We report the case of a 68-year-old Swiss woman who presented to a peripheral hospital in Switzerland after consulting her general doctor about loss of weight (8 kg) in the last month, a maculopapular rash, fatigue, loss of appetite, palpitations, headaches, and cough for 2 weeks. The general doctor assigned her to the peripheral hospital after measuring 39.5 C fever and noticing very high liver parameters in the blood test.
She had a history of pericarditis at the age of 65 years, and paroxysmal atrial fibrillation and depression were also noted.
The family history was negative for hematological diseases.
The laboratory workup at admission showed normocytic, normochromic nonregenerative moderate anemia, mild thrombocytopenia, high D-dimer, slightly lower fibrinogen, liver insufficiency, and high triglycerides. The ferritin level increased (7,069 mug/L, reference value: 10-120 mug/L). An ultrasound scan of the abdomen showed splenomegaly (12.5 cm). The SARS-CoV-2 polymerase chain reaction (PCR) test, chest X-ray, lumbar puncture, blood culture, serology for EBV, CMV, human immunodeficiency virus (HIV), hepatitis A, B, C, and E, Coxiella, parvovirus B19, and Bartonella, and search for Mycobacterium tuberculosis (QuantiFERON test) were negative. After one week of hospitalization, her clinical condition deteriorated, and she was transferred to our center with the suspicion of HLH. At admission, the patient presented with markedly reduced general conditions; she was febrile (38.6 C), hemodynamically compensated, her BMI was 18.5 kg/m2, and the laboratory tests showed a progressive increase in CRP up to 190 mg/l, hypoosmolar hyponatremia, increased liver values, coagulopathy, and pancytopenia (Table 2). An HScore for reactive HLH was calculated, showing 209/337 points with an estimated probability for HLH of 93% (Table 3). Therefore, therapy with dexamethasone 15 mg/day was immediately started. Additional investigations were performed, including transthoracic echocardiography, computed tomography (CT) of the chest, abdomen, and pelvis, and a biopsy of the liver, skin, and bone marrow; however, none of these examinations contributed to the identification of an underlying trigger for HLH. The bone marrow showed a large number of macrophages but did not show any sign of hemophagocytosis. Furthermore, a rheumatologic disease could be excluded based on negative screening for autoantibodies (antinuclear antibodies, Hep-2, SsA, PR3 antineutrophil cytoplasmic antibodies, and myeloperoxidase antineutrophil cytoplasmic antibodies) and missing related symptoms. After 1 week of treatment, slight clinical and laboratory improvements allowed doctors to start tapering dexamethasone, and the patient was discharged home after 4 weeks of hospitalization.
Four days later, she presented to her scheduled control in the outpatient clinic of hematology with worsened fatigue. The laboratory workup showed an increase of ferritin to 49'036 mcg/L while still being under 5 mg dexamethasone/day. We therefore increased the dexamethasone dose to 16 mg/day and started with cyclosporine, with a trough level goal between 100 and 200 ng/ml. Because up to that point no cause of HLH could be identified, the investigation was completed with positron emission tomography-computed tomography (PEC-CT), which showed intensive metabolic activity behind the right patella and in the ascending and sigmoid colon. Gastroscopy and colonoscopy performed afterward excluded gastrointestinal neoplasia and local inflammatory diseases. Additionally, leg magnetic resonance imaging (MRI) was performed, which suggested pigmented villonodular synovitis (PVNS), a benign entity unlikely to cause HLH, and thus considered an incidental finding.
Only after 3 months from the manifestation of symptoms, the patient reported a significant improvement in her general condition, including regaining appetite and weight.
Furthermore, we performed a genetic analysis searching for variants in genes related to primary HLH (perforin 1 (PRF1), syntaxin 11 (STX11), syntaxin binding protein 2 (STXBP2), and UNC13D), revealing no pathogenic variants.
The diagnostic workup is summarized in Table 4.
Vitamins and substrates (folic acid, iron, zinc, and vitamin B12) were administrated to sustain hematopoiesis.
Six months after the diagnosis, the patient was completely back to her routine life with no symptoms and completely normalized laboratory findings (Table 2). Slow tapering to discontinue cyclosporine was performed, but immediately before planned drug withdrawal, laboratory signs of inflammation with increased liver values at a 9-monthfollow-up were observed, and a low dose of cyclosporine was reinstalled. Currently, one year after the diagnosis, the patient is doing well, and tapering of cyclosporine is still ongoing.