A 76-year-old man presented with three days of persistent fever not accompanied by other symptoms including cough, sore throat, fatigue or myalgia. Then he was diagnosed antigen-positive SARS-Cov-2 infection on 16 December 2022 during the epidemic of Omicron variant. He did not receive antiviral treatment and took antipyretics orally for 1 day by himself without visiting the hospital. In the next half month, his temperature was normal and loss of appetite was his main complaint. However, the fever reappeared on 3 January 2023, so he was admitted to our hospital on 5 January 2023. There were no complaints of cough, sputum, hemoptysis, abdominal pain, diarrhea, arthralgia and erythema. There was no history of environmental, occupational or long-term drug exposure. He had a medical history of hypertension and denied having autoimmune diseases. The patient was clinically stable at the time of admission. His oxygen saturation was 98% on room air; heart rate was 68 beats per minute; respiratory rate was 18 breaths per minute; temperature was 37.5°C; and blood pressure was 134/81mmHg. Blood tests including complete blood count, liver and renal function tests, coagulation tests and inflammation markers (C-reactive protein, interleukin-6 and erythrocyte sedimentation rate) were almost within normal limits, except the ferritin was increased (480.2 ug/L, normal range: 23.9–336.2 ug/L). SARS-Cov-2 nasopharyngeal swabs were performed every three days and all of the tests were negative. Multiple cultures sets of blood, urine, and sputum were negative for bacteria, mycobacteria, or fungi. Twice next-generation sequencing of peripheral blood was negative. Viral infections (CMV, human immunodeficiency virus, hepatotropic viruses, herpes simplex virus, influenza virus, parvovirus, adenovirus and atypical respiratory pathogens) were promptly ruled out. EBV-DNA in peripheral blood lymphocytes was 1780 copies/mL (normal:500 copies/mL). EBV-DNA in plasma and EBV-IgM antibody were negative. No signs of malignant lesions were found in positron emission tomography-computed tomography (PET-CT) or bone marrow aspiration and biopsy. Hepatomegaly or splenomegaly were not detected by the ultrasound scan. Serum tumor markers, serum and urine immunofixation electrophoresis, ultrasound of superficial lymph nodes, and head MRI were performed and no obvious abnormalities were found except for the high serum carcinoembryonic antigen (CEA, 21ng/mL), which showed no significant change compared to last year’s result (25.7ng/mL). He had a history of high CEA for five years and underwent gastrointestinal endoscopy one year before, but no signs of tumor were found. Rheumatologic tests showed the 1:320 positive antinuclear antibody, 1:100 positive anti-dsDNA antibody and slightly low C3 complement level (0.546g/L, normal range: 0.6–1.5g/L). Other indications of connective tissue disease, such as anti-ENA antibodies, antiphospholipid antibodies, direct Coombs test, ANCA and rheumatoid factor, were all negative. During the hospitalization, a serious deterioration in clinical condition and laboratory parameters was observed (). His fever continued to increase and reached 39.8°C. We also noticed a change in his cognitive function. We found his leukocytes, hemoglobin and platelets were decreased; ferritin was raised; liver dysfunction, fibrinogen and natural killer (NK) cell activity decreased; and hemophagocytosis was present in bone marrow aspiration (). Triglyceride and soluble interleukin-2 receptor (SIL-2R/sCD25) were normal. A diagnosis of sHLH was made according to HLH-2004 criteria, including presence of fever, hypofibrinogenemia, ferritin > 500ug/L, hemophagocytosis in bone marrow and low NK-cell activity (). H-score for sHLH showed an 80–88% probability of HLH, with a total of 192 points (). From 22 January, he was treated with methylprednisolone 80mg/day intravenously for day 1 and day 2, sequential dexamethasone 20mg/day from day 3 to day 7, intravenous immunoglobulin 30g from day 1 to day 7 concomitantly, plus intravenous etoposide 180mg (100mg/m2) on day 3. But the clinical presentation was not relieved, accompanied by persistent fever, decreasing white blood cells, platelets and fibrinogen and progressively increasing ferritin. Then the therapy was adjusted to ruxolitinib 10mg twice a day and methylprednisolone 60mg daily intravenously from day 8. The patient’s symptoms improved significantly one week later, including the relief of fever and cognitive function, as well as the improvement of blood cell count, fibrinogen and ferritin (). The patient tolerated ruxolitinib well and no severe side effects occurred during treatment such as hemorrhage, secondary infection, renal or liver dysfunction. He had continuously decreased leukocytes and platelets for several days after treatment, which may not have been due to ruxolitinib but the progression of sHLH, as the blood cell count increased quickly. The clinical course of this patient is shown in.