Written informed consent was obtained from the patients and/or their families for publication of this case report and the accompanying images.
Case 1
A 72-year-old female farmer in a mountainous area was referred to the Public Toyooka Hospital by her family physician owing to fever (body temperature, approximately 38 °C), leukopenia, thrombocytopenia, and a mild consciousness disturbance. Four days previously, she had experienced severe fatigue, diarrhea, and nausea.
The patient had been receiving amlodipine at 5 mg/day for 10 years, as prescribed by her family physician. Her score on the Glasgow Coma Scale (GCS) was 14 points (eye opening, 3; verbal response, 5; and motor response, 6), and her vital signs were as follows: temperature, 37.6 °C; pulse rate, 70 beats per minute (regular); blood pressure, 99/58 mmHg; and respiration rate, 18 breaths per minute. A physical examination revealed splenomegaly and swelling of the inguinal lymph nodes. Contrast-enhanced computed tomography revealed splenomegaly and swollen axillary and inguinal lymph nodes. Laboratory findings were as follows: white blood cell (WBC) count, 1400/µL (lymphocyte count, 80/µL); red blood cell (RBC) count, 478 × 104/µL; hemoglobin (Hb) level, 13 g/dL; platelet count, 7.2 × 104/µL; aspartate aminotransferase (AST) level, 117 IU/L; alanine aminotransferase (ALT) level, 33 IU/L; LDH level, 646 IU/L; creatinine phosphokinase (CPK) level, 595 IU/L; blood urea nitrogen (BUN) level, 26.4 mg/dL; serum creatinine (Cr) level, 0.89 mg/dL; fibrinogen level, 134.2 mg/dL; fasting triglyceride level, 256 mg/dL; soluble interleukin-2 receptor (sIL-2R) level, 1320 U/mL (normal, 149–519 U/mL); and ferritin level, 1908 ng/mL. A capillary blood smear test showed no abnormal cells. A bone marrow aspiration smear showed that RBCs were ingested by macrophages (Fig. 1). The patient met six of the eight HLH2004 diagnostic criteria and was therefore diagnosed with hemophagocytic syndrome and admitted to the hospital. Although a workup was performed to determine the cause of this syndrome, no previously described etiologic agents or diseases were detected (e.g., malignant lymphoma, Epstein-Barr virus, human immunodeficiency virus, systemic lupus erythematosus, adult-onset Still’s disease, and rheumatoid arthritis).
The following day, a tick was found attached to the skin of the left popliteal fossa (Fig. 2).
The tick appeared to be swollen and was constantly biting the patient; it was subsequently removed by using fine-tipped tweezers. Hence, the patient was suspected of having SFTS. A viral genome detection test was performed via reverse transcription–polymerase chain reaction (RT–PCR; Yoshikawa et al. 2014) using total RNA extracted from a peripheral blood sample, a pharyngeal swab, and a urine specimen obtained on the day after admission. Three days after the initial test (hospital day 5), the test was repeated for whole blood and urine specimens. In the pharyngeal swab, the viral gene copy number (S segment) was 105.08/mL on hospital day 2 (6 days after disease onset). In the whole blood, the viral gene copy number was 104.43/mL on hospital day 2, but had decreased to 102.92/mL on hospital day 5.
Prior to the first viral genome detection test, the patient began treatment with 60 mg (1 mg/kg) prednisolone orally for hemophagocytic syndrome and 100 mg minocycline twice a day intravenously for a suspected Rickettsial infection. Four days after treatment initiation, her symptoms improved, and 5 days after treatment initiation, the whole blood cell count, liver enzyme levels (AST, ALT, and LDH), and ferritin values returned to normal. Ten days after admission, the tick was identified as Haemaphysalis longicornis, and a definitive diagnosis of SFTS was made by conventional viral genome amplification analysis (Fig. 3; Yoshikawa et al. 2014). The test results showed that the viral genome was amplified in the serum and swab specimens collected on hospital day 2. In the second test after treatment, the viral genome could not be amplified from the urine specimen collected on hospital day 5. By this time, prednisolone and minocycline treatment had been terminated because hemophagocytic syndrome was cured and the result of the Rickettsial infection test was negative. Subsequently, the results of a whole blood test were normal, and the patient’s general status was significantly improved.
Following the treatment, the patient was discharged from the hospital, returned to her usual lifestyle, and remains symptom-free in the 2 years post-treatment.
Case 2
An 82-year-old woman visited a primary care clinic owing to diarrhea and general fatigue.
She had hypertension but received no treatment at this time in the clinic. Because she was senseless and listless, she was referred to a community hospital on the following day. The results of a complete blood count were as follows: WBC count, 1060/µL (lymphocyte count, 230/µL); RBC count, 348 × 104/µL; Hb level, 10.3 g/dL; and platelet count, 5.1 × 104/µL. On the same day, she was referred to the Division of General Medicine at the hospital for further evaluation and treatment. When she presented at the hospital, her consciousness level was defined as groggy [GCS, 11 points (eye opening, 4; verbal response, 2; and motor response, 5)]. She had a body temperature of 37.7 °C, a blood pressure of 125/55 mmHg, and a pulse rate of 93 beats/min (regular). There were no remarkable findings on her physical examination. The laboratory findings were as follows: AST level, 274 IU/L; ALT level, 61 IU/L; LDH level, 935 IU/L; CPK level, 1485 IU/L; BUN level, 44.1 mg/dL; Cr level, 1.52 mg/dL; fibrinogen level, 126.2 mg/dL; fasting triglyceride level, 110 mg/dL; sIL-2R level, 3030 U/mL; and ferritin level, 3383 ng/mL. There were no remarkable findings on chest radiography or head computed tomography.
Abdominal computed tomography showed bilateral lymph node swelling in the para-aortic and inguinal regions. However, there was no splenomegaly. On hospital day 3, 4 days after disease onset, the patient had a high fever and severe diarrhea. A bone marrow biopsy and a smear test were performed, revealing that platelet cells were being ingested by macrophages (Fig. 4). The patient met six of the eight HLH2004 diagnostic criteria, and hence, hemophagocytic syndrome was diagnosed. Although a workup was performed to determine the cause of this syndrome, no previously described etiologic agents or diseases were detected. Methylprednisolone at 1000 mg/day was administered for three consecutive days, and cefepime at 2 g was administered intravenously thrice daily. However, the patient’s general condition worsened, and the results of the laboratory tests were exacerbated. On hospital day 6, the laboratory results were as follows: WBC count, 5900/µL; RBC count, 332/µL; platelet count, 1.9 × 104/µL; LDH level, 1583 IU/L; BUN level, 114.8 mg/dL; and Cr level, 4.58 mg/dL. The patient’s condition deteriorated progressively, and she died on hospital day 8. The patient’s family was informed, and an autopsy was performed.
Histological analysis revealed hemophagocytic lesions in multiple organs. There was no evidence of malignancy. As the patient had died, a frozen peripheral blood serum collected on hospital day 2 (3 days after disease onset) was tested for SFTS viral genome amplification via RT-PCR, and amplification was observed (Fig. 5). The patient was retrospectively diagnosed with SFTS. The viral gene copy number was 1 × 107.09. There was no evidence of tick bites in the patient.