Andy I. M. Hoepelman

Increased risk of common infections in patients with type 1 and type 2 diabetes mellitus

BACKGROUND Clinical data on the association of diabetes mellitus with common infections are virtually lacking, not conclusive, and often biased. We intended to determine the relative risks of common infections in patients with type 1 and type 2 diabetes mellitus (DM1 and DM2, respectively). METHODS In a 12-month prospective cohort study conducted as part of the Second Dutch National Survey of General Practice, we compared 705 adult patients who had DM1 and 6712 adult patients who had DM2 with 18,911 control patients who had hypertension without diabetes. Outcome measures were medically attended episodes of infection of the respiratory tract, urinary tract, and skin and mucous membranes. We applied multivariable and polytomous logistic regression analysis to determine independent risks of infections and their recurrences in patients with diabetes, compared with control patients. RESULTS Upper respiratory infections were equally common among patients with diabetes and control patients. Patients with diabetes had a greater risk of lower respiratory tract infection (for patients with DM1: adjusted odds ratio [AOR], 1.42 [95% confidence interval {CI}, 0.96-2.08]; for patients with DM2: AOR, 1.32 [95% CI, 1.13-1.53]), urinary tract infection (for patients with DM1: AOR, 1.96 [95% CI, 1.49-2.58]; for patients with DM2: AOR, 1.24 [95% CI, 1.10-1.39]), bacterial skin and mucous membrane infection (for patients with DM1: AOR, 1.59 [95% CI, 1.12-2.24]; for patients with DM2: AOR, 1.33 [95% CI, 1.15-1.54]), and mycotic skin and mucous membrane infection (for patients with DM1: AOR, 1.34 [95% CI, 0.97-1.84]; for patients with DM2: AOR, 1.44 [95% CI, 1.27-1.63]). Risks increased with recurrences of common infections. CONCLUSIONS Patients with DM1 and DM2 are at increased risk for lower respiratory tract infection, urinary tract infection, and skin and mucous membrane infection. Studies are warranted into management of such infections in patients with diabetes.

Efficacy of short-term monotherapy with maraviroc, a new CCR5 antagonist, in patients infected with HIV-1

We assessed the efficacy and safety of 10-d monotherapy with the orally administered CCR5 antagonist maraviroc in 63 HIV-1-positive individuals prescreened for the absence of CXCR4-using virus. Maximum reduction in viral load occurred at a median of 10–15 d, with a mean reduction of ≥1.6 log10 copies/ml at all twice daily doses ≥100 mg. These results provide proof of concept that CCR5 antagonism is a viable antiretroviral therapeutic approach.

Prevalence of Drug-Resistant HIV-1 Variants in Untreated Individuals in Europe: Implications for Clinical Management

BACKGROUND Infection with drug-resistant human immunodeficiency virus type 1 (HIV-1) can impair the response to combination therapy. Widespread transmission of drug-resistant variants has the disturbing potential of limiting future therapy options and affecting the efficacy of postexposure prophylaxis. METHODS We determined the baseline rate of drug resistance in 2208 therapy-naive patients recently and chronically infected with HIV-1 from 19 European countries during 1996-2002. RESULTS In Europe, 1 of 10 antiretroviral-naive patients carried viruses with > or = 1 drug-resistance mutation. Recently infected patients harbored resistant variants more often than did chronically infected patients (13.5% vs. 8.7%; P=.006). Non-B viruses (30%) less frequently carried resistance mutations than did subtype B viruses (4.8% vs. 12.9%; P<.01). Baseline resistance increased over time in newly diagnosed cases of non-B infection: from 2.0% (1/49) in 1996-1998 to 8.2% (16/194) in 2000-2001. CONCLUSIONS Drug-resistant variants are frequently present in both recently and chronically infected therapy-naive patients. Drug-resistant variants are most commonly seen in patients infected with subtype B virus, probably because of longer exposure of these viruses to drugs. However, an increase in baseline resistance in non-B viruses is observed. These data argue for testing all drug-naive patients and are of relevance when guidelines for management of postexposure prophylaxis and first-line therapy are updated.

Subgroup analyses of maraviroc in previously treated R5 HIV-1 infection.

BACKGROUND We conducted subanalyses of the combined results of the Maraviroc versus Optimized Therapy in Viremic Antiretroviral Treatment-Experienced Patients (MOTIVATE) 1 and MOTIVATE 2 studies to better characterize the efficacy and safety of maraviroc in key subgroups of patients. METHODS We analyzed pooled data from week 48 from the two studies according to sex, race or ethnic group, clade, CC chemokine receptor 5 (CCR5) delta32 genotype, viral load at the time of screening, the use or nonuse of enfuvirtide in optimized background therapy (OBT), the baseline CD4 cell count, the number of active antiretroviral drugs coadministered, the first use of selected background agents, and tropism at baseline. Changes in viral tropism and the CD4 count at treatment failure were evaluated. Data on aminotransferase levels in patients coinfected with hepatitis B virus (HBV) or hepatitis C virus (HCV) were also analyzed. RESULTS A treatment benefit of maraviroc plus OBT over placebo plus OBT was shown in all subgroups, including patients with a low CD4 cell count at baseline, those with a high viral load at screening, and those who had not received active agents in OBT. Analyses of the virologic response according to the first use of selected background drugs showed the additional benefit of adding a potent new drug to maraviroc at the initiation of maraviroc therapy. More patients in whom maraviroc failed had a virus binding to the CXC chemokine receptor 4 (CXCR4) at failure, but there was no evidence of a decrease in the CD4 cell count at failure in such patients as compared with those in whom placebo failed. Subanalyses involving patients coinfected with HBV or HCV revealed no evidence of excess hepatotoxic effects as compared with baseline. CONCLUSIONS Subanalyses of pooled data from week 48 indicate that maraviroc provides a valuable treatment option for a wide spectrum of patients with R5 HIV-1 infection who have been treated previously. (ClinicalTrials.gov numbers, NCT00098306 and NCT00098722.)

Virological follow-up of adult patients in antiretroviral treatment programmes in sub-Saharan Africa: a systematic review

Following large-scale roll-out of antiretroviral therapy in sub-Saharan Africa, the non-clinical efficacy of antiretroviral therapy has received little attention. We aimed to systematically review virological efficacy and drug-resistance outcomes of programmes of antiretroviral therapy in sub-Saharan Africa. 89 studies with heterogeneous design, definitions, and methods were identified. Overall, in on-treatment analysis, 10 351 (78%) of 13 288 patients showed virological suppression after 6 months of antiretroviral therapy, 7413 (76%) of 9794 after 12 months, and 3840 (67%) of 5690 after 24 months. Long-term virological data are scarce. Genotyping results were available for patients with virological failure (HIV-1 RNA greater than 1000 copies per mL). Most patients (839 of 849; 99%) were infected with a non-B HIV-1 subtype. However, drug-resistance patterns were largely similar to those in subtype B. Resistance profiles were associated with the antiretroviral drugs commonly used: the lamivudine-associated M184V mutation was most common, followed by K103N which is associated with non-nucleoside reverse transcriptase inhibitors. Thymidine-analogue mutations and the K65R mutation were less common. First-line antiretroviral therapy regimens used in sub-Saharan Africa are effective. Profiles of drug resistance suggest that a second-line treatment regimen based on protease inhibitors, with a backbone of nucleoside reverse transcriptase inhibitors, is a reasonable option for patients with HIV in sub-Saharan Africa who experience first-line treatment failure.

Discontinuation of prophylaxis for Pneumocystis carinii pneumonia in HIV-1-infected patients treated with highly active antiretroviral therapy

BACKGROUND Prophylactic drugs for Pneumocystis carinii pneumonia (PCP) are strongly recommended for HIV-1-infected patients with CD4 cell counts of less than 200 cells/microL. Because of the highly active antiretroviral therapy (HAART) currently available, we speculated that prophylaxis can be discontinued in patients with CD4 cell counts of more than 200 cells/microL. METHODS In this prospective observational study, PCP prophylaxis (primary or secondary) was discontinued in HIV-1-infected patients whose CD4 cell count had increased above 200 cells/microL (documented twice with an interval of at least 1 month) as a result of HAART. Patients and their CD4 cell counts were monitored every 3 months. The primary endpoint of the study was the occurrence or reoccurrence of PCP. FINDINGS 78 patients were enrolled: 62 patients were receiving prophylaxis for primary prevention of PCP and 16 patients for secondary prevention of PCP. At the time of discontinuation of prophylaxis, the mean CD4 cell count was 347 cells/microL, and HIV-1-RNA was not detectable in 61 patients. The lowest mean CD4 cell count during prophylaxis was 79 cells/microL. Patients stopped prophylaxis 9.8 (SD 6.4) months after they started HAART. The mean follow-up after discontinuation of prophylaxis was 12.7 (SD 7.6) months, and none of the patients developed PCP (97.5% one-sided CI 0-4.4%). INTERPRETATION The preliminary results of this study indicate that PCP prophylaxis can be stopped safely in HIV-1-infected patients whose CD4 cell counts have increased above 200 cells/microL after treatment with HAART.

Impact of Rapid Detection of Viral and Atypical Bacterial Pathogens by Real-Time Polymerase Chain Reaction for Patients with Lower Respiratory Tract Infection

Abstract Background. Rapid diagnostic tests with a high sensitivity for lower respiratory tract infection (LRTI) could lead to improved patient care and reduce unnecessary antibiotic use and associated costs. Diagnostic yields, feasibility, and costs of real-time polymerase chain reaction (PCR) of nasopharyngeal and oropharyngeal swab specimens in the routine diagnostic work-up for LRTI were determined. Methods. In a randomized controlled trial, nasopharyngeal and oropharyngeal swab specimens from patients admitted for antibiotic treatment of LRTI were evaluated by means of real-time PCR for respiratory viruses and atypical pathogens, as well as by conventional diagnostic procedures. Real-time PCR results for patients in the intervention group were reported to the treating physician; results for patients in the control group were not made available. Results. A total of 107 patients (mean age [± standard deviation], 63.6 ± 16.3 years) were included, of whom 55 were allocated to the intervention group. The pathogens detected most frequently were influenza virus (14 patients), Streptococcus pneumoniae (8), coronavirus (6), Staphylococcus aureus (5), and rhinoviruses (5). Real-time PCR increased the diagnostic yield from 23 cases (21% of patients) to 47 cases (43% of patients), compared with conventional diagnostic tests. The detection of viral pathogens by PCR was associated with the winter season, less infiltrates on chest radiographs, lower C-reactive protein levels, and shorter duration of symptoms. Use of real-time PCR results resulted in partial or total cessation of antibiotic treatment for 6 patients (11%; 95% confidence interval, 2–19), but overall antibiotic use was comparable in the intervention group and the control group (median duration of treatment, 10.0 vs. 9.0 days; P = not significant). Use of real-time PCR increased treatment and diagnostic costs with €318.17 per patient. Conclusions. Implementation of real-time PCR for the etiological diagnosis of LRTI increased the diagnostic yield considerably, but it did not reduce antibiotic use or costs.

Antibiotic treatment strategies for community-acquired pneumonia in adults.

BACKGROUND The choice of empirical antibiotic treatment for patients with clinically suspected community-acquired pneumonia (CAP) who are admitted to non-intensive care unit (ICU) hospital wards is complicated by the limited availability of evidence. We compared strategies of empirical treatment (allowing deviations for medical reasons) with beta-lactam monotherapy, beta-lactam-macrolide combination therapy, or fluoroquinolone monotherapy. METHODS In a cluster-randomized, crossover trial with strategies rotated in 4-month periods, we tested the noninferiority of the beta-lactam strategy to the beta-lactam-macrolide and fluoroquinolone strategies with respect to 90-day mortality, in an intention-to-treat analysis, using a noninferiority margin of 3 percentage points and a two-sided 90% confidence interval. RESULTS A total of 656 patients were included during the beta-lactam strategy periods, 739 during the beta-lactam-macrolide strategy periods, and 888 during the fluoroquinolone strategy periods, with rates of adherence to the strategy of 93.0%, 88.0%, and 92.7%, respectively. The median age of the patients was 70 years. The crude 90-day mortality was 9.0% (59 patients), 11.1% (82 patients), and 8.8% (78 patients), respectively, during these strategy periods. In the intention-to-treat analysis, the risk of death was higher by 1.9 percentage points (90% confidence interval [CI], -0.6 to 4.4) with the beta-lactam-macrolide strategy than with the beta-lactam strategy and lower by 0.6 percentage points (90% CI, -2.8 to 1.9) with the fluoroquinolone strategy than with the beta-lactam strategy. These results indicated noninferiority of the beta-lactam strategy. The median length of hospital stay was 6 days for all strategies, and the median time to starting oral treatment was 3 days (interquartile range, 0 to 4) with the fluoroquinolone strategy and 4 days (interquartile range, 3 to 5) with the other strategies. CONCLUSIONS Among patients with clinically suspected CAP admitted to non-ICU wards, a strategy of preferred empirical treatment with beta-lactam monotherapy was noninferior to strategies with a beta-lactam-macrolide combination or fluoroquinolone monotherapy with regard to 90-day mortality. (Funded by the Netherlands Organization for Health Research and Development; CAP-START ClinicalTrials.gov number, NCT01660204.).

Frequent Detection of Human Coronaviruses in Clinical Specimens from Patients with Respiratory Tract Infection by Use of a Novel Real-Time Reverse-Transcriptase Polymerase Chain Reaction

During the past years, human coronaviruses (HCoVs) have been increasingly identified as pathogens associated with more-severe respiratory tract infection (RTI). Diagnostic tests for HCoVs are not frequently used in the routine setting. It is likely that, as a result, the precise role that HCoVs play in RTIs is greatly underestimated. We describe a rapid, sensitive, and highly specific quantitative real-time reverse-transcriptase polymerase chain reaction (RT-PCR) for the detection of HCoV that can easily be implemented in the routine diagnostic setting. HCoV was detected in 28 (11%) of the 261 clinical specimens obtained from patients presenting with symptoms of RTI ranging from common cold to severe pneumonia. Only 1 (0.4%) of the 243 control specimens obtained from patients without symptoms of RTI showed the presence of HCoV. We conclude that HCoVs can be frequently detected in patients presenting with RTI. Real-time RT-PCR provides a tool for large-scale epidemiological studies to further clarify the role that coronavirus infection plays in RTI in humans.

CD27 deficiency is associated with combined immunodeficiency and persistent symptomatic EBV viremia

BACKGROUND CD27 is a lymphocyte costimulatory molecule that regulates T-cell, natural killer (NK) cell, B-cell, and plasma cell function, survival, and differentiation. On the basis of its function and expression pattern, we considered CD27 a candidate gene in patients with hypogammaglobulinemia. OBJECTIVE We sought to describe the clinical and immunologic phenotypes of patients with genetic CD27 deficiency. METHODS A molecular and extended immunologic analysis was performed on 2 patients lacking CD27 expression. RESULTS We identified 2 brothers with a homozygous mutation in CD27 leading to absence of CD27 expression. Both patients had persistent symptomatic EBV viremia. The index patient was hypogammaglobulinemic, and immunoglobulin replacement therapy was initiated. His brother had aplastic anemia in the course of his EBV infection and died from fulminant gram-positive bacterial sepsis. Immunologically, lack of CD27 expression was associated with impaired T cell-dependent B-cell responses and T-cell dysfunction. CONCLUSION Our findings identify a role for CD27 in human subjects and suggest that this deficiency can explain particular cases of persistent symptomatic EBV viremia with hypogammaglobulinemia and impaired T cell-dependent antibody generation.