Hirohisa Yazaki

Outbreak of Pneumocystis jiroveci pneumonia in renal transplant recipients: P. jiroveci is contagious to the susceptible host.

Background. Prophylaxis against Pneumocystis jiroveci pneumonia (PCP) is only recommended during some periods after renal transplantation. Recent advances in immunosuppressive therapy have considerably reduced acute rejection. However, the reported PCP outbreaks are increasing in renal transplant recipients. Methods. Only three sporadic PCP cases had occurred since 1976 in our Renal Transplant Unit until the index case in July 2004. A PCP outbreak of 27 cases occurred mainly in the outpatient clinic within 1 year, followed by six additional cases during the next 3 years. Molecular analysis of P. jiroveci and surveys of reservoir were performed. Results. Molecular analysis documented that all cases were caused by the same strain. Among 27 cases of the outbreak, human-to-human transmissions were traceable in 22 cases based on dates of outpatient clinic visits and in four cases during hospitalization. Based on the confirmed cases, airborne transmission was suspected with an estimated median PCP incubation period of 53 days (range 7–188 days). Surveys for reservoir of P. jiroveci identified asymptomatic carriers and environmental contamination. Some sporadic cases might be caused by reservoirs. Among the 33 cases, none had received PCP prophylaxis, 22 cases had PCP over 12 months, and six cases over 10 years after renal transplantation. Conclusion. On documentation of a PCP case, we recommend PCP prophylaxis for a maximum period of 6 months (upper limit of incubation period) in all renal transplant recipients including those on regular maintenance immunosuppressive therapy.

Serum (1→3) β-d-Glucan as a Noninvasive Adjunct Marker for the Diagnosis of Pneumocystis Pneumonia in Patients with AIDS

High serum (1-->3) beta-D-glucan levels are described in patients with Pneumocystis pneumonia (PCP). We evaluated the diagnostic value of beta-D-glucan in 111 patients with AIDS who had PCP and confirmed its usefulness. However, it does not correlate with disease severity and is not suitable for monitoring response to treatment.

Impact of small body weight on tenofovir-associated renal dysfunction in HIV-infected patients: a retrospective cohort study of Japanese patients.

Background Treatment with tenofovir is sometimes associated with renal dysfunction. Limited information is available on this side effect in patients with small body weight, although the use of tenofovir will spread rapidly in Asia and Africa, where patients are likely to be of smaller body weight. Methods In a single-center cohort, Japanese patients with HIV infection who started tenofovir-containing antiretroviral therapy were retrospectively analyzed. The incidence of tenofovir-associated renal dysfunction, defined as more than 25% decrement of estimated glomerular filtration rate (eGFR) from the baseline, was determined. The effects of small body weight and body mass index (BMI) on tenofovir-associated renal dysfunction, respectively, were estimated in univariate and multivariate Cox hazards models as the primary exposure. Other possible risk factors were evaluated by univariate analysis and those found significant were entered into the multivariate analysis. Results The median weight of 495 patients was 63 kg. Tenofovir-related renal dysfunction occurred in 97 (19.6%) patients (incidence: 10.5 per 100 person-years). Univariate analysis showed that the incidence of tenofovir-related renal dysfunction was significantly associated with smaller body weight and BMI, respectively (per 5 kg decrement, HR = 1.23; 95% CI, 1.10–1.37; p<0.001)(per 1 kg/m2 decrement, HR = 1.14; 95% CI, 1.05–1.23; p = 0.001). Old age, high baseline eGFR, low serum creatinine, low CD4 count, high HIV viral load, concurrent nephrotoxic drugs, hepatitis C infection, and current smoking were also associated with tenofovir-related renal dysfunction. Multivariate analysis identified small body weight as a significant risk (adjusted HR = 1.13; 95% CI, 1.01–1.27; p = 0.039), while small BMI had marginal significance (adjusted HR = 1.07; 95% CI 1.00–1.16; p = 0.058). Conclusion The incidence of tenofovir-associated renal dysfunction in Japanese patients was high. Small body weight was identified as an independent risk factor for tenofovir-associated renal dysfunction. Close monitoring of renal function is advocated for patients with small body weight treated with tenofovir.

Outbreaks of Pneumocystis Pneumonia in 2 Renal Transplant Centers Linked to a Single Strain of Pneumocystis: Implications for Transmission and Virulence

BACKGROUND There have been numerous reports of clustered outbreaks of Pneumocystis pneumonia (PCP) at renal transplant centers over the past 2 decades. It has been unclear whether these outbreaks were linked epidemiologically to 1 or several unique strains, which could have implications for transmission patterns or strain virulence. METHODS Restriction fragment length polymorphism (RFLP) analysis was used to compare Pneumocystis isolates from 3 outbreaks of PCP in renal transplant patients in Germany, Switzerland, and Japan, as well as nontransplant isolates from both human immunodeficiency virus (HIV)-infected and uninfected patients. RESULTS Based on RFLP analysis, a single Pneumocystis strain caused pneumonia in transplant patients in Switzerland (7 patients) and Germany (14 patients). This strain was different from the strain that caused an outbreak in transplant patients in Japan, as well as strains causing sporadic cases of PCP in nontransplant patients with or without HIV infection. CONCLUSIONS Two geographically distinct clusters of PCP in Europe were due to a single strain of Pneumocystis. This suggests either enhanced virulence of this strain in transplant patients or a common, but unidentified, source of transmission. Outbreaks of PCP can be better understood by enhanced knowledge of transmission patterns and strain variation.

Renal function declines more in tenofovir- than abacavir-based antiretroviral therapy in low-body weight treatment-naïve patients with HIV infection.

Objective To compare the rate of decline of renal function in tenofovir- and abacavir-based antiretroviral therapy (ART) in low-body weight treatment-naïve patients with HIV infection. Design We conducted a single-center retrospective cohort study of 503 Japanese patients who commenced on either tenofovir- or abacavir-based initial ART. Methods The incidence of renal dysfunction, defined as more than 25% fall in estimated glomerular filtration rate (eGFR) from the baseline, was determined in each group. The effect of tenofovir on renal dysfunction was estimated by univariate and multivariate Cox hazards models as the primary exposure. Changes in eGFR until 96 weeks were estimated in both groups with a repeated measures mixed model. Results The median body weight of the cohort was 64 kg. The estimated incidence of renal dysfunction in the tenofovir and the abacavir arm was 9.84 per 100 and 4.55 per 100 person-years, respectively. Tenofovir was significantly associated with renal dysfunction by univariate and multivariate analysis (HR = 1.747; 95% CI, 1.152–2.648; p = 0.009) (adjusted HR = 2.080; 95% CI, 1.339–3.232; p<0.001). In subgroup analysis of the patients stratified by intertertile baseline body weight, the effect of tenofovir on renal dysfunction was more evident in patients with lower baseline body weight by multivariate analysis (≤60 kg: adjusted HR = 2.771; 95%CI, 1.494–5.139; p = 0.001) (61–68 kg: adjusted HR = 1.908; 95%CI, 0.764–4.768; p = 0.167) (>68 kg: adjusted HR = 0.997; 95%CI, 0.318–3.121; p = 0.995). The fall in eGFR was significantly greater in the tenofovir arm than the abacavir arm after starting ART (p = 0.003). Conclusion The incidence of renal dysfunction in low body weight patients treated with tenofovir was twice as high as those treated with abacavir. Close monitoring of renal function is recommended for patients with small body weight especially those with baseline body weight <60 kg treated with tenofovir.

Evaluation of an Automated Rapid Diagnostic Assay for Detection of Gram-Negative Bacteria and Their Drug-Resistance Genes in Positive Blood Cultures

We evaluated the performance of the Verigene Gram-Negative Blood Culture Nucleic Acid Test (BC-GN; Nanosphere, Northbrook, IL, USA), an automated multiplex assay for rapid identification of positive blood cultures caused by 9 Gram-negative bacteria (GNB) and for detection of 9 genes associated with β-lactam resistance. The BC-GN assay can be performed directly from positive blood cultures with 5 minutes of hands-on and 2 hours of run time per sample. A total of 397 GNB positive blood cultures were analyzed using the BC-GN assay. Of the 397 samples, 295 were simulated samples prepared by inoculating GNB into blood culture bottles, and the remaining were clinical samples from 102 patients with positive blood cultures. Aliquots of the positive blood cultures were tested by the BC-GN assay. The results of bacterial identification between the BC-GN assay and standard laboratory methods were as follows: Acinetobacter spp. (39 isolates for the BC-GN assay/39 for the standard methods), Citrobacter spp. (7/7), Escherichia coli (87/87), Klebsiella oxytoca (13/13), and Proteus spp. (11/11); Enterobacter spp. (29/30); Klebsiella pneumoniae (62/72); Pseudomonas aeruginosa (124/125); and Serratia marcescens (18/21); respectively. From the 102 clinical samples, 104 bacterial species were identified with the BC-GN assay, whereas 110 were identified with the standard methods. The BC-GN assay also detected all β-lactam resistance genes tested (233 genes), including 54 bla CTX-M, 119 bla IMP, 8 bla KPC, 16 bla NDM, 24 bla OXA-23, 1 bla OXA-24/40, 1 bla OXA-48, 4 bla OXA-58, and 6 bla VIM. The data shows that the BC-GN assay provides rapid detection of GNB and β-lactam resistance genes in positive blood cultures and has the potential to contributing to optimal patient management by earlier detection of major antimicrobial resistance genes.

Detection of HIV Type 1 Load by the Roche Cobas TaqMan Assay in Patients with Viral Loads Previously Undetectable by the Roche Cobas Amplicor Monitor

OR, 6.2; 95% CI, 2.5–15.4). There was no increase in the risk of T. vaginalis infection among women who were infected with T. vaginalis during the immediately preceding interval (4.4%), compared with women who were not (3.9%). However, 13 (62%) of 21 new infections occurred in women who had been previously infected with T. vaginalis, and 11 (85%) of 13 had negative test results during the immediately preceding interval (figure 1). Some of the women might have acquired infections during sexual contact that they did not report, and some might have had infections that were not detected at the baseline visit. However, many women were treated for infection, had negative test results, and then had positive test results again, which suggests that T. vaginalis was undetected by testing but still present for months after treatment. The possibility of long-term asymptomatic carriage is consistent with the age distribution of infected women; T. vaginalis is found more often in older women [8, 9]. This pattern is different from the pattern for bacterial sexually transmitted diseases but similar to that for incurable viral infections, such as herpes simplex virus type 2 [10]. Trials have suggested cure rates of 190%, but most have tested women once within a few weeks after treatment [11]. When women were tested again a few months after treatment, some of the previously cured women had infection detected again [11], and none of the studies continued testing women beyond a few months. Cultures might not detect infections if the concentration of T. vaginalis is low, which would be expected in asymptomatic infections [6, 12, 13]. Nucleic acid amplification tests may be better, but reports are inconsistent and the tests are not commercially available in the United States [14]. Similarly, self-obtained vaginal swab specimens occasionally miss infections, but the sensitivity of tests performed with self-obtained specimens has compared favorably with that of tests performed with clinician-obtained specimens [15]. Treatment failure could explain many of our findings, because 13 women had a documented preceding infection. However, our results were not simply attributable to treatment failure. Most of the women ( ) had an intervening negn p 11 ative test result before having a positive result during an interval when they reported not having sex. This suggests that, after treatment, T. vaginalis infection can become nondetectable for months and then reappear. Because these findings were unexpected and obtained with a small number of participants, additional studies are needed to confirm or refute these observations.

Long-term exposure to tenofovir continuously decrease renal function in HIV-1-infected patients with low body weight: results from 10 years of follow-up.

Objectives:To investigate the effect of long-term tenofovir disoproxil fumarate (TDF) use on renal function, especially in patients with low body weight who are vulnerable to TDF nephrotoxicity. Design:A single-center, observational study in Tokyo, Japan. Methods:We performed a 10 years cohort study of 792 HIV-1-infected patients. The effect of long-term TDF use on estimated glomerular filtration rate (eGFR) was investigated on treatment-naive patients who started TDF-containing antiretroviral therapy (n = 422) and those who started abacavir-containing antiretroviral therapy as control (n = 370). Three renal endpoints were examined by the logistic regression model: decrement in eGFR of higher than 10 ml/min per 1.73 m2 relative to the baseline, more than 25% decrement in eGFR, and eGFR lower than 60 ml/min per 1.73 m2 at least 3 months apart. The loss in eGFR was estimated using linear mixed models for repeated measures. Results:The median weight at baseline was 63 kg. TDF use increased the risk of all three renal outcomes compared with the control group: higher than 10 ml/min per 1.73 m2 decrement in eGFR [adjusted odds ratio (OR) = 2.1, 95% confidence interval (CI) 1.45–3.14, P < 0.001], more than 25% decrement (adjusted OR = 2.1, 95% CI 1.50–2.90, P < 0.001), and eGFR lower than 60 ml/min per 1.73 m2 at least 3 months apart (adjusted OR = 3.9, 95% CI 1.62–9.36, P = 0.002). The cumulative mean loss relative to the control after 1, 2, 3, 4, and 5 years of TDF exposure was −3.8, −3.6, −5.5, −6.6, and −10.3 ml/min per 1.73 m2, respectively, indicating that the loss in eGFR increased over time (P < 0.001). Conclusion:In this cohort of patients with low body weight, TDF exposure increased the risk of renal dysfunction. Furthermore, the loss in eGFR relative to the control increased continuously up to 5 years.

Factors Associated with Esophageal Candidiasis and Its Endoscopic Severity in the Era of Antiretroviral Therapy

Background Candidia esophagitis (CE) is an AIDS-defining condition, usually occurring in individuals with low CD4 counts of <200 cells/µL. Endoscopy is a valuable definitive diagnostic method for CE but may not be indicated for asymptomatic patients or for those with high CD4 counts or without oral candidiasis. This study assessed such patients to clarify the factors associated with CE and its severity on endoscopy in the highly active antiretroviral therapy (HAART) era. Methodology/ Principal Findings A total of 733 HIV-infected patients who underwent upper gastrointestinal (GI) endoscopy were analyzed. Sexual behavior, CD4+ count, HIV-RNA viral load (VL), history of HAART, GI symptoms, GI diseases, and oral candidiasis were assessed. Endoscopic severity of CE was classified as mild (Kodsis grade I/II) or severe (grade III/IV). Of the 733 subjects, 62 (8.46%) were diagnosed with CE (mild, n = 33; severe, n = 29). Of them, 56.5% (35/62) had no GI symptoms, 30.6% (19/62) had CD4 + ≥200 cells/μL, and 55.3% (21/38) had no oral candidiasis. Univariate analysis found lower CD4+ counts, higher HIV VL, and no history of HAART to be significantly associated with CE. With lower CD4+ counts and higher HIV VL, CE occurrence increased significantly (P<0.01 for trend in odds). Multivariate analysis showed low CD4+ counts and high HIV VL to be independently associated with CE. Of the severe CE patients, 55.2% (16/29) had no GI symptoms and 44.4% (8/18) had no oral candidiasis. Median CD4+ counts in severe cases were significantly lower than in mild cases (27 vs. 80; P = 0.04). Conclusions Low CD4+ counts and high HIV VL were found to be factors associated with CE, and advanced immunosuppression was associated with the development of severity. Endoscopy is useful as it can detect CE, even severe CE, in patients without GI symptoms, those with high CD4 counts, and those without oral candidiasis.

Predictive Clinical Factors in the Diagnosis of Gastrointestinal Kaposi's Sarcoma and Its Endoscopic Severity

Background The diagnosis of gastrointestinal (GI) involvement in Kaposis sarcoma (KS) is important to make because the need for treatment depends on the extent of the disease. Moreover, severe GI lesions can cause serious complications. Endoscopy with biopsy is an extremely useful method to diagnose GI-KS. However, determining the indications for endoscopy is difficult because KS can occur without GI symptoms or cutaneous KS. This study sought to clarify predictive clinical factors for GI-KS and its severity on endoscopy. Methodology/Principal Findings A total of 1,027 HIV-infected patients who underwent endoscopy were analyzed. Sexual behavior, CD4 count, HIV RNA, history of highly active antiretroviral therapy (HAART), GI symptoms, and cutaneous KS were assessed. Endoscopic severity including bulky tumor, ulceration, and number of lesions were evaluated. Thirty-three patients had GI-KS and 46 patients cutaneous KS. Among the GI-KS patients, 78.8% (26/33) had no GI symptoms and 24.2% (8/33) had no cutaneous KS. Univariate analysis identified men who have sex with men (MSM), CD4 <100 cells/µL, HIV RNA ≥10,000 copies/mL, no history of HAART, and cutaneous KS were significantly associated with GI-KS. Among these factors, cutaneous KS was closely related to GI-KS on multivariable analysis. Among patients without cutaneous KS, MSM and CD4 count <100 cells/µL were the only independent clinical factors related to GI-KS. Bulky tumor was significantly associated with CD4 <100 cells/µL and large number of lesions was significantly associated with HIV-RNA ≥10,000 copies/mL. Conclusions To diagnose GI-KS, clinical factors need to be considered before endoscopy. The presence of GI symptoms is not useful in predicting GI-KS. MSM and CD4 count <100 cells/µL are predictive factors among patients without cutaneous KS. Caution should be exercised especially in patients with low CD4 counts or high HIV viral loads as they are more likely to develop severe GI-KS lesions.