Response to imatinib mesylate in a patient with idiopathic hypereosinophilic syndrome associated with cyclic eosinophil oscillations.

A 26-year-old man with idiopathic hypereosinophilic syndrome (HES) was treated with imatinib mesylate following a 5-year history of prednisolone therapy. The patient had hypereosinophilia (absolute eosinophil counts >1500/microL) occurring in cyclic oscillations as well as histologically diagnosed eosinophilic vasculitis, bursitis, and periodic soft-tissue swellings. Laboratory data revealed high levels of serum tryptase and increased numbers of mast cells in the bone marrow, but serum interleukin 5 levels were within the normal range. The disease initially responded well to 100 mg/day of imatinib mesylate but recurred 8 weeks later. Thereafter, a daily 200-mg dose was temporarily effective. Despite the response to imatinib, the FIP1L1-PDGFRA fusion gene was not detected by fluorescence in situ hybridization analysis. Additional molecular and cytogenetic studies showed neither translocations of platelet-derived growth factor receptor (PDGFR) genes nor mutations in the c-KIT or the PDGFR genes. Although imatinib mesylate is a choice of treatment for patients with HES, its precise molecular mechanism in individual cases remains to be clarified.

Longitudinal follow-up of patients with Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis.

BACKGROUND AND OBJECTIVES: Although immunochemotherapy has been reported to be an effective initial treatment for patients with Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH), the long-term outcome of these patients remains unknown. The main purpose of this study was to determine the outcome of the EBV-HLH patients treated between 1992 and 2001. DESIGN AND METHODS: During this period, a total of 78 EBV-HLH patients were consecutively registered in 3 separate studies. The rates of initial response, reactivation, and survival as well as causes of death were analyzed. The outcome of the patients who received hematopoietic stem cell transplantation was also studied. RESULTS: With a median follow-up of 43 months, clinical reactivation was noted in 13 patients (19.4%) and a total of 12 patients needed hematopoietic stem cell transplantation, of whom 9 are alive and well. There had been 19 deaths: early deaths were due to hemorrhages and infections (n=11), while late deaths were related to late reactivation (n=4), transplant-associated causes (n=3) and secondary leukemia (n=1). Overall, after a median follow-up of 43 months, 59 (75.6%) of the 78 patients are alive and well. INTERPRETATION AND CONCLUSIONS: The majority of successfully treated EBV-HLH patients have a good outcome and remain disease-free.

Hemophagocytic syndrome associated with severe adenoviral pneumonia: usefulness of real-time polymerase chain reaction for diagnosis.

In infection-associated hemophagocytic syndrome (HPS) the causative pathogen is often undetected, except in cases of herpes virus infections. We describe a 12-year-old girl with life-threatening pneumonia with HPS caused by an adenovirus. She was admitted with complaints of persistent fever and systemic petechiae/purpura. The day after admission the patient developed sudden dyspnea with massive infiltration of the bilateral lower lung field. She exhibited coagulopathy, hepatic dysfunction, and remarkable elevations in serum levels of cytokine, ferritin, and urinary beta2-microglobulin. A diagnosis of HPS was made, and the patient was treated with dexamethasone and cyclosporin A on the second hospital day. Her fever went down quickly, and the abnormal laboratory and chest radiographic findings returned to normal over a period of 2 weeks. Antibody analysis was not successful in identifying the pathogen responsible. However, a polymerase chain reaction (PCR) assay of lung tissue biopsied on the fifth hospital day was positive for an adenovirus (subgroup B), and quantitative adenoviral DNA analysis by real-time PCR using primers covering serotypes 3, 7,11, and 35 (all subgroup B) confirmed this initial finding (93 copies/microg DNA in the biopsied lung and no detectable adenovirus DNA in the lung tissues of control subjects). This approach may provide important clues for improving outcomes and clarifying the exact etiology in cases of often fatal, infection-associated HPS.

Risk of etoposide-related acute myeloid leukemia in the treatment of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis.

We studied the impact of etoposide on the prognosis of 81 patients (77 of whom were children <15 years old) with Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH). The study group received a median cumulative dose of 1,500 mg/m2 etoposide (range, 0-14,550 mg/m2), with a median follow-up period of 44 months (range, 20-88 months) from the diagnosis. Only 1 patient, who received 3150 mg/m2 etoposide, developed therapy-related acute myeloid leukemia (t-AML), at 31 months after diagnosis. Excluding 9 patients who underwent hemopoietic stem cell transplantation during the course of treatment, the prognosis was poorer for those patients who received less than a 1,000 mg/m2 cumulative dose of etoposide. Our results indicate that the risk of etoposide-related t-AML is low. An appropriate dosage of etoposide for the treatment of EBV-HLH would be in the range of 1,000 to 3,000 mg/m2. However, even at these doses, care must be taken to prevent the rare risk of t-AML.

Quantitative analysis of cell-free Epstein-Barr virus genome copy number in patients with EBV-associated hemophagocytic lymphohistiocytosis.

To determine whether the EBV genome content in serum or plasma reflects clinical features and outcome in EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH), we quantified the cell-free EBV genome copy number by real-time PCR in 38 patients with EBV-HLH, and compared this to the values from 15 patients with infectious mononucleosis (IM). The median (range) cell-free EBV genome copy number at diagnosis was 3.0 x 10(3) (undetectable -5.5 x 10(7)) copies/ml in EBV-HLH, which was significantly higher than the 6.6 x 10(1) (undetectable -1.0 x 10(3)) copies/ml in IM (P = 0.0008). We serially analyzed cell-free EBV genome copy number in 10 cases of EBV-HLH up to 4 months from diagnosis. In four patients who achieved remission, the EBV genome became undetectable soon after starting therapy. In the remaining six patients who responded poorly to therapy, the EBV genome copy number in the serum or plasma remained at high levels except for one case. In addition, we confirmed that the EBV genome became undetectable after hematopoietic stem cell transplantation in 4 EBV-HLH cases. These results suggest that the quantitative analysis of cell-free EBV genome copy number is useful for evaluating disease activity and for predicting the response to therapy in EBV-HLH.

Sensorineural hearing loss in a case of familial hemophagocytic lymphohistiocytosis.

Severe sensorineural hearing loss (bilateral >80 dB) was diagnosed in a case of familial hemophagocytic lymphohistiocytosis (FHL). The female patient developed HLH at 3 months of age and underwent allogeneic cord blood transplantation at 11 months of age following 7 months of immuno-chemotherapy. The type 2 FHL patient had a homozygous perforin gene mutation of 1090-1091delCT, and was noted to have hearing loss at 3.5 years of age. Retrospective evaluation did not clarify the exact causes of hearing loss. Reports on Kawasaki disease, suggesting a correlation between severe inflammatory status in infancy and the development of sensorineural hearing loss, may shed some light on this rare complication in this case of FHL. Considering the markedly improved prognosis of FHL due to recent advances made in the molecular diagnosis and in the management including allogeneic hematopoietic stem cell transplantation, auditor by screening might be warranted for surviving FHL patients.

Occurrence of haemophagocytic lymphohistiocytosis at less than 1 year of age: analysis of 96 patients.

UNLABELLED: We analysed data of 96 infants (under 1 year of age) with haemophagocytic lymphohistiocytosis (HLH) from the registry of an HLH study conducted during 1986-2002 in Japan. The cases were classified into five groups. The diagnosis of familial HLH (FHL) as group 1 (n = 27) was made with positive family history and/or recent molecular test for perforin and Munc13-4 mutations. Neonatal enterovirus- or herpes simplex virus-associated HLH as group 2a (n = 7), Epstein-Barr virus-associated HLH (n = 12) as group 2b, adenovirus- or cytomegalovirus-associated HLH as group 3 (n = 9) were mostly diagnosed by viral isolation or by the detection of viral genome. Juvenile rheumatoid arthritis-associated macrophage activation syndrome was classified as group 4 (n = 4) and the remaining without known triggers as group 5 (n = 37). The peak onset age was 1-2 months for group 1, 1-2 weeks for group 2a, 12 months for group 2b, none for group 3, 9 months for group 4 and 2 months for group 5. Future novel diagnostic measures are required to define the precise nature of HLH in group 5. CONCLUSION: These data may provide useful information for neonatologists/ paediatricians in the differential diagnosis of haemophagocytic lymphohistiocytosis in early infancy.

A novel type of encephalopathy associated with mushroom Sugihiratake ingestion in patients with chronic kidney diseases.

BACKGROUND: The etiology of encephalopathy in uremic patients is multiple. We recently encountered a novel type of encephalopathy which occurred exclusively in patients with chronic kidney diseases after ingestion of a mushroom called Sugihiratake. While the exact etiology of this encephalopathy remained mysterious, we aimed to describe its clinical features. METHODS: A total of 32 patients with chronic kidney diseases who had presented with encephalopathy following ingestion of Sugihiratake were enrolled from seven prefectures in Japan., with 24 of the 32 patients undergoing regular hemodialysis. The patient's clinical data were from surveillance by The Japanese Society of Nephrology. RESULTS: There was a significant association between Sugihiratake ingestion and the occurrence of encephalopathy in 524 hemodialysis patients questioned for a recent ingestion of this mushroom (P= 0.0006). The latent asymptomatic period before the onset of symptoms varied from 1 to 31 days (mean 9.1 +/- 7.3) days. The patient's symptoms consisted of disturbed consciousness in 30 patients (93.8%), convulsions in 25 (78.1%), myoclonus in 15 (46.9%), dysarthria in ten (31.3%), ataxia in eight (25.0%), paresis or paralysis in seven (21.9%), and skin parasthesia in two patients (6.3%). Nine (27.2%) patients died, mostly due to respiratory failure. The other patients were either discharged or still in hospitals with various degrees of clinical improvement. CONCLUSION: Patients with chronic kidney diseases are at risk of having serious encephalopathy following Sugihiratake ingestion and must refrain from eating it. Physicians, in those parts of the world, where this mushroom harvesting is common, should be aware of this complication.

Invasive adenoviral infection in a recipient of unrelated bone marrow transplantation: Problems with diagnostic PCR.

A hematopoietic stem cell transplantation (SCT) recipient developed severe diarrhea and fever. A rapid test for the presence of adenovirus (AdV)-specific antigen in the patient's stools was positive; however, AdV genome was not detected by conventional or real-time polymerase chain reaction (PCR). AdV was confirmed by specific PCR for AdV serotype 7 and by an AdV hexon/fiber gene DNA sequence homology search of the PCR product. We suspect that conventional/real-time PCR failed to detect AdV due to nine silent single base substitutions in the extracted AdV genome. Treatment with 1 mg/kg cidofovir (CDV) intravenously three times a week was effective.

Treatment of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) in young adults: a report from the HLH study center.

BACKGROUND: Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH), also known as EBV-associated hemophagocytic syndrome, develops mostly in children and young adults and may be fatal. Early etoposide treatment has been confirmed to be effective in children. However, it is unclear whether the same treatment is useful in adults. PROCEDURE: To assess whether etoposide is effective in treating young adult cases, we retrospectively studied the therapeutic measures taken and outcomes in 20 young adult cases of EBV-HLH. Eleven cases were registered in our HLH study center in Kyoto and nine derived from the literature. The patients were between 17 and 33 years old and eight were males. The influence of gender, cell lineage (T- or natural killer-), EBV serology pattern, jaundice and treatment on the outcome was assessed. RESULTS AND CONCLUSIONS: Patients receiving etoposide within four weeks after diagnosis had a good prognosis as five of the seven patients survived compared to one of 13 not treated with etoposide or treated late (chi-square test for survival, P = 0.0095). The Kaplan-Meier analysis showed the 2.5-year survival of 85.7 +/- 13.2% in the early etoposide-treated patients, compared to 10.3 +/- 9.4% in the remaining patients (log-rank test, P = 0.0141). Thus, early etoposide treatment is effective in treating EBV-HLH in young adults as well as in children.