Acute Kidney Injury with Epstein Barr Virus-Associated Hemophagocytic Syndrome

A 59-year-old man, who was treated for schizophrenia and psoriasis vulgaris with risperidone and cyclosporine, presented with high fever and myalgia. Those did not respond to treatment for neuroleptic malignant syndrome for two weeks, and multiple organ dysfunction developed, so he was admitted to our hospital, but died two days later. Autopsy detected the hemophagocytosis, Epstein Barr Virus (EBV)-reactivated cells, and the absence of glomerulonephritis and interstitial tubulitis. We considered that hemophagocytic syndrome (HPS) and myalgia were caused by reactivated EBV and the viremia under immunosuppression, and renal failure was caused by sepsis-like state by cytokine storm of HPS.


Introduction
Hemophagocytic syndrome (HPS) is a rare disorder of the immune system that is synonymous with macrophage activation syndrome [1].Natural killer (NK)/T cells that, for hereditary or acquired reasons, are unable to lyse target cells, such as infected or malignant cells, proliferate and release a large amount of interferon-γ.This induces the proliferation of macrophages, invasion into the liver, spleen, and lymph nodes, and the release of further inflammatory cytokines including TNF-α [2].HPS causes a cytokine storm.
We herein report a case of EBV-associated HPS receiving immunosuppressive therapy.We also discuss the pathophysiology of acute kidney injury (AKI) and the clinical symptoms preceding HPS.

Case Report
A 59-year-old man, who had been treated for schizophrenia and psoriasis vulgaris with the oral administration of 1 mg risperidone and 300 mg cyclosporine, presented to another hospital with high fever and myalgia.He was diagnosed with neuroleptic malignant syndrome, and was admitted to the hospital for treatment; however, these symptoms persisted for more than two weeks.Moreover, renal and liver dysfunction developed; therefore, he was admitted to our hospital.A physical examination revealed a body temperature of 38.8˚C, pulse rate of 110 beats per minute, respiratory rate of 30 breaths per minute, and blood pressure of 80/55 mmHg.He was drowsy and had leg edema.Laboratory data showed pancytopenia, metabolic acidosis, and liver and kidney dysfunction (Table 1).Urinary findings were mild hematuria and proteinuria (Table 1).Chest and abdominal computed tomography (CT) showed that there were no obvious inflammatory findings, except for mild swelling of the superficial lymph nodes (Figure 1).In order to treat circulatory failure and multiple organ dysfunction, he underwent continuous hemodiafiltration and endotoxin adsorption using catecholamine and antibiotics under artificial ventilation.In spite of intensive care, he died after two days.Autopsy showed that hemophagocytosis was present in bone marrow (Figure 2(a)).Macrophages had infiltrated the lymph nodes and liver (Figures 2(b)-(e)), and EBV-reactivated cells were detected in bone marrow, the lymph nodes, and spleen by staining for the    EBV-ZEBRA protein, which is an EBV immediate-early transcription factor that triggers the switch from latent to lytic infection (Figures 2(f)-(h)).Despite serological renal dysfunction, glomerulonephritis, interstitial tubulitis, and fibrosis were not present in renal histology (Figures 3(a)-(d)).

Discussion
HPS often has a very poor prognosis with acute progression and a mortality rate of 41% [4]; therefore, it is important to consider the preceding symptoms for an earlier diagnosis and treatment.In our case, HPS developed due to the reactivation of EBV preceded by myalgia under immunosuppressive therapy.In addition, despite clinical renal dysfunction, autopsy showed that there was no obvious renal injury.We herein discuss myalgia preceding HPS and AKI without obvious histological injury.Common symptoms in HPS include high fever that does not respond to antibiotics, liver dysfunction, hepatosplenomegaly, and coagulopathy, which occur with HPS, but do not precede it [1].Myalgia was detected in the present case, and had not previously been identified as a symptom of HPS.On the other hand, myalgia is a common symptom of EBV infection, and rhabdomyolysis associated with EBV infection has been reported [10] [11].In the development of EBV-associated HPS, latent EBV in B cells is reactivated under immunosuppression, proliferates, and infects NK/T cells through the viremia of EBV.Therefore, myalgia may be a symptom of the viremia of reactivated EBV preceding HPS; however, it was initially considered to be induced by neuroleptic malignant syndrome because of psychometric medical treatment.
AKI is the most frequent renal manifestation, accounting for 62% of renal involvement cases in HPS [12].HPS-induced AKI has been attributed to various pathophysiologies including acute tubular necrosis and glomerulopathy such as minimal change disease, focal segmental glomerulosclerosis, and thrombotic microangiopathy [4]; however, renal histology revealed that there was no obvious damage to the glomerulus, interstitium, or tubules in our case.Concerning the cytokine storm including TNF-α in HPS, AKI in our case may resemble sepsis-induced AKI.
Sepsis is characterized by an excessive inflammatory response to infection through the interaction of biochemical mediators and amplification cascades, and induces the release of inflammatory cytokines such as TNF-α [13] [14].Sepsis-induced AKI is known as septic AKI, in which efferent arteriolar vasodilatation de-creases glomerular filtration pressure and urine production by several cytokines without obvious damage in the histology [15] [16].Therefore, the pathophysiology of no obvious histological damage and the cytokine storm in HPS appear to support the hypothesis of a similarity with septic AKI and HPS-induced AKI in our case.

Conclusion
In conclusion, HPS-induced AKI in our case may have resembled septic AKI due to the cytokine storm.In addition, myalgia under immunosuppressive therapy and psychometric medical treatment may be due to the viremia of reactivated EBV as well as neuroleptic malignant syndrome.Since HPS has a severely poor prognosis with acute progression, it is important to consider the preceding symptoms for an earlier diagnosis and treatment.

Table 1 .
Laboratory data on admission.