Hemophagocytic lymphohistiocytosis (HLH) is a rare but life-threatening syndrome of excessive immune activation. Secondary HLH in adults is increasingly recognized and can be triggered by infections, malignancies, or autoimmune diseases. It is crucial to achieve early diagnosis of this challenging disorder, and it needs timely intervention to improve patient survival.  

We report a diagnostically complex case of a 60-year-old female presenting with pyrexia of unknown origin, abdominal pain, significant weight loss, and pancytopenia. Her medical history included treated gastric MALT lymphoma, Sjögren’s syndrome, and Raynaud’s phenomenon.

A comprehensive infectious and autoimmune workup was negative, although she had positive ANA, anti-Ro, pANCA, and low complements—findings consistent with underlying Sjögren’s syndrome. Despite empirical antimicrobials, her symptoms persisted. The initial working diagnosis was a recurrence of lymphoma. However, CT TAP and PET-CT revealed widespread lymphadenopathy and pericardial effusion, but no definitive signs of lymphoma relapse. Notably, the PET-CT showed a diffuse splenic uptake.

Over time, she developed markedly elevated ferritin levels (>33,000 µg/L). HLH screening blood tests showed hypertriglyceridemia, elevated soluble CD25, and borderline low fibrinogen, with a high H score. These findings supported a diagnosis of HLH per HLH-2004 criteria. Bone marrow and trephine biopsies revealed reactive changes with rare histiocytic hemophagocytes.

The patient was referred to the HLH multidisciplinary team and started on high-dose glucocorticoids, anakinra, and mycophenolate mofetil, along with antimicrobial prophylaxis. She demonstrated significant clinical and hematologic improvement within a few months.

In conclusion, HLH should be considered in the differential diagnosis for patients with autoimmune disease presenting with pyrexia of unknown origin and cytopenia. Diagnosing HLH requires a high index of suspicion and timely application of clinical scoring systems, such as the H score and HLH-2004 criteria. Biologic agents like Anakinra offer effective treatment in autoimmune-associated HLH. 

Aye Aye Nyein graduated with M.B.,B.S from the University of Medicine (1), Myanmar, and is working as a resident doctor in the acute medical ward at University Hospitals Birmingham NHS Trust.