnostic performance; 1 study showed only 83% sensitivity and 60% specificity. Thus, up to nearly half of early or MAS-associated HLH cases may show little or no hemophagocytosis, making clinical and laboratory findings far more reliable than marrow morphology alone. ¹⁰ Therefore, diagnosis must rely on the totality of evidence rather than marrow findings alone, as emphasized in expert guidelines and contemporary reviews.^2,10

Therapeutically, the patient’s response further reinforced the diagnosis. The decline in ferritin, improvement in encephalopathy, and normalization of sCD25 after etoposide initiation are features characteristic of true HLH physiology rather than MG crisis or sepsis. Etoposide remains a central component of HLH-94, HLH-2004, and adult HLH treatment algorithms due to its targeted cytotoxicity against activated CD8+ T cells and macrophages.^2,7-9 The decision to avoid IVIG due to thrombotic risk in the context of antiphospholipid antibodies further reflects individualized, evidence-based care.

This case reinforces the need for high clinical suspicion for MAS-HLH in patients with autoimmune neuromuscular disease who develop multiorgan involvement, hyperferritinemia, and neurocognitive changes out of proportion to an autoimmune flare. Early multidisciplinary involvement and timely initiation of HLH-directed therapy remain critical to preventing irreversible organ damage and improving survival.^1,2,7

Conclusion

This case highlights an uncommon but compelling instance of MAS-HLH triggered by MG and reinforces the importance of considering HLH when autoimmune neuromuscular disorders present with disproportionate systemic inflammation. The combination of extreme hyperferritinemia, markedly elevated sCD25, neurocognitive decline, and refractory fevers should prompt early hematology involvement and expedited diagnostic assessment. Etoposide-based therapy in conjunction with corticosteroids led to rapid clinical and immunologic improvement, underscoring the effectiveness of early cytokine-directed treatment in adult HLH. Prompt recognition, multidisciplinary coordination, and timely initiation of immunosuppression remain essential to improving outcomes in secondary MAS-HLH.