Case Presentation: A 64-year-old male presented to the Emergency Room with one week of worsening productive cough, fevers (Tmax 103F), vomiting, diarrhea, and malaise. His past medical history was significant for Rheumatoid Arthritis (RA), treated with etanercept, hydroxychloroquine, leflunomide and sulfasalazine. On physical examination, he was febrile, normotensive with tachycardia, and tachypneic with diminished breath sounds over bilateral lung bases and SpO2 below 92%. Labs revealed new onset pancytopenia with acanthocytosis and spherocytosis, and derangement in both liver and kidney function. (WBC 1.3 k/ul, RBC 3.48 m/ul, platelets 20 k/ul, Creatinine 1.43 mg/dL, ALT 64 U/L; AST 364 U/L, bilirubin 0.6 mg/dL, triglycerides 392 mg/dL, LDH 2090 U/L, fibrinogen 314 mg/dL). Ferritin was greater than 20,000 ng/mL (ref < 500 ng/mL). Tests for SARS-CoV-2, HIV, EBV and CMV were negative. Chest X-Ray was normal. The patient was given 3L O2 and admitted. On hospital day 1 (HD 1), ceftriaxone and azithromycin were initiated for sepsis management. Bone marrow aspiration and biopsy was performed on HD 3, to narrow down the differential for sudden onset pancytopenia. On HD 4, the clinical course was complicated by hypotension, raising suspicion of septic shock. Norepinephrine was initiated, and antibiotic coverage broadened to include vancomycin, cefepime, and metronidazole. Flow cytometry results came back on HD 4 and were compatible with mature T-cell lymphoproliferative disorder (CD1, CD34, TdT). The patient’s clinical condition deteriorated further with new-onset atrial fibrillation with rapid ventricular response. The patient’s care was then transitioned to the intensive care unit on HD 5. On HD 5, results of Interleukin-2 receptor levels came back and were found to be 5046 pg/mL (ref 175-858 pg/mL). Secondary Hemophagocytic Lymphohistiocytosis (HLH) then seemed to be the more likely diagnosis. Etoposide was initiated. Unfortunately, the patient succumbed to progressive multiorgan failure on HD 6. Bone marrow biopsy reported pathognomonic hemophagocytosis 6 days after it was initially obtained, on what would have been HD 9. With these findings, the patient posthumously met 6/8 criteria for HLH, per the 2004 guidelines.

Discussion: Secondary HLH has poor prognosis and high mortality. Its diagnosis is difficult as it can mimic septic shock with progressive multiorgan failure, a common reason for ICU admission. The 2004 HLH Criteria, Modified 2009 HLH Criteria and H scores are options for diagnosis, based on expert consensus. Infections, autoimmune diseases or malignancies can trigger secondary HLH. For management, graded approaches and treatments tailored to the underlying trigger have been suggested.Our experience shows that :(1) Markedly elevated ferritin (marker of inflammatory activity), which was present in this case, can suffice as an early clue of HLH. Reliance on a set of diagnostic criteria can delay treatment, due to the time cost of waiting for additional laboratory results.(2) Tailoring management to the underlying trigger can be difficult. This patient had multiple triggers for secondary HLH : (a) respiratory infection of unknown cause, (b) pre-existing autoimmune disease (RA) and (c) underlying lymphoproliferative disorder discovered during hospital admission.

Conclusions: Marked hyperferritinemia can be an early clue of HLH. Multiple triggers of HLH in the same person make tailored management difficult.