In late August 2020, a 46-year-old male was admitted to our emergency department, with complaints of intermittent fever associated with fatigue and anorexia lasting for a month. He also complained of 30-kg weight loss within 5 months. The patient first visited a local hospital 2 weeks ago. Because of fever and lymphadenopathy, a bone marrow aspiration was performed. The bone marrow smear revealed hemophagocytosis and yeast-like bacteria; fungal infection was considered. However, no fungus was cultured in the bone marrow culture. Therefore, empirical antifungal treatment of Voriconazole was prescribed. After taking the drug, the patient developed insomnia and was replaced by itraconazole, without symptom improvement. He works as a cooker and gets up at 1 a.m. every day. He contacted with a soil-based environment for building and construction around his house. He lived in a rural area in Southeast China for more than 40 years and never traveled to foreign countries.
At physical examination, the patient has temperature of 39.7 C, pulse rate of 129/min, respiratory rate of 18/min, and blood pressure of 119/63mm of hg and has normal oxygen saturation. He had pallor and hepatosplenomegaly. Heart and lung auscultation were unremarkable.
The laboratory examination indicated pancytopenia at admission: hemoglobin, 63 g/L; platelet, 44 x 109/L; leucocytes, 1.6 x 109/L; neutrophils, 1.3 x 109/L. The C-reactive protein (CRP) level was 44.4 (normal, < 8) mg/L, and procalcitonin (PCT) level was 1.65 (normal, <0.15) ng/ml. Fibrinogen levels was decreased (1.0g/L). Serum ferritin was markedly elevated (2,775.0 ng/ml). The CD4 cell count was 120 cells/mul. He had mild abnormal serum levels of aspartate aminotransferase (AST) with 81U/L, alanine aminotransferase (ALT) with 53 U/L, and glutamyl transpeptidase (GGT) with 118 U/L, respectively. There was a decline in albumin levels, 32.0 g/L. The kidney function markers were within normal ranges. The patient had a detectable level of (1   3)-beta-d-glucan, 212.56 (normal, < 60) pg/ml, and the GM (galactomannan) level was not elevated. Serological results for human immunodeficiency virus (HIV), Epstein-Barr virus, cytomegalovirus, hepatitis virus B and C, COVID-19, and the T-cell spot test for tuberculosis infection (T-SPOT) were negative. His blood culture did not grow any pathogenic organism.  Table 1  shows the results of relevant blood investigations.
Computed tomography (CT) of the chest was normal but the abdominal CT showed hepatosplenomegaly and posterior peritoneum lymphadenopathy ( Figure 1 ). PET/CT revealed hepatosplenomegaly and posterior peritoneum lymphadenopathy and bone marrow with high FDG uptake, suggesting lymphoma probably. A bone marrow puncture was done at admission which displayed hemophagocytosis and negative result for bacterial culture. Hematoxylin and eosin (HE)-stained bone marrow demonstrated oval or round organisms with amaranth nuclei and capsule-like unstained halos around these organisms observed in the cytoplasm of phagocytes ( Figure 2 ). The fungus culture of bone marrow was also sent to laboratory for further identification. After 8 weeks of initial plating on potato dextrose agar (PDA) medium at 25 C and subsequently sub-cultured at intervals of 2 weeks in Columbia blood agar medium at 25 C. These are shown in  Figure 3 , which finally confirmed as Histoplasma capsulatum.
The patient received empirical treatment with oral itraconazole from the day of admission (200 mg three times daily for 7 days). At day 2 after admission, the body temperature was back to normal. The laboratory examination were repeated at day 4 after admission: hemoglobin, 69 g/L; platelet, 67 x 109/L; leucocytes, 4.7 x 109/L, neutrophils: 4.2 x 109/L. Serum ferritin declined to 1,264.3 ng/ml. After the results of the bone marrow puncture come out, liposomal amphotericin B was prescribed (1.0 mg/kg daily for 10 days), followed by oral itraconazole (200 mg twice daily for a total of at least 12 months). For HLH, the patient received treatment with prednisone 40 mg daily and intravenous immunoglobulin 20 g daily for 5 days. The blood cell count, CRP, PCT, and serum ferritin improved substantially after a week. The CD4 cell count also recovered normal after a week.
In this case, the patient presented with HLH with fever, splenomegaly, elevated ferritin, hypofibrinogenemia, blood cell abnormalities, and hemophagocytosis. Although he had no immunocompromised disease and never went to epidemic area, but he had been short of sleeping time for long time, and there was a lot of dust around his house because of building a road. It is unclear whether this may have been a risk factor for disease.