A 60-year-old woman was admitted because of persistent fever of unknown origin lasting for several days. She had been in a good state of health prior to admission and had no specific underlying disease. She had no related family history and medication history. Upon physical examination, the vital signs were as follows: blood pressure, 120/80 mmHg; pulse rate, 87 beats per minute; and body temperature, 37.8  C. There were no palpable lymph nodes in the neck, armpit and groin areas. Both legs had pitting edema and petechial rashes. She also complained of diffuse abdominal pain and oliguria that had been present for several days.
Laboratory findings are summarized in Fig. 1. Pancytopenia (white blood cell count, 2750/muL; hemoglobin, 8 g/dL; platelet count, 63,000 /muL) was detected and serum creatinine level was significantly elevated (4.59 mg/dL). Serum ferritin, C-reactive protein and lactate dehydrogenase were increased as well. Prothrombin times (PT), activated partial thromboplastin times (aPTT) and fibrinogen were within normal limits. There was no dyslipidemia, including hypertriglyceridemia. The patient's soluble interleukin-2 receptor level in serum was 5.2 % (normal range 5-30 %) and natural killer (NK) cells activity was decreased (NK cells activity, 3.7 %; normal range 6-29 %). Urinary protein/creatinine ratio was 906.4 mg/g. Peripheral blood smear showed normocytic normochromic anemia and thrombocytopenia. The examination revealed no schistocytes and anisocytosis, which suggested absence of microangiopathic hemolytic anemia (MAHA). Abdominal computerized tomography (CT) scan for the evaluation of abdominal pain showed no abnormal findings for the bowel, pancreas or the biliary tract. Both kidney sizes were normal without chronic change, but there was significant splenomegaly, multifocal ascites and pleural effusion were detected.
At first, we used broad-spectrum antibiotics for neutropenic fever and initiated hemodialysis for acute renal failure. However, we did not find any etiology for neutropenic fever from urine or blood culture studies. In addition, virus studies, including epstein-barr virus, parvovirus B19, adenovirus, human immunodeficiency virus, hepatitis B and influenza virus were negative on serologic tests. Anti-hepatitis C virus antibody was positive but alanine transaminase and aspartate transaminase levels were normal, which suggested that hepatitis C virus was in an inactive state. The patient showed no evidence of tuberculosis in chest X-ray, sputum acid-fast bacillus (AFB) stain and AFB culture, sputum and urine tuberculosis polymerase chain reaction. Autoimmune disorders such as systemic lupus erythematosus or rheumatoid arthritis were carefully ruled out by clinical symptoms and signs and by autoantibody tests.
Consequently, we decided to perform a bone marrow (BM) biopsy to determine the reason for fever and pancytopenia. BM biopsy revealed about 10 % cellularity and numerous histiocytes with engulfed lymphocytes, polymorphonuclear and red blood cells, which were suggestive of hemophagocytosis (Fig. 2). Finally, the patient was diagnosed with HLH based on fever, progressive pancytopenia, hyperferritinemia, splenomegaly, decreased NK cell activity and hemophagocytosis in BM and negative results on viral and autoimmune marker studies.
Meanwhile, a kidney biopsy was performed to investigate the cause of acute kidney injury because renal function did not improve. PT times (PT INR, 1.13) and aPTT times (aPTT, 23.3 seconds) were within normal limits. But complete blood count showed thrombocytopenia. We used prophylactic transfusion of platelets in preparation for a kidney biopsy that could cause bleeding. Under light microscopic examination, glomeruli were slightly enlarged with hypercellularity involving mesangial and endothelial cells. Capillary lumens were frequently filled with fragmented red blood cells and platelet aggregates (Fig. 3a). Tubules revealed focal moderate atrophy and loss with interstitial fibrosis (Fig. 3b). In an immunofluorescence study, staining for immunoglobulin G, immunoglobulin M, immunoglobulin A, C4, fibrinogen, kappa and lambda were negative. In electron microscopy, no electron-dense deposits were found and epithelial foot process showed focal marked effacement (Fig. 3c). The above histologic findings were compatible with renal TMA.
At this time, we planned 6 cycles of cytotoxic therapy comprised of dexamethasone, etoposide at 100 mg/m2 and cyclosporine at 200 mg/day for the treatment of HLH based on the HLH-2004 protocol. Dexamethasone started at 10 mg/ m2 for 2 weeks, and then reduced to 50 % of initial dose every 2 weeks. As etoposide is cleared by both renal and hepatic routes, dose adjustment of etoposide based on renal function is recommended for the HLH-2004 protocol. We started at etoposide 100 mg/m2 with dose reductions of 25 % based on the patient's renal function. The general condition of the patient gradually improved and the fever subsided 7 days after the initiation of cytotoxic therapy. Concomitantly, urine output also increased and we ceased hemodialysis at 28 days from the first initiation of hemodialysis. After the 4th cycle of etoposide treatment, she suffered neutropenic fever due to vancomycin-resistant enterococci infection, which was successfully treated with linezolid and recombinant human granulocyte colony stimulating factor. After 7 cycles of etoposide treatment, she was discharged with normal kidney function and no signs of fever or neutropenia. At 6 months after the initial presentation, she showed no signs of HLH recurrence. A bone marrow aspiration and biopsy was done and the bone marrow biopsy looked normal cellular with normal hematopoiesis. Her serum creatinine level were in the normal range (0.99 mg/dL).