Showing papers in "The Journal of Infectious Diseases in 2008"
TL;DR: The research agenda of the National Institute of Allergy and Infectious Diseases (NIAID) for antimicrobial resistance is detailed, indicating that NIAID funding of antimicrobial research has grown considerably over the past decade, now totaling more than $800 million annually.
Abstract: The discovery of potent and safe antimicrobial agents is arguably the single greatest health care advance in history. The availability of these agents rapidly reduced the morbidity and mortality associated with a host of formerly fatal diseases. In addition, the confidence that infections could be prevented or treated by antibiotics allowed major leaps forward in the treatment of noninfectious diseases, including serious heart disease, cancers, and organ failure requiring transplants. Medical care, as we now know it, could not exist without the availability of effective antibiotics. The widespread use of antibiotics has been associated with what we now know to be the predictable emergence of resistance. Early confidence that infections would eventually be conquered has given way to a greater appreciation of the genetic flexibility of common human pathogens. Moreover, we have come to appreciate the role played by microorganisms in our homeostasis. Microorganisms are an intrinsic part of us, and we would do well to learn to live with them. Where we cannot live with them is in the hospital, because patients with compromised defenses are particularly vulnerable to bacterial diseases. Although many bacteria remain susceptible to most of our antimicrobial agents, a coterie has emerged that escape the lethal action of antibiotics. In hospitals in both the developed and the developing world, this small group Enterococcus faeciumy Staphylococcus aureusy Klebsiella pneumoniaey Acinetobacter baumanni, Pseudomonas aeruginosa, and Enterobacter species, hereafter referred to as "the ESKAPE bugs" is the same. The ESKAPE bugs are extraordinarily important, not only because they cause the lion's share of nosocomial infections but also because they represent paradigms of pathogenesis, transmission, and resistance. If we learn to control these microorganisms, our hospitals will be immeasurably safer, because the lessons learned could be applied to virtually any species that attempts to take their place. Unfortunately, the ESKAPE bugs are increasingly prevalent in our hospitals and increasingly resistant to many of our antimicrobial agents. In this issue of the Journal Peters et al. [ 1 ] detail the research agenda of the National Institute of Allergy and Infectious Diseases (NIAID) for antimicrobial resistance. As the primary federal agency for conducting and supporting medical research, the National Institutes of Health (NIH) is the standard-bearer for the federal government's commitment to health research. NIAID manages most, but certainly not all, of the work performed by the NIH in the areas of antimicrobial resistance and infectious diseases. As such, the NIAID agenda defines the weight of federal government efforts in the area of infectious diseases. One need look no further than the pivotal role played by NIAID in the enormous success of the AIDS research effort over the past 2 decades to understand the profound impact this institute's agenda can have on the growth and success of individual research areas. Peters et al. indicate that NIAID funding of antimicrobial research has grown considerably over the past decade, now totaling more than $800 million annually. In considering this very large number, it is important to realize that it represents NIAID's total commitment to all areas defined as being related to antimicrobial therapy. This category includes research on antibacterial, antifungal, antiparasitic, and antiviral therapies, whether related to the treatment of diseases or to their prevention through the use of vaccines. It is therefore difficult to get a firm grip on what level of support is devoted to antibacterial therapy and resistance, particularly in reference to the ESKAPE bugs. Regarding research specific to issues involving antimicrobial resistance, Peters Received 26 December 2007; accepted 3 January 2008; electronically published 7 March 2008. Potential conflicts of interest: none reported. Reprints or correspondence: Dr. Louis Rice, Medical Service 111(W), Louis Stokes Cleveland VA Medical Center. 10701 East Blvd.. Cleveland, OH 44106 (louis.rice@va.gov).
1,631 citations
TL;DR: If severe pandemic influenza is largely a problem of viral-bacterial copathogenesis, pandemic planning needs to go beyond addressing the viral cause alone (e.g., influenza vaccines and antiviral drugs).
Abstract: Background
Despite the availability of published data on 4 pandemics that have occurred over the past 120 years, there is little modern information on the causes of death associated with influenza pandemics.
1,448 citations
TL;DR: The fecal communities in patients with recurrent CDAD were highly variable in bacterial composition and were characterized by markedly decreased diversity, suggesting preservation and restoration of the microbial diversity could represent novel strategies for prevention and treatment of recurrentCDAD.
Abstract: Antibiotic-associated diarrhea due to Clostridium difficile (CDAD) is thought to reflect colonization of a disrupted microbial community by the pathogen. We profiled the fecal microbiota of patients with CDAD (both initial and recurrent episodes) by culture-independent phylogenetic analysis of 16S rRNA-encoding gene sequences. Compared with those from control subjects and patients with an initial episode, the fecal communities in patients with recurrent CDAD were highly variable in bacterial composition and were characterized by markedly decreased diversity. Preservation and restoration of the microbial diversity could represent novel strategies for prevention and treatment of recurrent CDAD, which is often recalcitrant to existing therapies.
970 citations
TL;DR: Nal colonization with MRSA has increased in the United States, despite an overall decrease in nasal colonization with S. aureus, and PFGE types associated with community transmission only partially account for the increase.
Abstract: Background. Staphylococcus aureus is a common cause of infection, particularly in persons colonized by this organism. Virulent strains of methicillin-resistant S. aureus (MRSA) have emerged in the general community. Methods. A nationally representative survey of nasal colonization with S. aureus was conducted from 2001 through 2004 as part of the National Health and Nutrition Examination Survey. MRSA isolates were identified by the oxacillin disk-diffusion method. The pulsed-field gel electrophoresis (PFGE) type was determined for all MRSA isolates. A t statistic was used to compare the prevalence of colonization across biennia and across population subgroups. Cofactors independently associated with colonization were determined with backward stepwise logistic modeling. Results. The prevalence of colonization with S. aureus decreased from 32.4% in 2001-2002 to 28.6% in 2003-2004 (P <.01), whereas the prevalence of colonization with MRSA increased from 0.8% to 1.5% (P <.05). Colonization with MRSA was independently associated with healthcare exposure in males and with having been born in the United States, age ≥60 years, diabetes, and poverty in females. In 2003-2004, a total of 19.7% (95% confidence interval, 12.4%-28.8%) of MRSA-colonized persons carried a PFGE type associated with community transmission. Conclusions. Nasal colonization with MRSA has increased in the United States, despite an overall decrease in nasal colonization with S. aureus. PFGE types associated with community transmission only partially account for the increase in MRSA colonization.
948 citations
TL;DR: Primary and late-stage HIV-1 infection are more infectious than previously estimated, but for shorter periods.
Abstract: ackground. The epidemiological impact of public health interventions targeted at reducing transmission of human immunodeficiency virus type 1 (HIV-1) during early or late-stage infection depends on the contribution of these disease stages to transmission within a particular epidemic.
Methods. Transmission hazards and durations of periods of high infectivity during primary, asymptomatic, and late-stage infection were estimated for HIV-1-serodiscordant heterosexual couples in Rakai, Uganda, by use of a robust probabilistic framework.
Results. Primary infection and late-stage infection were estimated to be 26 and 7 times, respectively, more infectious than asymptomatic infection. High infectiousness during primary infection was estimated to last for ∼3 months after seroconversion, whereas high infectiousness during late-stage infection was estimated to be concentrated between 19 months and 10 months before death.
Conclusions. Primary and late-stage HIV-1 infection are more infectious than previously estimated, but for shorter periods. In a homogeneous population, the asymptomatic stage of infection will typically contribute more to the net transmission of HIV-1 over the lifetime of an infected individual, because of its longer duration. The dependence of the relative contribution of infectious stages on patterns of sexual behavior and the phase of epidemics is discussed.
663 citations
TL;DR: HIV controllers have abnormally high T cell activation levels, which may contribute to progressive CD4(+) T cell loss even without measurable viremia.
Abstract: Fewer than 1% of chronically HIV-infected individuals are capable of maintaining clinically undetectable plasma HIV RNA levels (<75 copies/mL) in the absence of antiretroviral medications [1–4]. We and others have been systematically recruiting these “elite controllers” to characterize fully the correlates of protective immunity. For example, controllers have much stronger polyfunctional HIV-specific CD8+ T cell responses than chronically HIV-infected patients maintaining antiretroviral treatment–mediated viral suppression [5], and they are enriched for protective class I HLA haplotypes associated with delayed disease progression [3, 6–11]. Furthermore, controllers maintain high frequencies of CD4+ T cells that secrete interleukin-2 and proliferate in response to HIV peptides [12, 13]. These observations have led to the consensus that controllers are capable of containing HIV replication at very low levels with strong and durable HIV-specific immune responses.
Much less attention has been paid to the non–HIV-specific immune function of these individuals. Indeed, although lower plasma HIV RNA levels in the absence of antiretroviral therapy predict slower rates of clinical progression [14], the extent of viral replication may explain less than half of the variability in the rates of subsequent CD4+ T cell decline and progression to AIDS [15, 16], and some patients maintaining undetectable or nearly undetectable plasma HIV RNA levels in the absence of antiretroviral therapy have experienced clinical progression [4, 17]. These observations suggest that factors other than the level of viral replication contribute to immunodeficiency in HIV infection. One such factor is the ability of HIV to cause generalized T cell activation. We and others have demonstrated that higher CD8+ T cell activation levels are associated with more-rapid clinical progression and CD4+ T cell decline in untreated patients [18–23] as well as fewer antiretroviral therapy–mediated CD4+ T cell gains [24–27], independent of plasma HIV RNA level. T cell activation may distinguish pathogenic from nonpathogenic simian immunodeficiency virus (SIV) infection [28], and generalized T cell activation in the absence of viral infection appears to be capable of inducing CD4+ T cell depletion and immunodeficiency in a murine model [29]. To our knowledge, no study to date has specifically addressed whether controllers have abnormal levels of generalized T cell activation, potentially contributing to immunodeficiency.
To address these issues, we compared T cell activation levels between controllers and 3 comparator groups: HIV-uninfected patients at risk for HIV infection from a study of nonoccupational postexposure prophylaxis, HIV-infected patients maintaining undetectable plasma HIV RNA levels as a consequence of antiretroviral therapy, and untreated HIV-infected patients with detectable viremia. We also assessed the relationship between T cell activation and CD4+ T cell counts among controllers. Finally, we explored indirect mechanisms by which HIV might cause T cell activation despite clinically undetectable plasma HIV RNA levels. Specifically, because mucosal translocation of bacterial products may contribute to T cell activation in HIV infection [30], we assessed the relationship between T cell activation and plasma lipopolysaccharide (LPS) levels among controllers.
624 citations
TL;DR: Even low-level viremia among HIV controllers was associated with measurable T cell dysfunction, which has implications for current prophylactic vaccine strategies.
Abstract: Background Spontaneous control of human immunodeficiency virus (HIV) infection has been documented in a minority of HIV-infected individuals. The mechanisms behind this outcome remain largely unknown, and a better understanding of them will likely influence future vaccine strategies. Methods HIV-specific T cell and antibody responses as well as host genetics were examined in untreated HIV-infected patients who maintain comparatively low plasma HIV RNA levels (hereafter, controllers), including those with levels of 10,000 copies/mL (chronic progressors, n = 30). Results CD8+ T cells from both controller groups preferentially target Gag over other proteins in the context of diverse HLA class I alleles, whereas responses are more broadly distributed in persons with progressive infection. Elite controllers represent a distinct group of individuals who have significantly more CD4 and CD8 T cells that secrete interferon-gamma and interleukin-2 and lower levels of HIV-neutralizing antibodies. Individual responses were quite heterogeneous, and none of the parameters evaluated was uniquely associated with the ability to control viremia. Conclusions Elite controllers are a distinct group, even when compared to persons with low level viremia, but they exhibit marked genetic and immunologic heterogeneity. Even low-level viremia among HIV controllers was associated with measurable T cell dysfunction, which has implications for current prophylactic vaccine strategies.
537 citations
TL;DR: It is suggested that the GALT may play a major role in the persistence of HIV in such individuals who had been receiving effective antiviral therapy for prolonged periods of time, and a possible mechanism for the maintenance of viral reservoirs revolving around the Galt of HIV-infected individuals despite long-term viral suppression is provided.
Abstract: Human immunodeficiency virus (HIV) persists in peripheral blood mononuclear cells despite sustained, undetectable plasma viremia resulting from long-term antiretroviral therapy. However, the source of persistent HIV in such infected individuals remains unclear. Given recent data suggesting high levels of viral replication and profound depletion of CD4(+) T cells in gut-associated lymphoid tissue (GALT) of animals infected with simian immunodeficiency virus and HIV-infected humans, we sought to determine the level of CD4(+) T cell depletion as well as the degree and extent of HIV persistence in the GALT of infected individuals who had been receiving effective antiviral therapy for prolonged periods of time. We demonstrate incomplete recoveries of CD4(+) T cells in the GALT of aviremic, HIV-infected individuals who had received up to 9.9 years of effective antiretroviral therapy. In addition, we demonstrate higher frequencies of HIV infection in GALT, compared with PBMCs, in these aviremic individuals and provide evidence for cross-infection between these 2 cellular compartments. Together, these data provide a possible mechanism for the maintenance of viral reservoirs revolving around the GALT of HIV-infected individuals despite long-term viral suppression and suggest that the GALT may play a major role in the persistence of HIV in such individuals.
498 citations
Centers for Disease Control and Prevention1, Vanderbilt University2, Colorado Department of Public Health and Environment3, University of California, Berkeley4, Veterans Health Administration5, Johns Hopkins University6, Connecticut Agricultural Experiment Station7, Oregon Department of Human Services8, Emory University9, University of Oxford10, University of Texas at Austin11
TL;DR: PCV7 ineffectiveness against serotype 19A, antibiotic resistance, clonal expansion and emergence, and capsular switching have contributed to the genetic diversity of 19A and to its emergence as the predominant invasive pneumococcal serotype in the United States.
Abstract: Background. Serotype 19A invasive pneumococcal disease (IPD) increased annually in the United States after the introduction of the 7-valent conjugate vaccine (PCV7). To understand this increase, we characterized serotype 19A isolates recovered during 2005. Methods. IPD cases during 1998-2005 were identified through population-based surveillance. We performed susceptibility testing and multilocus sequence typing on 528 (95%) of 554 serotype 19A isolates reported in 2005. Results. The incidence of IPD due to serotype 19A increased from 0.8 to 2.5 cases per 100,000 population between 1998 and 2005 (P <.05), whereas the overall incidence of IPD decreased from 24.4 to 13.8 cases per 100,000 population (P <.05). Simultaneously, the incidence of IPD due to penicillin-resistant 19A isolates increased from 6.7% to 35% (P <.0001). Of 151 penicillin-resistant 19A isolates, 111 (73.5%) belonged to the rapidly emerging clonal complex 320, which is related to multidrug-resistant Taiwan 19F -14. The remaining penicillin-resistant strains were highly related to other clones of PCV7 serotypes or to isolates within major 19A clonal complex 199 (CC199). In 1999, only CC199 and 3 minor clones were apparent among serotype 19A isolates. During 2005, 11 multiple-isolate clonal sets were detected, including capsular switch variants of a serotype 4 clone. Conclusions. PCV7 ineffectiveness against serotype 19A, antibiotic resistance, clonal expansion and emergence, and capsular switching have contributed to the genetic diversity of 19A and to its emergence as the predominant invasive pneumococcal serotype in the United States.
492 citations
Journal Article•
TL;DR: In this article, the authors found incomplete recoveries of CD4 + T cells in the GALT of aviremic, HIV-infected individuals who had received up to 9.9 years of effective antiretroviral therapy.
Abstract: Human immunodeficiency virus (HIV) persists in peripheral blood mononuclear cells despite sustained, undetectable plasma viremia resulting from long-term antiretroviral therapy. However, the source of persistent HIV in such infected individuals remains unclear. Given recent data suggesting high levels of viral replication and profound depletion of CD4 + T cells in gut-associated lymphoid tissue (GALT) of animals infected with simian immunodeficiency virus and HIV-infected humans, we sought to determine the level of CD4 + T cell depletion as well as the degree and extent of HIV persistence in the GALT of infected individuals who had been receiving effective antiviral therapy for prolonged periods of time. We demonstrate incomplete recoveries of CD4 + T cells in the GALT of aviremic, HIV-infected individuals who had received up to 9.9 years of effective antiretroviral therapy. In addition, we demonstrate higher frequencies of HIV infection in GALT, compared with PBMCs, in these aviremic individuals and provide evidence for cross-infection between these 2 cellular compartments. Together, these data provide a possible mechanism for the maintenance of viral reservoirs revolving around the GALT of HIV-infected individuals despite long-term viral suppression and suggest that the GALT may play a major role in the persistence of HIV in such individuals.
458 citations
TL;DR: The impact of vaccination with MCC vaccine on the prevalence of carriage of group C meningococci was consistent with herd immunity, and the high impact on the carriage of ST-11 complex serogroup C could be attributed to high levels of capsule expression.
Abstract: BACKGROUND: In 1999, meningococcal serogroup C conjugate (MCC) vaccines were introduced in the United Kingdom for those under 19 years of age. The impact of this intervention on asymptomatic carriage of meningococci was investigated to establish whether serogroup replacement or protection by herd immunity occurred. METHODS: Multicenter surveys of carriage were conducted during vaccine introduction and on 2 successive years, resulting in a total of 48,309 samples, from which 8599 meningococci were isolated and characterized by genotyping and phenotyping. RESULTS: A reduction in serogroup C carriage (rate ratio, 0.19) was observed that lasted at least 2 years with no evidence of serogroup replacement. Vaccine efficacy against carriage was 75%, and vaccination had a disproportionate impact on the carriage of sequence type (ST)-11 complex serogroup C meningococci that (rate ratio, 0.06); these meningococci also exhibited high rates of capsule expression. CONCLUSIONS: The impact of vaccination with MCC vaccine on the prevalence of carriage of group C meningococci was consistent with herd immunity. The high impact on the carriage of ST-11 complex serogroup C could be attributed to high levels of capsule expression. High vaccine efficacy against disease in young children, who were not protected long-term by the schedule initially used, is attributed to the high vaccine efficacy against carriage in older age groups.
TL;DR: It is found that deletion of type IV SCCmec did not affect competitive fitness, whereas deletion of ACME significantly attenuated the pathogenicity or fitness of USA300, consistent with a model in which ACME enhances growth and survival of America300, allowing for genetic "hitchhiking" of SCCMec.
Abstract: The epidemic character of community-associated methicillin-resistant Staphylococcus aureus, especially the geographically widespread clone USA300, is poorly understood. USA300 isolates carry a type IV staphylococcal chromosomal cassette mec (SCCmec) element conferring beta-lactam antibiotic class resistance and a putative pathogenicity island, arginine catabolic mobile element (ACME). Physical linkage between SCCmec and ACME suggests that selection for antibiotic resistance and for pathogenicity may be interconnected. We constructed isogenic mutants containing deletions of SCCmec and ACME in a USA300 clinical isolate to determine the role played by these elements in a rabbit model of bacteremia. We found that deletion of type IV SCCmec did not affect competitive fitness, whereas deletion of ACME significantly attenuated the pathogenicity or fitness of USA300. These data are consistent with a model in which ACME enhances growth and survival of USA300, allowing for genetic "hitchhiking" of SCCmec. SCCmec in turn protects against exposure to beta-lactams.
TL;DR: Initiation of ART at CD4+ cell counts >350 cells/ microL compared with <250 cells/microL may reduce both OD and serious non-AIDS events and require validation in a large, randomized clinical trial.
Abstract: BACKGROUND: The SMART study randomized 5,472 human immunodeficiency virus (HIV)-infected patients with CD4+ cell counts 250 cells/microL may reduce both OD and serious non-AIDS events These findings require validation in a large, randomized clinical trial
TL;DR: Salmonella serotypes are closely related genetically yet differ significantly in their pathogenic potentials, and understanding the mechanisms responsible for this may be key to a more general understanding of the invasiveness of intestinal bacterial infections.
Abstract: Background Most human infections are caused by closely related serotypes within 1 species of Salmonella. Few data are available on differences in severity of disease among common serotypes. Methods We examined data from all cases of Salmonella infection in FoodNet states during 1996-2006. Data included serotype, specimen source, hospitalization, and outcome. Results Among 46,639 cases, 687 serotypes were identified. Overall, 41,624 isolates (89%) were from stool specimens, 2524 (5%) were from blood, and 1669 (4%) were from urine; 10,393 (22%) cases required hospitalization, and death occurred in 219 (0.5%). The case fatality rate for S. Newport (0.3%) was significantly lower than for Typhimurium (0.6%); Dublin (3.0%) was higher. With respect to invasive disease, 13 serotypes had a significantly higher proportion than Typhimurium (6%), including Enteritidis (7%), Heidelberg (13%), Choleraesuis (57%), and Dublin (64%); 13 serotypes were significantly less likely to be invasive. Twelve serotypes, including Enteritidis (21%) and Javiana (21%), were less likely to cause hospitalization than Typhimurium (24%); Choleraesuis (60%) was significantly more so. Conclusions Salmonella serotypes are closely related genetically yet differ significantly in their pathogenic potentials. Understanding the mechanisms responsible for this may be key to a more general understanding of the invasiveness of intestinal bacterial infections.
TL;DR: In this paper, the authors reported an inverse association between Helicobacter pylori seropositivity and childhood asthma in children, using data from National Health and Nutrition Examination Survey (NHANES) 1999-2000.
Abstract: Background. Asthma, a serious health problem worldwide, is becoming more common. Colonization with Helicobacter pylori, a major human indigenous (commensal) microbe, during early life may be relevant to the risk of childhood asthma. Methods. We conducted cross-sectional analyses, using data from 7412 participants in the National Health and Nutrition Examination Survey (NHANES) 1999 –2000, to assess the association between H. pylori and childhood asthma. Results. H. pylori seropositivity was inversely associated with onset of asthma before 5 years of age and current asthma in children aged 3–13 years. Among participants 3–19 years of age, the presence of H. pylori was inversely related to ever having had asthma (odds ratio [OR], 0.69; 95% confidence interval [CI], 0.45–1.06), and the inverse association with onset of asthma before 5 years of age was stronger (OR, 0.58; 95% CI, 0.38 – 0.88). Among participants 3–13 years of age, H. pylori positivity was significantly inversely associated with current asthma (OR, 0.41; 95% CI, 0.24 – 0.69). H. pylori seropositivity also was inversely related to recent wheezing, allergic rhinitis, and dermatitis, eczema, or rash. Conclusions. This study is the first to report an inverse association betweenH.pylori seropositivity and asthma in children. The findings indicate new directions for research and asthma prevention.
TL;DR: MRSA has emerged as an important etiology in the authors' region and was higher among individuals with MRSA than among those with MSSA, and rates of methicillin-resistant S. aureus bacteremia dramatically increased.
Abstract: Background. Reports have suggested that the epidemiological profile of invasive Staphylococcus aureus infections is changing. We sought to describe the epidemiological profile of S. aureus bacteremia and to assess whether the incidence and severity of and the antimicrobial resistance rates associated with this bacteremia are increasing. Methods. Population-based surveillance for S. aureus bacteremias was conducted in the Calgary Health Region (population, 1.2 million) during 2000-2006. Results. The annual incidence of S. aureus bacteremia was 19.7 cases/100,000 population. Although rates of health care-associated and nosocomial methicillin-susceptible S. aureus (MSSA) bacteremia were similar throughout the study, rates of community-acquired MSSA bacteremia gradually decreased, and rates of methicillin-resistant S. aureus (MRSA) bacteremia dramatically increased. The clonal type predominantly isolated was CMRSA-2 (i.e., Canadian [C] MRSA-2), but CMRSA-10 (USA300) strains have been increasingly isolated, especially from community-onset infections, since 2004. Dialysis dependence, organ transplantation, HIV infection, cancer, and diabetes were the most important risk factors and were comparable for MSSA and MRSA bacteremias. The overall case-fatality rate was higher among individuals with MRSA (39%) than among those with MSSA (24%; P <.0001). The annual overall population mortality rate associated with S. aureus bacteremia did not significantly change during the study. Conclusions. Although the overall influence of S. aureus bacteremia has not significantly changed, MRSA has emerged as an important etiology in our region.
TL;DR: The hypothesis that boosting VZV-CMI protects older adults against herpes zoster and postherpetic neuralgia is supported, as it paralleled the clinical effects of the vaccine observed during the efficacy trial.
Abstract: Herpes zoster (HZ) is an often painful neurocutaneous syndrome resulting from reactivation of varicella-zoster virus (VZV) that has remained latent in sensory ganglia after primary VZV infection (varicella) [1–3]. The frequency and severity of HZ and its most common debilitating complication, postherpetic neuralgia (PHN), increase with age [4–9]. This age-related increase in disease correlates closely with the decline in VZV-specific T cell mediated immunity (VZV-CMI) that accompanies aging [10–14]. It is very unlikely that antibodies to VZV play a role in this relationship, because they do not decline with aging [13, 14]. Furthermore, HZ frequently occurs in circumstances when VZV-CMI is depressed while levels of VZV antibody are maintained by intravenous γ-globulin, such as those following hematopoietic stem cell transplantation [15–17]
On the basis of these observations, it was hypothesized that HZ might be prevented or attenuated (i.e., less pain and PHN) in elderly individuals if their waning VZV-CMI could be boosted with a VZV vaccine [18–20]. Pilot studies indicated that VZV-CMI could be boosted in subjects ⩾60 years old with live attenuated Oka strain VZV vaccines [13, 14, 21, 22]. Subsequent trials demonstrated the safety and immunogenicity of a high-potency Oka/Merck VZV vaccine in elderly subjects, including persons with diabetes and chronic lung disease, and established the optimal vaccine formulation and potency (M.J. Levin et al., unpublished data)
A double-blind, placebo-controlled trial (Veterans Affairs Cooperative Study 403: “The Shingles Prevention Study”) that involved 38,546 subjects ⩾60 years of age demonstrated that a high potency live attenuated Oka/Merck VZV vaccine (hereafter, “zoster vaccine”) significantly reduced the burden of illness due to HZ, understood in terms of a severity-by-duration measure of HZ pain and discomfort (i.e., the vaccine decreased the incidence of HZ and decreased the average severity of HZ in vaccinees who developed HZ), and substantially reduced the incidence of PHN in vaccine recipients [9]. The trial included an immunology substudy in which a subset of subjects had immunologic assessments performed before and after vaccination. We describe here the magnitude and kinetics of VZV-specific immune responses to zoster vaccine measured during the immunology substudy and their possible association with the occurrence of HZ
TL;DR: Treatment with TDF and PI/r was associated with greater declines in renal function over 48 weeks compared with T DF+NNRTI-based regimens, and tenofovir plasma concentration was not associated with CrCl over time.
Abstract: Background Plasma concentrations of tenofovir increase when the drug is coadministered with some ritonavir-boosted protease inhibitors (PI/r). We hypothesized that tenofovir disoproxil fumarate (TDF)-treated patients taking PI/r-based regimens would have a greater decline in renal function than patients receiving nonnucleoside reverse-transcriptase inhibitor (NNRTI)-based therapy. Methods We compared the estimated decline in renal function among 146 human immunodeficiency virus type 1 (HIV-1)-infected patients receiving a TDF+PI/r- (n = 51), TDF+NNRTI- (n = 29), or non-TDF-containing (n = 66) regimen. Plasma tenofovir concentrations were measured at study week 2, and rates of creatinine clearance (CrCl) were estimated using the Cockcroft-Gault (C-G) and Modification of Diet in Renal Disease (MDRD) equations. Mixed-effects models were used to analyze regimen type and tenofovir concentration as predictors of change in CrCl from baseline to weeks 24 and 48. Results Decreases in C-G estimates of CrCl were not significantly different among the 3 groups during the first 24 weeks of therapy. However, in adjusted analyses, patients receiving TDF+PI/r had a greater rate of decline in CrCl than did the TDF+NNRTI group (for C-G, -13.9 vs. -6.2 mL/min/year [P = .03]; for MDRD, -14.7 vs. -4.5 mL/min/1.73 m(2)/year [P = .02]). Among TDF-treated patients, tenofovir plasma concentration was not associated with CrCl over time. Conclusions Treatment with TDF and PI/r was associated with greater declines in renal function over 48 weeks compared with TDF+NNRTI-based regimens.
TL;DR: The variable rate of progression by lineage suggests that tuberculosis variability matters in clinical settings and should be accounted for in studies evaluating tuberculosis vaccines and treatment regimens for latent tuberculosis infection.
Abstract: Considerable variability exists in the outcome of M. tuberculosis infection. We hypothesized that M. africanum was less likely than M. tuberculosis to transmit and progress to tuberculosis disease.
In a cohort study of tuberculosis patients and their household contacts in the Gambia, we categorized 1,808 HIV negative tuberculosis contacts according to exposure to M. tuberculosis or to M. africanum. A positive skin test indicated transmission and development of tuberculosis during 2 years of follow-up indicated progression to disease. Transmission was similar, but progression to disease was significantly lower in contacts exposed to M. africanum than to M. tuberculosis (1.0% vs 2.9%; Hazard Ratio (HR) 3.1, 95% CI 1.1–8.7). Within M. tuberculosis sensu stricto, contacts exposed to a Beijing family strain were most likely to progress to disease (5.6%; HR 6.7 (2.0–22) relative to M. africanum).
M. africanum and M. tuberculosis transmit equally well to household contacts, but contacts exposed to M. africanum are less likely to progress to tuberculosis disease than those exposed to M. tuberculosis. The variable rate of progression by lineage suggests that TB variability matters in clinical settings and should be taken into account in studies evaluating tuberculosis vaccines and treatment regimens for latent tuberculosis infection.
TL;DR: The results show that MMR vaccine-induced antibodies wane significantly after the second dose, and the protection induced by MMR vaccination in Finland seems to persist at least until early adulthood.
Abstract: Background The persistence of antibodies against measles, mumps, and rubella induced by the measles-mumps-rubella (MMR) vaccine and the kinetics of antibody decline after the second MMR vaccine dose were studied in the same cohort for 20 years. Methods Measles, mumps, and rubella antibodies were measured by enzyme immunoassay in 20-year follow-up serum samples (n= 183) of twice-vaccinated individuals, and measles antibodies were also measured in oral fluids (n = 177). Antibody decay was determined in a group (n = 58) with subsequent samples collected 1, 8, and 15 years after the second MMR dose. Results In total, 95%, 74%, and 100% of 183 vaccinees were still seropositive for measles, mumps, and rubella, respectively, and 85% of 177 vaccinees had measurable measles antibodies in their oral fluids. The antibody levels declined significantly after the second dose, but subsequently the rate of decline was slower. Conclusions A high rate of seropositivity was found 20 years after the first MMR dose, particularly for rubella and measles. Our results show that MMR vaccine-induced antibodies wane significantly after the second dose. According to epidemiological data, the protection induced by MMR vaccination in Finland seems to persist at least until early adulthood. However, the situation requires constant vigilance.
TL;DR: T. vaginalis infection is strongly associated with an increased risk for HIV infection in this general population of African women and may have a substantial impact on preventing HIV acquisition among women.
Abstract: Trichomoniasis vaginalis is the most common nonviral sexually transmitted infection (STI) worldwide with a particularly high prevalence in regions of human immunodeficiency virus (HIV) endemicity. However its impact as a cofactor for HIV acquisition is poorly understood. Samples from 213 women who experienced HIV seroconversion (cases) during a longitudinal study involving 4450 women in Uganda and Zimbabwe were matched with samples from HIV-uninfected women (controls). All samples underwent polymerase chain reaction (PCR) analysis for Trichomonas vaginalis DNA. For cases analyzed samples were from the visit in which HIV seroconversion was detected and the visit preceding detection of seroconversion; for controls one analyzed sample was from the visit matched by follow-up duration to the cases seroconversion visit and the other sample was from the visit immediately preceding the matched visit. The prevalence of T. vaginalis infection before HIV infection was 11.3% in cases and 4.5% in controls (P = .002). In multivariable analysis controlling for hormonal contraception other STIs behavioral and demographic factors the adjusted odds ratio for HIV acquisition was 2.74 (95% confidence interval 1.25-6.00) for T. vaginalis-positive cases. The presence of behavioral risk factors for HIV infection study recruitment from a referral population at high-risk for HIV primary sex partner-associated risk for HIV infection and herpes simplex virus type 2 seropositivity were also predictive of incident HIV infection. T. vaginalis infection is strongly associated with an increased risk for HIV infection in this general population of African women. Given the high prevalence of T. vaginalis infection in HIV-endemic areas T. vaginalis control may have a substantial impact on preventing HIV acquisition among women. (authors)
TL;DR: HIV disease progression is affected by HIV-1 subtype and this finding may impact decisions on when to initiate antiretroviral therapy and may have implications for future trials of HIV- 1 vaccines aimed at slowing disease progression.
Abstract: Human immunodeficiency virus type 1 (HIV-1) subtypes differ in biological characteristics that may affect pathogenicity. We determined the HIV-1 subtype-specific rates of disease progression among 350 HIV-1 seroconverters. Subtype viral load and CD4+ cell count were determined. Cox proportional hazards regression modeling was used to estimate adjusted hazard ratios (HRs) of progression to acquired immunodeficiency syndrome (AIDS) (defined as a CD4+ cell count of less than or equal to 250 cells/mm3) and to AIDS-associated death. A total of 59.1% of study subjects had subtype D strains 15.1% had subtype A 21.1% had intersubtype recombinant subtypes 4.3% had multiple subtypes and 0.3% had subtype C. Of the 350 subjects 129 (37%) progressed to AIDS and 68 (19.5%) died of AIDS. The median time to AIDS onset was shorter for persons with subtype D(6.5 years) recombinant subtypes (5.6 years) or multiple subtypes (5.8 years) compared with persons with subtype A (8.0 years; P = .022). Relative tosubtype A adjusted HRs of progression to AIDS were 2.13 [95% confidence interval {CI} 1.10-4.11] for subtype D 2.16 [95% CI 1.05-4.45] for recombinant subtypes and 4.40 [95% CI 1.71-11.3] for multiple subtypes. The risk of progression to death was significantly higher for subtype D (adjusted HR 5.65; 95% CI 1.37-23.4) recombinant subtypes (adjusted HR 6.70; 95% CI 1.56-28.8) and multiple subtypes (adjusted HR 7.67; 95% CI 1.27-46.3) compared with subtype A. HIV disease progression is affected by HIV-1 subtype. This finding may impact decisions on when to initiate antiretroviral therapy and may have implications for future trials of HIV-1 vaccines aimed at slowing disease progression. (authors)
TL;DR: Hepatitis E is endemic in Germany and likely exists as a food-borne zoonosis and Implicated meat products should be investigated to provide recommendations for preventive measures.
Abstract: Background Hepatitis E is a classic water-borne disease in developing countries. In Germany, hepatitis E virus (HEV) infections are notifiable. The number of non-travel-associated infections has increased in recent years, but the route of transmission in most is unknown. Our objective was to determine risk factors for autochthonous HEV infections in Germany. Methods Cases of HEV met clinical definitions and were confirmed by laboratory analysis (defined as detection of HEV by polymerase chain reaction [PCR] or immunoglobulin M by serologic testing). PCR products from blood or stool samples were genotyped for phylogenetic analysis. A case-control study included case subjects with autochthonous HEV infection and matched control subjects who were randomly recruited from a population-based telephone list. Results From May 2006 through August 2007, 76 of 96 persons for whom HEV infection had been reported to the routine surveillance system were interviewed. Sixty-six persons had disease that fulfilled the inclusion criteria: 45 (68%) had autochthonous infection, and 21 (32%) had travel-associated disease. Genotypes 3 or 4 were present in 15 of 15 persons with autochthonous infection, and genotype 1 was present in 8 of 9 persons with travel-associated infection. In conditional logistic regression involving 45 case subjects and 135 control subjects, consumption of offal (41% vs. 19%; odds ratio [OR], 2.7; 95% confidence interval [CI], 1.2-6.2) and wild-boar meat (20% vs. 7%; OR, 4.3; 95% CI, 1.2-15.9) were independently associated with autochthonous HEV infection. Conclusion Hepatitis E is endemic in Germany and likely exists as a food-borne zoonosis. Implicated meat products should be investigated to provide recommendations for preventive measures.
Journal Article•
TL;DR: In this article, the authors found that Trichomoniasis vaginalis infection is strongly associated with an increased risk for HIV infection in a general population of African women, and that T. vaginalis control may have a substantial impact on preventing HIV acquisition among women.
Abstract: Background. Trichomoniasis vaginalis is the most common nonviral sexually transmitted infection (STI) worldwide, with a particularly high prevalence in regions of human immunodeficiency virus (HIV) endemicity. However, its impact as a cofactor for HIV acquisition is poorly understood. Methods. Samples from 213 women who experienced HIV seroconversion (cases) during a longitudinal study involving 4450 women in Uganda and Zimbabwe were matched with samples from HIV-uninfected women (controls). All samples underwent polymerase chain reaction (PCR) analysis for Trichomonas vaginalis DNA. For cases, analyzed samples were from the visit in which HIV seroconversion was detected and the visit preceding detection of seroconversion; for controls, one analyzed sample was from the visit matched by follow-up duration to the cases' seroconversion visit, and the other sample was from the visit immediately preceding the matched visit. Results. The prevalence of T. vaginalis infection before HIV infection was 11.3% in cases and 4.5% in controls (P = .002). In multivariable analysis controlling for hormonal contraception, other STIs, behavioral, and demographic factors, the adjusted odds ratio for HIV acquisition was 2.74 (95% confidence interval, 1.25-6.00) for T. vaginalis-positive cases. The presence of behavioral risk factors for HIV infection, study recruitment from a referral population at high-risk for HIV, primary sex partner-associated risk for HIV infection, and herpes simplex virus type 2 seropositivity were also predictive of incident HIV infection. Conclusions. T. vaginalis infection is strongly associated with an increased risk for HIV infection in this general population of African women. Given the high prevalence of T. vaginalis infection in HIV-endemic areas, T. vaginalis control may have a substantial impact on preventing HIV acquisition among women.
TL;DR: For the first time, the intradermal vaccination route has been used to elicit immune responses significantly superior to those noted in association with the conventional intramuscular vaccination route, expected to enhance annual protection against influenza in this vulnerable population.
Abstract: BACKGROUND: Enhanced influenza vaccines are needed to provide improved protection for elderly individuals. The intradermal vaccination route was hypothesized to provide immunogenicity superior to that provided by the intramuscular vaccination route. METHODS: In a multicenter, randomized study, 1107 volunteers >60 years of age received intradermal trivalent inactivated influenza vaccine containing 15 or 21 microg of hemagglutinin per strain or intramuscular control vaccine. Intradermal vaccines used a novel microinjection system designed to ensure easy, convenient, consistent vaccination. The primary end points of the study were the strain-specific hemagglutination inhibition geometric mean titers (GMTs) noted 21 days after vaccination. Groups were compared using noninferiority and superiority analyses. RESULTS: For each strain, the GMTs noted in association with each intradermal vaccine were superior to those noted with the intramuscular control (adjusted P< .0001). Seroprotection rates, seroconversion rates, and mean titer increases were also superior for intradermally administered vaccine in all but one of the analyses undertaken. Systemic reactogenicity was comparable between routes. Local injection site reactions, particularly erythema but not pain, were more commonly associated with intradermal vaccination. CONCLUSIONS: For the first time, the intradermal vaccination route has been used to elicit immune responses significantly superior to those noted in association with the conventional intramuscular vaccination route. This was done using an easy-to-use, reliable microinjection system. This superior response is expected to enhance annual protection against influenza in this vulnerable population. TRIAL REGISTRATION: Clinicaltrials.gov registry number: NCT00296829.
TL;DR: Assessment of the contribution of PVL in the genetic background of BALB/c mice supports the observation that PVL does not contribute to the pathogenesis of staphylococcal infection of mice.
Abstract: Increases in the incidence and severity of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) infections have spawned efforts to define unique virulence properties among prevalent strains. Panton-Valentine leukocidin (PVL), a pore-forming cytotoxin, has garnered attention because of its epidemiologic association with CA-MRSA. Using both the clinical isolate LAC, which is representative of the epidemic USA300 strain, and its isogenic PVL-negative strain in murine models of staphylococcal skin infection and pneumonia, we expanded upon recent studies by assessing the contribution of PVL in the genetic background of BALB/c mice. The data presented in this report support the observation that PVL does not contribute to the pathogenesis of staphylococcal infection of mice.
TL;DR: In neonates with symptomatic congenital CMV disease, valganciclovir oral solution provides plasma concentrations of ganciclovIR comparable to those achieved with administration of intravenous gancallovir, and the results of the present study cannot be extrapolated to extemporaneously compounded liquid formulations of valganCiclovirs.
Abstract: Background. Intravenous ganciclovir administered for 6 weeks improves hearing outcomes in infants with symptomatic congenital cytomegalovirus (CMV) disease involving the central nervous system. Methods. Twenty-four subjects received antiviral therapy for 6 weeks. Serial pharmacokinetic assessments were performed after administration ofvalganciclovir oral solution and of intravenous ganciclovir. Results. On the basis of a previous pharmacokinetic study of the use of intravenous ganciclovir in this population, a target AUC 12 (area under the concentration-time curve over a 12-h period) of 27 mg X h/L was defined. The median dose of oral valganciclovir administered in the present trial was 16 mg/kg, which produced a geometric mean AUC 12 of 27.4 mg X h/L. The bioavailability of valganciclovir was 41.1%. Of the 18 subjects who had detectable CMV in whole blood at baseline or during therapy, 11 had <4 log viral DNA copies/mL at baseline, and 7 had 3≥4 log viral DNA copies/mL at baseline; subjects who started the study with the higher viral burden experienced greater decreases in viral load but did not clear virus during the 42-day course of therapy. Neutropenia of grade 3 or 4 developed in 38% of subjects. Conclusions. In neonates with symptomatic congenital CMV disease, valganciclovir oral solution provides plasma concentrations of ganciclovir comparable to those achieved with administration of intravenous ganciclovir. The results of the present study cannot be extrapolated to extemporaneously compounded liquid formulations of valganciclovir.
TL;DR: Evidence for the occurrence of Pneumocystis colonization in animals as well as the epidemiology and risk factors for Pneumocytes colonization in various human populations are discussed.
Abstract: Pneumocystis pneumonia has long been recognized as a cause of morbidity and mortality in immunocompromised populations, particularly those with HIV infection. Pneumocystis colonization-that is, detection of the organism or its DNA, without signs or symptoms of pneumonia-has recently been described, and accumulating evidence suggests that it may be an important clinical phenomenon. Sensitive molecular techniques such as polymerase chain reaction are frequently used to identify Pneumocystis colonization. Low levels of Pneumocystis in the lungs may stimulate pulmonary inflammation and may play a role in the development of lung diseases such as chronic obstructive pulmonary disease. In this review, we discuss evidence for the occurrence of Pneumocystis colonization in animals as well as the epidemiology and risk factors for Pneumocystis colonization in various human populations. We also evaluate the clinical significance of Pneumocystis colonization and its relationship to lung disease.
TL;DR: The results indicate a high risk of HPV infection in young women who have had just 1 male sex partner, and the risk was increased when the first male partner was sexually experienced.
Abstract: To quantify the risk of human papillomavirus (HPV) acquisition associated with a first male sex partner and to identify associated risk factors, we analyzed data from women who were enrolled before or within 3 months of first intercourse with a male partner and were censored at the report of a second partner. The 1-year cumulative incidence of first HPV infection was 28.5% (95% confidence interval, 20.6%-38.6%) and increased to almost 50% by 3 years. The risk was increased when the first male partner was sexually experienced. Our results indicate a high risk of HPV infection in young women who have had just 1 male sex partner.
TL;DR: Most rhinovirus infections in young children are symptomatic, but secondary infections in adults are often asymptomatic, and multiple virus types circulate simultaneously in families.
Abstract: Background. Rhinoviruses are the most common cause of respiratory tract infections, but the transmission in families has not been studied using sensitive and specific molecular detection methods. Methods. Children hospitalized for any infection were screened for rhinoviruses. Eight families with a rhinovirus-positive index child and 16 families with a rhinovirus-negative index child were monitored for 3 weeks for disease symptoms, and the presence and quantity of rhinoviruses in nasal swab samples were determined by quantitative reverse transcription-polymerase chain reaction. Rhinoviruses were further identified by melting temperature and partial sequence analysis. Results. The rates of rhinovirus infection were 1.00 cases per person among the 17 siblings and 0.50 cases per person among the 14 parents of rhinovirus-positive index patients; the rates were 0.54 cases per person among the 24 siblings and 0.23 cases per person among the 30 parents of rhinovirus-negative index patients. Symptomatic infections were associated with an age of<7 years but not with a high copy number ofrhinovirus genomes. Virus typing revealed the transmission routes of the viruses and showed that several virus types could circulate in the families simultaneously. Conclusions. Rhinoviruses are frequently transmitted from children to other family members. Most rhinovirus infections in young children are symptomatic, but secondary infections in adults are often asymptomatic. Multiple virus types circulate simultaneously in families.