Relationships between Causes of Fever of Unknown Origin and Inflammatory Markers: A Multicenter Collaborative Retrospective Study.

OBJECTIVE: Although inflammatory markers, such as the white blood cell (WBC) count, erythrocyte sedimentation rate (ESR) and levels of C-reactive protein (CRP) and procalcitonin, are widely used to differentiate causes of fever of unknown origin (FUO), little is known about the usefulness of this approach. We evaluated relationships between the causes of classical FUO and the levels of inflammatory markers. METHODS: A nationwide retrospective study including 17 hospitals affiliated with the Japanese Society of Hospital General Medicine was conducted. PATIENTS: This study included 121 patients ≥18 years old diagnosed with "classical FUO" (axillary temperature ≥38.0°C at least twice over a ≥3-week period without elucidation of the cause on three outpatient visits or during three days of hospitalization) between January and December 2011. RESULTS: The causative disease was infectious diseases in 28 patients (23.1%), non-infectious inflammatory disease (NIID) in 37 patients (30.6%), malignancy in 13 patients (10.7%), other in 15 patients (12.4%) and unknown in 28 patients (23.1%). The rate of malignancy was significantly higher for a WBC count of <4,000/µL than for a WBC count of 4,000-8,000/µL (p=0.015). Among the patients with a higher WBC count, the rate of FUO due to NIID tended to be higher and the number of unknown cases tended to be lower. All FUO patients with malignancy showed an ESR of >40 mm/h. A normal ESR appeared to constitute powerful evidence for excluding a diagnosis of malignancy. In contrast, the concentrations of both serum CRP and procalcitonin appeared to be unrelated to the causative disease. CONCLUSION: The present study identified inflammatory markers that should be considered in the differential diagnosis of classical FUO, providing useful information for future diagnosis.

Glycated albumin as a diagnostic tool for diabetes in a general Japanese population.

OBJECTIVE: Diabetes mellitus is a major cause of cardiovascular, kidney, neurologic, and eye diseases, and may be preventable in some cases by lifestyle modification. Screening tests for diabetes mellitus include fasting plasma glucose (FPG) and glycated hemoglobin (HbA1c). Our objective was to evaluate the utility of plasma glycated albumin (GA) in the diagnosis of diabetes mellitus. DESIGN AND METHODS: A cross-sectional, community-based population study of 908 non-diabetic Japanese residents was conducted. Of these subjects, 176 with FPG value between 5.5 and 6.9mmol/l, and an HbA1c level of <6.5% received an oral glucose tolerance test (OGTT). RESULTS: The OGTT results were used for the diagnosis of diabetes mellitus using World Health Organization criteria. Receiver operating characteristic (ROC) analyses demonstrated that optimal threshold values for the diagnosis of diabetes in this population were 15.2% for GA and 5.9% for HbA1c, respectively. Using these cutoff levels, the sensitivity of GA at 62.1% for detecting diabetes was the same as that of HbA1c. However the specificity for GA for detecting diabetes was 61.9%, while for HbA1c it was higher at 66.7%. CONCLUSIONS: Our results indicate that the measurement of glycated albumin may serve as a useful screening test for diabetes in a general Japanese population.

The kinetics of the hepatitis B surface antigen level after the initiation of antiretroviral therapy for hepatitis B virus and human immunodeficiency virus coinfected patients.

BACKGROUND: Hepatic flares (HF), which reflect hepatitis B virus (HBV)-related immune reconstitution inflammatory syndrome (IRIS), frequently occur in patients with HBV and human immunodeficiency virus (HIV) coinfection after the start of antiretoroviral therapy (ART). The rate of hepatitis B envelope antigen (HBeAg) and hepatitis B surface antigen (HBsAg) loss is higher for patients with HF after the initiation of ART. METHODS: We retrospectively examined the kinetics of the HBsAg and HBeAg levels of six HBV/HIV coinfected patients after the commencement of ART that included tenofovir. All were male and HBeAg positive. RESULTS: Three patients developed HF after the initiation of ART. All subsequently lost HBeAg and one of them lost HBsAg after HF. None who did not experience HF lost HBeAg. The HBsAg and HBeAg levels remarkably decreased when HF occurred, but the decline of HBsAg was very slow in the periods before and after HF. The median decline of the HBsAg level at 48 weeks was 2.20 Log IU/mL for patients with HF, but only 1.00 Log IU/ml for patients without HF. Little decline was seen for either group in the median decline of the HBsAg level from 48 weeks to 96 weeks, 0.28 Log IU/mL in the HF group and 0.06 Log IU/mL in the non-HF group. CONCLUSION: The immune reconstitution of a HBV/HIV coinfected patient plays an important role in the clearance of HBV. If HBsAg and HBeAg levels decrease rapidly when HF occurs, the hepatic flare would be due to HBV-related IRIS.

Subclinical carotid atherosclerosis and triglycerides predict the incidence of chronic kidney disease in the Japanese general population: results from the Kyushu and Okinawa Population Study (KOPS).

OBJECTIVE: To examine whether or not subclinical atherosclerosis independently predicts the incidence of chronic kidney disease (CKD) in the Japanese general population. METHODS: This study is part of the Kyushu and Okinawa Population Study (KOPS), a survey of vascular events associated with lifestyle-related diseases. Participants who attended both baseline (2004-2007) and follow-up (2009-2012) examinations were eligible. The common carotid intima-media thickness (IMT) was assessed for each participant at baseline. The end point was the incidence of CKD, defined as an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m(2) during the follow-up of participants without CKD at baseline. RESULTS: During the five-year follow-up, 224 of the 1824 participants (12.3%) who developed CKD had higher carotid IMT (0.74 ± 0.22 vs. 0.65 ± 0.14 mm, P < 0.001), higher triglycerides (1.6 ± 0.8 vs. 1.3 ± 0.7 mmol/L, P < 0.001), and lower high density lipoprotein cholesterol (1.5 ± 0.4 vs. 1.6 ± 0.4 mmol/L, P < 0.001) at baseline than those who did not. In logistic regression analysis adjusted for significant covariates, eGFR (Odds ratio [OR] 0.83, 95% confidence interval (CI) 0.80-0.85, P < 0.001), carotid IMT (0.10 mm increase: OR 1.17, 95% CI 1.04-1.33, P = 0.010), and triglycerides (OR 1.35, 95% CI 1.06-1.73, P = 0.015) at baseline were independent predictors for the development of CKD. CONCLUSIONS: Higher carotid IMT and hypertriglyceridemia were independently associated with the development of CKD in the population studied.

Hepatitis B virus-related immune reconstitution inflammatory syndrome in two patients coinfected with human immunodeficiency virus diagnosed with a liver biopsy.

Hepatic flares occurred in two patients with HBV/HIV coinfection following the commencement of antiretroviral therapy (ART). At that time, the HIV RNA and HBV DNA levels had decreased. The results of liver biopsies showed lymphocytic infiltration that was diffusely positive for CD8(+) T cells in the portal areas and lobules. These findings suggested HBV-related immune reconstitution inflammatory syndrome (IRIS). The alanine aminotransferase levels of both patients gradually decreased with the continuation of ART. Because there are few reports of the liver histology of HBV-related IRIS, these cases provide a better understanding of the pathogenesis of HBV-related IRIS.

A case of successful treatment with telaprevir-based triple therapy for hepatitis C infection after treatment failure with vaniprevir-based triple therapy.

Recently direct-acting antiviral agents, such as hepatitis C virus (HCV) non-structural 3/4A (NS3/4A) protease inhibitors (PI), have been introduced, and triple therapy regimens that include PI with conventional pegylated interferon α and ribavirin have significantly improved the sustained virological response (SVR) rate, up to 80% for both treatment-naïve and treatment-experienced patients with HCV genotype 1. We here report for the first time a case of the successful treatment of HCV genotype 1 infection with a first generation PI drug (telaprevir) based triple therapy after treatment failure with a second generation PI drug (vaniprevir) based triple therapy. A 67-year-old treatment-naïve Japanese man with HCV genotype 1b infection took part in a phase III clinical trial of vaniprevir-based triple therapy. His serum HCV RNA had become undetectable at week 2 and SVR was highly expected, but HCV RNA reappeared at week 4 after vaniprevir treatment. Polymerase chain reaction direct sequence of the HCV NS3/4A gene at week 8 after vaniprevir treatment showed the emergence of a vaniprevir-resistance mutation (D168V), the probable reason for the treatment failure. Six months later, retreatment with telaprevir-based triple therapy was started. Although the dosages of telaprevir and ribavirin had to be reduced due to severe anemia, the patient achieved an SVR. This case shows the value of repeating PI-based triple therapy with a different drug, a process that would reduce the chance of drug resistant mutation.

A case of successful hepatitis C virus eradication by 24 weeks of telaprevir-based triple therapy for a hemophilia patient with hepatitis C virus/human immunodeficiency virus co-infection who previously failed pegylated interferon-α and ribavirin therapy.

In Japan, the human immunodeficiency virus (HIV) and hepatitis C virus (HCV) coinfection of some patients with hemophilia was caused by the transfusion of imported blood products, such as unheated coagulation factor. With the development of antiretroviral therapy (ART) for HIV, chronic HCV infection has become a major cause of liver disease and mortality for hemophiliac patients coinfected with HCV/HIV. Data is limited regarding the efficacy and safety of antiviral therapy with the HCV protease inhibitor telaprevir (TVR) in combination with pegylated interferon-α (PegIFN-α) and ribavirin (RBV) for hemophilia patients coinfected with HCV/HIV. We report a case of a Japanese patient with hemophilia and HCV/HIV coinfection who had partial response to prior to PegIFN-α and RBV therapy. This is the first published report of 24-week TVR-based triple therapy for a hemophilia patient coinfected with HCV/HIV. The patient had HCV genotype 1a infection with a high viral load. His single-nucleotide polymorphism of the interleukin 28B (rs8099917) gene was the TT major allele. He presented with undetectable HIV RNA and a high CD4(+) T cell counts by taking ART including tenofovir, emtricitabine and raltegravir. He was again treated for HCV with TVR plus PegIFN-α2b and RBV for the first 12 weeks, followed by the continuation of PegIFN-α2b and RBV for 12 additional weeks while continuing ART. He had rapid virological response and achieved sustained virological response with the 24-week treatment. No serious adverse events such as skin rash, severe anemia or exacerbated bleeding tendency were observed, only a mild headache. No dose adjustment was necessary when tenofovir and raltegravir were used in combined with TVR, and no HIV breakthrough was observed. TVR-based triple therapy with ART could can an effective treatment for hemophilia patients coinfected with HCV (genotype 1)/HIV regardless of prior response. TVR can be used in combination with tenofovir, emtricitabine and raltegravir for patients with hemophilia. Furthermore, patients with undetectable HCV RNA at week 4 could be successfully treated with a 24-week regimen.

Therapeutic drug monitoring of telaprevir in chronic hepatitis C patients receiving telaprevir-based triple therapy is useful for predicting virological response.

OBJECTIVES: This prospective, pharmacokinetic study was done to investigate the impact of telaprevir plasma trough concentration (Ctrough) in the early stage of treatment on the response to telaprevir-based triple therapy for chronic hepatitis C patients. METHODS: Participants were 70 chronic hepatitis C patients infected with genotype 1. All patients received 12 week triple therapy that included telaprevir (2250 mg/day), pegylated interferon-α2b (pegylated-IFNα2b) (60-150 µg/week) and ribavirin (600-1000 mg/day) followed by a 12 week dual therapy that included pegylated-IFNα2b and ribavirin. Plasma telaprevir Ctrough was determined by a validated assay using HPLC at days 3, 7 and 14. The study was registered as a clinical trial on the University Hospital Medical Information Network (ID 000009656). RESULTS: The rates of undetectable hepatitis C virus RNA at week 4 [rapid virological response (RVR)] and at 24 weeks after therapy [sustained virological response (SVR)] were 71.4% and 82.9%, respectively. Of the patients with RVR, 90% achieved SVR. The mean telaprevir Ctrough levels at days 3, 7 and 14 of SVR patients (2.748, 2.733 and 2.999 µg/mL, respectively) were significantly higher than those of non-SVR patients (1.616, 1.788 and 2.314 µg/mL, respectively) (all P < 0.05). Multiple logistic regression analysis of possible predictors of SVR extracted higher telaprevir Ctrough at day 3 (OR 1.012 by 0.001 µg/mL, P < 0.0001) and interleukin 28B (rs8099917) TT allele (OR 6.16 versus non-TT alleles, P < 0.0001). CONCLUSIONS: Therapeutic drug monitoring of telaprevir in the early stage of treatment is useful in clinical practice for predicting the virological response of patients receiving telaprevir-based triple therapy.

Diagnostic workup for fever of unknown origin: a multicenter collaborative retrospective study.

OBJECTIVE: Fever of unknown origin (FUO) can be caused by many diseases, and varies depending on region and time period. Research on FUO in Japan has been limited to single medical institution or region, and no nationwide study has been conducted. We identified diseases that should be considered and useful diagnostic testing in patients with FUO. DESIGN: A nationwide retrospective study. SETTING: 17 hospitals affiliated with the Japanese Society of Hospital General Medicine. PARTICIPANTS: This study included patients ≥18 years diagnosed with 'classical fever of unknown origin' (axillary temperature ≥38°C at least twice over a ≥3-week period without elucidation of a cause at three outpatient visits or during 3 days of hospitalisation) between January and December 2011. RESULTS: A total of 121 patients with FUO were enrolled. The median age was 59 years (range 19-94 years). Causative diseases were infectious disease in 28 patients (23.1%), non-infectious inflammatory disease in 37 (30.6%), malignancy in 13 (10.7%), other in 15 (12.4%) and unknown in 28 (23.1%). The median interval from fever onset to evaluation at each hospital was 28 days. The longest time required for diagnosis involved a case of familial Mediterranean fever. Tests performed included blood cultures in 86.8%, serum procalcitonin in 43.8% and positron emission tomography in 29.8% of patients. CONCLUSIONS: With the widespread use of CT, FUO due to deep-seated abscess or solid tumour is decreasing markedly. Owing to the influence of the ageing population, polymyalgia rheumatica was the most frequent cause (9 patients). Four patients had FUO associated with HIV/AIDS, an important cause of FUO in Japan. In a relatively small number of cases, cause remained unclear. This may have been due to bias inherent in a retrospective study. This study identified diseases that should be considered in the differential diagnosis of FUO.

A case report of human immunodeficiency virus-associated anaplastic lymphoma kinase protein-negative anaplastic large cell lymphoma.

Human immunodeficiency virus (HIV)-associated anaplastic large cell lymphoma (ALCL) is not so common, and anaplastic lymphoma kinase protein (ALK)-negative ALCL is rare and has a low survival rate. We report a case of a 31-year-old Japanese man diagnosed with HIV-associated ALK-negative ALCL who presented with long-lasting fever of unknown origin. The diagnosis was based on a full work-up that included inguinal lymph-node biopsy. Eight-cycle chemotherapy that included cyclophosphamide, doxorubicin, vincristine, and prednisone in addition to antiretroviral therapy for HIV infection provided a complete remission of his ALCL and over 5-year survival for him.

Early phase viral kinetics of chronic hepatitis C patients receiving telaprevir-based triple therapy: a comparison of two real-time PCR assays.

Monitoring hepatitis C virus (HCV) kinetics during antiviral treatment is recommended for determining the best form of treatment management. We compared the measurement of HCV RNA by two Real-time PCR assays during the first 12weeks phase of telaprevir in combination with pegylated interferon α2b and ribavirin treatment for chronic hepatitis C patients. The viral kinetics of 65 patients with HCV genotype 1b was assessed. HCV RNA was tested at baseline, on day 3, and every week from 1 to 12 by both the first-generation Roche COBAS® AmpliPrep/COBAS® TaqMan® HCV (CAP/CTM) assay and the Abbott RealTime HCV (ART) assay. A total of 910 serum samples were obtained from the 65 patients. Of these, 168 (28.5%) of the 590 samples HCV RNA negative by CAP/CTM were positive by ART. In contrast, 17 (3.9%) of the 439 samples HCV RNA negative by ART were positive by CAP/CTM. The rates of HCV RNA negativity by ART at weeks 3, 4, and 5 were significantly lower than those by CAP/CTM (21.5% vs. 50.8%, 36.9% vs. 70.8% and 44.6% vs. 81.5%; P<0.001, P<0.0001 and P<0.05, respectively). Although the ART is superior for the determination of HCV RNA negativity, the predictive value of detectable HCV RNA for non-sustained virological response (non-SVR) by CAP/CTM is higher than by ART at weeks 4, 6, and 8. We also found that 16 (24.6%) by CAP/CTM and 28 (43.1%) by ART had a reappearance of residual HCV RNA during the telaprevir treatment period. However, the reappearance of residual HCV RNA was not associated with non-SVR. In conclusion, a significant difference was found between the two real-time PCR assays for the assessment of virological response based on undetectable HCV RNA.

[A case of hepatitis B virus/human immunodeficiency virus coinfection in a patient who achived hepatitis B surface antigen seroclearance after interferon therapy followed by antiretroviral therapy without developing immune reconstitution inflammatory syndrome].

Coinfection with human immunodeficiency virus (HIV) and hepatitis B virus (HBV) is common worldwide. The current guidelines for the treatment of HIV infection recommend that HIV patients coinfected with HBV receive antiretoroviral therapy (ART) with two nucleoside analogs against HBV. However, an increase in liver enzymes that is usually attributed to HBV immune reconstitution inflammatory syndrome (IRIS) sometimes occurs in HBV/HIV-coinfected patients after the commencement of ART. We report a case of HBV/HIV-coinfection in which the chronic hepatitis B was successfully treated using interferon (IFN) therapy followed by ART without the development of IRIS. A Japanese man in thirties was referred to our hospital because of an acute HIV infection two months after the diagnosis of an acute HBV infection, which had progressed to a chronic HBV infection. The laboratory test results were as follows:hepatitis B surface antigen (HBsAg) positive, hepatitis B e antigen (HBeAg) positive, HBV DNA level of 8.8 Log copies/mL, HBV genotype A, alanine aminotransferase of 834 IU/L, HIV RNA level of 5 Log copies/mL, and a CD4+ T cell count of 437/microL. The initial treatment was natural IFNalpha therapy for chronic hepatitis B, and HBeAg seroclearance was achieved 20 weeks after the start of therapy. Four months after the end of IFN therapy for 24 weeks, ART including tenofovir and emtricitabine against HBV was commenced. Six months after starting ART, the patient's serum HBV DNA level had decreased and become undetectable and HBsAg seroclearance was achieved without an elevation in liver enzymes. The present case suggests that IFN therapy prior to ART contributes to a successful outcome for chronic hepatitis B patients coinfected with HIV, if the HIV status does not require the immediate start of ART.