Showing papers in "The Journal of Infectious Diseases in 2006"

Randomized, Double‐Blind, Placebo‐Controlled Efficacy Trial of a Bivalent Recombinant Glycoprotein 120 HIV‐1 Vaccine among Injection Drug Users in Bangkok, Thailand

Abstract: In Thailand phase 1/2 trials of monovalent subtype B and bivalent subtype B/E (CRF01_AE) recombinant glycoprotein 120 human immunodeficiency virus type 1 (HIV-1) vaccines were successfully conducted from 1995 to 1998 prompting the first HIV-1 vaccine efficacy trial in Asia. This randomized double-blind placebo-controlled efficacy trial of AIDSVAX B/E (VaxGen) which included 36-months of follow-up was conducted among injection drug users (IDUs) in Bangkok Thailand. The primary end point was HIV-1 infection; secondary end points included plasma HIV-1 load CD4 cell count onset of acquired immunodeficiency syndrome-defining conditions and initiation of antiretroviral therapy. A total of 2546 IDUs were enrolled between March 1999 and August 2000; the median age was 26 years and 93.4% were men. The overall HIV-1 incidence was 3.4 infections/100 person-years (95% confidence interval [CI] 3.0-3.9 infections/100 person-years) and the cumulative incidence was 8.4%. There were no differences between the vaccine and placebo arms. HIV-1 subtype E (83 vaccine and 81 placebo recipients) accounted for 77% of infections. Vaccine efficacy was estimated at 0.1% (95% CI -30.8% to 23.8%; P = .99 log-rank test). No statistically significant effects of the vaccine on secondary end points were observed. Despite the successful completion of this efficacy trial the vaccine did not prevent HIV-1 infection or delay HIV-1 disease progression. (authors)

Prevalence of Staphylococcus aureus Nasal Colonization in the United States, 2001–2002

Abstract: confidence interval [CI], 30.7%–34.1%) and 0.8% (95% CI, 0.4%–1.4%), respectively, and population estimates were 89.4 million persons (95% CI, 84.8–94.1 million persons) and 2.3 million persons (95% CI, 1.2–3.8 million persons), respectively. S. aureus colonization prevalence was highest in participants 6–11 years old. MRSA colonization was associated with age60 years and being female but not with recent health-care exposure. In unweighted analyses, the SCCmec type IV gene was more frequent in isolates from participants of younger age and of nonHispanic black race/ethnicity; the PVL gene was present in 9 (2.4%) of 372 of isolates tested. Conclusions. Many persons in the United States are colonized with S. aureus; prevalence rates differ demographically. MRSA colonization prevalence, although low nationally in 2001–2002, may vary with demographic and organism characteristics.

Prevalence of HPV Infection among Men: A Systematic Review of the Literature

Abstract: BACKGROUND Human papillomavirus (HPV) infection is estimated to be the most common sexually transmitted infection; an estimated 62 million persons are newly infected every year in the United States There are limited data on HPV infection in heterosexual men METHODS We conducted a systematic review of the literature by searching MEDLINE using the terms "human papillomavirus," "HPV," "male," "seroprevalence," and "serology" to retrieve articles published from 1 January 1990 to 1 February 2006 We included studies that had data on population characteristics and that evaluated male genital anatomic sites or specimens for HPV DNA or included assessments of seropositivity to HPV type 6, 11, 16, or 18 in men We excluded studies that had been conducted only in children or immunocompromised persons (HIV infected, transplant recipients, or elderly) RESULTS We included a total of 40 publications on HPV DNA detection and risk factors for HPV in men; 27 evaluated multiple anatomic sites or specimens, 10 evaluated a single site or specimen, and 3 evaluated risk factors or optimal anatomic sites/specimens for HPV detection Twelve studies assessed site- or specimen-specific HPV DNA detection HPV prevalence in men was 13%-729% in studies in which multiple anatomic sites or specimens were evaluated; 15 (56%) of these studies reported > or =20% HPV prevalence HPV prevalence varied on the basis of sampling, processing methods, and the anatomic site(s) or specimen(s) sampled We included 15 publications reporting HPV seroprevalence Rates of seropositivity depended on the population, HPV type, and methods used In 9 studies that evaluated both men and women, all but 1 demonstrated that HPV seroprevalence was lower in men than in women CONCLUSION HPV infection is highly prevalent in sexually active men and can be detected by use of a variety of specimens and methods There have been few natural-history studies and no transmission studies of HPV in men The information that we have reviewed may be useful for future natural-history studies and for modeling the potential impact of a prophylactic HPV vaccine

Is Panton‐Valentine Leukocidin the Major Virulence Determinant in Community‐Associated Methicillin‐Resistant Staphylococcus aureus Disease?

Abstract: Methicillin-resistant Staphylococcus aureus (MRSA) remains a major problem in hospitals, and it is now spreading in the community. A single toxin, Panton-Valentine leukocidin (PVL), has been linked by epidemiological studies to community-associated MRSA (CA-MRSA) disease. However, the role that PVL plays in the pathogenesis of CA-MRSA has not been tested directly. To that end, we used mouse infection models to compare the virulence of PVL-positive with that of PVL-negative CA-MRSA representing the leading disease-causing strains. Unexpectedly, strains lacking PVL were as virulent in mouse sepsis and abscess models as those containing the leukotoxin. Isogenic PVL-negative (lukS/F-PV knockout) strains of USA300 and USA400 were as lethal as wild-type strains in a sepsis model, and they caused comparable skin disease. Moreover, lysis of human neutrophils and pathogen survival after phagocytosis were similar between wild-type and mutant strains. Although the toxin may be a highly linked epidemiological marker for CA-MRSA strains, we conclude that PVL is not the major virulence determinant of CA-MRSA.

High Recurrence Rates of Bacterial Vaginosis over the Course of 12 Months after Oral Metronidazole Therapy and Factors Associated with Recurrence

Abstract: Background We wished to determine recurrences of bacterial vaginosis (BV) after treatment over the course of 12 months and to establish factors associated with recurrence. Methods Women with symptomatic BV (a Nugent score [NS] of 7-10 or of 4-6 with >or=3 Amsel criteria) were enrolled. BV was treated with 400 mg of oral metronidazole twice a day for 7 days. Participants completed a questionnaire and vaginal swabs were collected at 1, 3, 6, and 12 months; the study end point was an NS of 7-10. Results A total of 121 (87%) women with an NS of 7-10 and 18 (13%) with an NS of 4-6 and >or=3 Amsel criteria were enrolled; 130 (94%) returned >or=1 vaginal samples. Sixty-eight women (58% [95% confidence interval {CI}, 49%-66%]) had a recurrence of BV (NS 7-10), and 84 (69% [95% CI, 61%-77%]) had a recurrence of abnormal vaginal flora (NS 4-10) by 12 months. A past history of BV, a regular sex partner throughout the study, and female sex partners were significantly associated with recurrence of BV and abnormal vaginal flora by multivariate analysis; the use of hormonal contraception had a negative association with recurrence. Conclusion Current recommended treatment is not preventing the recurrence of BV or abnormal vaginal flora in the majority of women; factors associated with recurrence support a possible role for sexual transmission in the pathogenesis of recurrent BV.

The Survival Benefits of AIDS Treatment in the United States

Abstract: BACKGROUND As widespread adoption of potent combination antiretroviral therapy (ART) reaches its tenth year, our objective was to quantify the cumulative survival benefits of acquired immunodeficiency syndrome (AIDS) care in the United States. METHODS We defined eras corresponding to advances in standards of human immunodeficiency virus (HIV) disease care, including opportunistic infection prophylaxis, treatment with ART, and the prevention of mother-to-child transmission (pMTCT) of HIV. Per-person survival benefits for each era were determined using a mathematical simulation model. Published estimates provided the number of adult patients with new diagnoses of AIDS who were receiving care in the United States from 1989 to 2003. RESULTS Compared with survival associated with untreated HIV disease, per-person survival increased 0.26 years with Pneumocystis jiroveci pneumonia prophylaxis alone. Four eras of increasingly effective ART in addition to prophylaxis resulted in per-person survival increases of 7.81, 11.05, 11.57, and 13.33 years, compared with the absence of treatment. Treatment for patients with AIDS in care in the United States since 1989 yielded a total survival benefit of 2.8 million years. pMTCT averted nearly 2900 infant infections, equivalent to 137,000 additional years of survival benefit. CONCLUSIONS At least 3.0 million years of life have been saved in the United States as a direct result of care of patients with AIDS, highlighting the significant advances made in HIV disease treatment.

Global Incidence of Multidrug-Resistant Tuberculosis

Abstract: Background. The global number of incident cases of multidrug-resistant (MDR) tuberculosis (TB) in 2000 was estimated to be 272,906 (95% confidence interval [CI], 184,948‐414,295). For accurate planning of TB control programs, this estimate and others have been revised using data from additional countries and by including in the model previously treated TB cases, which had not been accounted for in the previous analysis. Methods. Multiple logistic regression was used to identify variables that were predictive of MDR-TB frequency among new and previously treated cases surveyed in 90 and 77 countries, respectively. These variables were then used to estimate MDR-TB frequencies in countries that had not been surveyed. Results. The total number of MDR-TB cases estimated to have occurred worldwide in 2004 is 424,203 (95% CI, 376,019‐620,061), or 4.3% (95% CI, 3.8%‐6.1%) of all new and previously treated TB cases. In the same year, 181,408 (95% CI, 135,276‐319,017) MDR-TB cases were estimated to have occurred among previously treated TB cases alone. Three countries—China, India, and the Russian Federation—accounted for 261,362 (95% CI, 180,779‐414,749) MDR-TB cases, or 62% of the estimated global burden. Conclusions. These updated sets of estimates incorporating previously treated TB cases call for an urgent plan to expand appropriate diagnostic and treatment services for patients with MDR-TB in low-resource settings. Multidrug-resistant (MDR) tuberculosis (TB) presents a formidable challenge to TB control in several settings,

The survival benefits of AIDS treatment in the United States. Commentary

Abstract: Background. As widespread adoption of potent combination antiretroviral therapy (ART) reaches its tenth year, our objective was to quantify the cumulative survival benefits of acquired immunodeficiency syndrome (AIDS) care in the United States. Methods. We defined eras corresponding to advances in standards of human immunodeficiency virus (HIV) disease care, including opportunistic infection prophylaxis, treatment with ART, and the prevention of mother-to-child transmission (pMTCT) of HIV. Per-person survival benefits for each era were determined using a mathematical simulation model. Published estimates provided the number of adult patients with new diagnoses of AIDS who were receiving care in the United States from 1989 to 2003. Results. Compared with survival associated with untreated HIV disease, per-person survival increased 0.26 years with Pneumocystis jiroveci pneumonia prophylaxis alone. Four eras of increasingly effective ART in addition to prophylaxis resulted in per-person survival increases of 7.81, 11.05, 11.57, and 13.33 years, compared with the absence of treatment. Treatment for patients with AIDS in care in the United States since 1989 yielded a total survival benefit of 2.8 million years. pMTCT averted nearly 2900 infant infections, equivalent to 137,000 additional years of survival benefit. Conclusions. At least 3.0 million years of life have been saved in the United States as a direct result of care of patients with AIDS, highlighting the significant advances made in HIV disease treatment.

Vascular leakage in severe dengue virus infections: a potential role for the nonstructural viral protein NS1 and complement.

Abstract: Background Vascular leakage and shock are the major causes of death in patients with dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Thirty years ago, complement activation was proposed to be a key underlying event, but the cause of complement activation has remained unknown. Methods The major nonstructural dengue virus (DV) protein NS1 was tested for its capacity to activate human complement in its membrane-associated and soluble forms. Plasma samples from 163 patients with DV infection and from 19 patients with other febrile illnesses were prospectively analyzed for viral load and for levels of NS1 and complement-activation products. Blood and pleural fluids from 9 patients with DSS were also analyzed. Results Soluble NS1 activated complement to completion, and activation was enhanced by polyclonal and monoclonal antibodies against NS1. Complement was also activated by cell-associated NS1 in the presence of specific antibodies. Plasma levels of NS1 and terminal SC5b-9 complexes correlated with disease severity. Large amounts of NS1, complement anaphylatoxin C5a, and the terminal complement complex SC5b-9 were present in pleural fluids from patients with DSS. Conclusions Complement activation mediated by NS1 leads to local and systemic generation of anaphylatoxins and SC5b-9, which may contribute to the pathogenesis of the vascular leakage that occurs in patients with DHF/DSS.

Decreasing pfmdr1 copy number in plasmodium falciparum malaria heightens susceptibility to mefloquine, lumefantrine, halofantrine, quinine, and artemisinin.

Abstract: The global dissemination of drug-resistant Plasmodium falciparum is spurring intense efforts to implement artemisinin (ART)-based combination therapies for malaria, including mefloquine (MFQ)-artesunate and lumefantrine (LUM)-artemether. Clinical studies have identified an association between an increased risk of MFQ, MFQ-artesunate, and LUM-artemether treatment failures and pfmdr1 gene amplification. To directly address the contribution that pfmdr1 copy number makes to drug resistance, we genetically disrupted 1 of the 2 pfmdr1 copies in the drug-resistant FCB line, which resulted in reduced pfmdr1 mRNA and protein expression. These knockdown clones manifested a 3-fold decrease in MFQ IC(50) values, compared with that for the FCB line, verifying the role played by pfmdr1 expression levels in mediating resistance to MFQ. These clones also showed increased susceptibility to LUM, halofantrine, quinine, and ART. No change was observed for chloroquine. These results highlight the importance of pfmdr1 copy number in determining P. falciparum susceptibility to multiple agents currently being used to combat malaria caused by multidrug-resistant parasites.

Rationale and Uses of a Public HIV Drug-Resistance Database

Abstract: Knowledge regarding the drug resistance of human immunodeficiency virus (HIV) is critical for surveillance of drug resistance, development of antiretroviral drugs, and management of infections with drug-resistant viruses. Such knowledge is derived from studies that correlate genetic variation in the targets of therapy with the antiretroviral treatments received by persons from whom the variant was obtained (genotype-treatment), with drug-susceptibility data on genetic variants (genotype-phenotype), and with virological and clinical response to a new treatment regimen (genotype-outcome). An HIV drug-resistance database is required to represent, store, and analyze the diverse forms of data underlying our knowledge of drug resistance and to make these data available to the broad community of researchers studying drug resistance in HIV and clinicians using HIV drug-resistance tests. Such genotype-treatment, genotype-phenotype, and genotype-outcome correlations are contained in the Stanford HIV RT and Protease Sequence Database and have specific usefulness.

Roles of 34 Virulence Genes in the Evolution of Hospital- and Community-Associated Strains of Methicillin-Resistant Staphylococcus aureus

Abstract: BACKGROUND: The extent to which the horizontal transfer of virulence genes has contributed to the emergence of contemporary virulent strains of methicillin-resistant Staphylococcus aureus (MRSA) in hospital and community settings is poorly understood. METHODS: Epidemiologically well-characterized MRSA isolates collected over 8.5 years were genotyped and tested for the presence of 34 virulence genes. RESULTS: Six strain types accounted for 88.2% of all MRSA infections. The evolution of contemporary hospital and community phenotypes within the CC8 and CC30 lineages--2 background genomes that produced historical pandemic MRSA clones--were associated with multiple horizontal acquisitions of virulence genes. The epidemic community phenotype of a CC8 strain, designated ST8:USA300, was linked to the acquisition of staphylococcal cassette chromosome (SCC)mec type IV, the genes for Panton-Valentine leukocidin (PVL), and the enterotoxin Q and K genes. Similarly, the epidemic community phenotype of a CC30 strain, ST30:USA1100, was linked to the acquisition of SCCmec type IV and the pvl genes. In contrast, the epidemic hospital phenotype of another CC30 strain, ST36:USA200, was associated with the acquisition of SCCmec type II, the enterotoxin A gene, and the toxic shock syndrome toxin 1 gene. The pvl genes appear not to be essential for the evolution OF other community-associated strains of mrsa, including ST8:USA500 and ST59:USA1000. CONCLUSIONS: The horizontal transfer of virulence genes, although infrequent, is epidemiologically associated with the emergence of new virulent strains of MRSA.

Human Bocavirus Infection in Young Children in the United States: Molecular Epidemiological Profile and Clinical Characteristics of a Newly Emerging Respiratory Virus

Abstract: Background. Human bocavirus (HBoV) is a newly identified human parvovirus that was originally identified in the respiratory secretions of children with respiratory tract disease. To further investigate the epidemiological profile and clinical characteristics of HBoV infection, we screened infants and children <2 years of age (hereafter referred to as "children") for HBoV. Methods. Children for whom respiratory specimens submitted to a diagnostic laboratory tested negative for respiratory syncytial virus, parainfluenza viruses (types 1-3), influenza A and B viruses, and adenovirus, as well as asymptomatic children, underwent screening for HBoV by use of polymerase chain reaction (PCR). Respiratory specimens were obtained from the children from 1 January 2004 through 31 December 2004. Results. Twenty-two (5.2%) of the 425 children who had a respiratory specimen submitted to the diagnostic laboratory and 0 of the 96 asymptomatic children were found to be positive for HBoV by PCR (P =.02). Fever, rhinorrhea, cough, and wheezing were observed in ≥50% of the HBoV-positive children. Of the 17 children who had chest radiography performed, 12 (70.6%) had abnormal findings. HBoV appeared to have a seasonal distribution. Nucleotide polymorphisms were detected in the viral capsid protein (VP) 1/VP2 genes. Two distinct HBoV genotypes circulated during the study period. Conclusions. HBoV is circulating in the United States and is associated with both upper and lower respiratory tract disease in infants and young children.

MassTag Polymerase-Chain-Reaction Detection of Respiratory Pathogens, Including a New Rhinovirus Genotype, That Caused Influenza-Like Illness in New York State during 2004–2005

Abstract: In New York State during winter 2004, there was a high incidence of influenza-like illness that tested negative both for influenza virus, by molecular methods, and for other respiratory viruses, by virus culture. Concern that a novel pathogen might be implicated led us to implement a new multiplex diagnostic tool. MassTag polymerase chain reaction resolved 26 of 79 previously negative samples, revealing the presence of rhinoviruses in a large proportion of samples, half of which belonged to a previously uncharacterized genetic clade. In some instances, knowledge of the detected viral and/or bacterial (co)infection could have altered clinical management.

Phase 1 Safety and Immunogenicity Evaluation of a Multiclade HIV‐1 Candidate Vaccine Delivered by a Replication‐Defective Recombinant Adenovirus Vector

Abstract: More than 40 million people are living with HIV/AIDS. Three million deaths occur annually because of HIV/ AIDS, with ∼5 million new infections occurring in 2005 [1]. Development of an effective vaccine would be an important intervention to help control the expanding global pandemic. Adenovirus serotype 5 (Ad5) has been developed as a replication-defective recombinant vector (rAd5) to deliver intracellular genes via a number of routes [2]. Vaccination with rAd5 results in transient intracellular gene expression followed by rapid clearance [3]. Cellular and humoral immune responses have been induced in preclinical studies of rAd5 vaccines for HIV-1, simian immunodeficiency virus (SIV), and simian-human immunodeficiency virus (SHIV) [4–7]. This approach builds on previous successes with other infectious disease models, particularly for Ebola virus, against which nonhuman primates have been protected from lethal challenge [8, 9]. Recently, immunization of chimpanzees with rAd expressing hepatitis C virus (HCV) nonstructural genes resulted in T cell–mediated protection against heterologous HCV challenge [10]. These preclinical studies support the concept that gene-based vaccination can induce effective immunity against viral infections in primates. The development of an HIV vaccine that is effective against multiple circulating viral clades remains a scientific priority and urgent public health need [11]. The rAd5 vaccine evaluated in the present clinical trial was designed to express an HIV-1 clade B Gag-Pol fusion protein and Env glycoproteins from HIV-1 clades A, B, and C. Here, we report the findings from the first phase 1 clinical trial of this multigene, multiclade rAd5 HIV-1 candidate vaccine.

Clinical manifestations of human monkeypox influenced by route of infection

Abstract: Background. In April 2003, an outbreak of monkeypox occurred in the United States following the importation of monkeypox virus (MPXV)-infected animals in a consignment of exotic pets from West Africa. Transmission of the virus to non-African captive species, including prairie dogs, preceded human disease. Methods. We evaluated the influence of the route of infection on clinical illness for persons with confirmed and probable cases of human monkeypox. Exposures were categorized as being "noninvasive" (e.g., the person touched an infected animal, cleaned an infected animal's cage, and/or stood within 6 feet of an infected animal) or "complex" (e.g., invasive bite or scratch from an ill prairie dog plus potential noninvasive exposure), and associations between exposure, illness manifestation, and illness progression (i.e., elapsed time from first exposure to an ill prairie dog through various benchmarks of illness) were assessed. Results. Patients with complex exposures were more likely than patients with noninvasive exposures to have experienced pronounced signs of systemic illness (49.1% vs. 16.7%; P = .041) and to have been hospitalized during illness (68.8% vs. 10.3%; P<.001). Complex exposures were also associated with shorter incubation periods (9 days for complex exposures vs. 13 days for noninvasive exposures) and the absence of a distinct febrile prodrome. Conclusions. The findings of this study indicate that route of infection can influence monkeypox illness manifestations.

Prior H1N1 influenza infection and susceptibility of Cleveland Family Study participants during the H2N2 pandemic of 1957: an experiment of nature.

Abstract: During a pandemic, influenza vaccines that rely on neutralizing antibodies to protect against matched viruses might not be available early enough. Much broader (heterosubtypic) immune protection is seen in animals. Do humans also have cross-subtype immunity? To investigate this issue, archival records from the Cleveland Family Study, which was conducted before and during the 1957 pandemic (during which a shift from subtype H1N1 to H2N2 occurred), were analyzed. Only 5.6% of the adults who had had symptomatic influenza A in earlier study years developed influenza during the pandemic, despite living in households with participants who had influenza. In contrast, 55.2% of the children who had had symptomatic influenza A contracted it again. These findings suggest an impact of accumulated heterosubtypic immunity during a pandemic. Such immunity, as well as its implications for vaccination, should be further investigated.

A Community-Wide Outbreak of Legionnaires Disease Linked to Industrial Cooling Towers—How Far Can Contaminated Aerosols Spread?

Abstract: A community-wide outbreak of legionnaires disease occurred in Pas-de-Calais, France, in November 2003-January 2004. Eighteen (21%) of 86 laboratory-confirmed cases were fatal. A case-control study identified smoking, silicosis, and spending >100 min outdoors daily as risk factors for acquiring the disease. Legionella pneumophila strain Lens was isolated from cooling towers, wastewater, and air samples from plant A. This unique strain matched all 23 clinical isolates, as assessed by pulsed-field gel electrophoresis subtyping. Modeling of atmospheric dispersion of aerosols emitted from plant A cooling towers showed good coverage of the communes where patients lived and showed that the dispersion extended over a distance of at least 6 km from plant A. No other aerosol-producing installation was identified as a plausible source, and no common source of indoor exposure was found. These findings implicate plant A as the most likely outbreak source and suggest that the distance of airborne transmission of L. pneumophila may be greater than previously reported.

Epidemiology of Seasonal Influenza: Use of Surveillance Data and Statistical Models to Estimate the Burden of Disease

Abstract: The US Centers for Disease Control and Prevention (CDC) uses a 7-component national surveillance system for influenza that includes virologic, influenza-like illness, hospitalization, and mortality data. In addition, some states and health organizations collect additional influenza surveillance data that complement the CDC's surveillance system. Current surveillance data from these programs, together with national hospitalization and mortality data, have been used in statistical models to estimate the annual burden of disease associated with influenza in the United States for many years. National influenza surveillance data also have been used in suitable models to estimate the possible impact of future pandemics. As part of the public health response to the 2003-2004 influenza season, which was noteworthy for its severe effect among children, new US surveillance activities were undertaken. Further improvements in national influenza surveillance systems will be needed to collect and analyze data in a timely manner during the next pandemic.

Capsular serotype-specific attack rates and duration of carriage of Streptococcus pneumoniae in a population of children.

Abstract: Background. The relative invasiveness rates (attack rates) of Streptococcus pneumoniae of different capsular serotypes in children are not known. Estimates of capsular serotype invasiveness (designated “invasive odds ratios”) that are based on cross-sectional prevalence carriage data have been published, but these estimates could be biased by variation in the duration of carriage. Methods. The relative attack rates of invasive pneumococci were measured using national UK surveillance data on invasive pneumococcal disease (IPD) incidence and data on incidence of pneumococcal acquisition from longitudinal studies of nasopharyngeal pneumococcal carriage. Results. We found significant differences in capsular serotype–specific attack rates. For example, capsular serotypes 4, 14, 7F, 9V, and 18C were associated with rates of 120 IPD cases/100,000 acquisitions, whereas capsular serotypes 23F, 6A, 19F, 16F, 6B, and 15B/C were associated with !10 IPD cases/100,000 acquisitions. There was an inverse relationship between duration of carriage and attack rate by capsular serotype ( ). Attack rates P ! .0001 were significantly correlated with invasive odds ratios ( ). P ! .0001 Conclusions. The capsular serotype is a major determinant of both pneumococcal duration of carriage and attack rate. Published invasive odds ratios are a reliable and practical method of determining capsular serotype invasiveness and will be valuable for investigating and characterizing emerging capsular serotypes in the context of conjugate vaccination. Streptococcus pneumoniae is a human-restricted bacterial commensal. Most, if not all, people acquire it at some time, and it usually colonizes the nasopharynx of individuals harmlessly. Of the pneumococci acquired by individuals, a few will go on to cause a spectrum of mild and severe diseases. Accumulatively, the diseases caused by pneumococci make it one of the leading causes of infectious diseases in people of all ages, but particularly in young children and the elderly. The prin

Indirect effect of conjugate vaccine on adult carriage of Streptococcus pneumoniae: an explanation of trends in invasive pneumococcal disease.

Abstract: Background. Use of heptavalent protein-polysaccharide pneumococcal conjugate vaccine (PCV7) has been associated with decreases in PCV7-type invasive pneumococcal disease and nasopharyngeal (NP) carriage in children. Vaccine use has also indirectly decreased the rate of invasive disease in adults, presumably through decreased transmission of pneumococci from vaccinated children to adults. Methods. We conducted NP carriage surveys in 8 villages in Alaska in 1998-2004. Streptococcus pneumoniae isolates were characterized by serotype and antimicrobial susceptibility. We analyzed trends in serotype distribution, antibiotic resistance, and factors associated with adult carriage of PCV7-serotype pneumococci before and after the introduction of PCV7 in 2001. Results. We collected 15,598 NP swabs; overall, 52% of adults living in the villages surveyed participated in the colonization study. The proportion of adult carriers with PCV7-type pneumococcal carriage decreased from 28% of carriers in 1998-2000 to 4.5% of carriers in 2004 (P<.0001). Among adults, the proportion of colonizing isolates that were resistant to penicillin decreased from 13% in 1998-2000 to 6% in 2004 (P =.05), whereas the percentage of isolates with intermediate susceptibility to penicillin increased from 12% in 1998-2000 to 19% in 2004 (P<.01). Adults were more likely to carry PCV7-type pneumococci if they lived with a child <5 years old or if they lived with a child who had not been age-appropriately vaccinated with PCV7. Conclusions. Pediatric vaccination with PCV7 has resulted in decreased PCV7-type pneumococcal carriage among adults and helps to explain recent decreases in the rate of PCV7-type invasive pneumococcal disease among adults.

Molecular and Epidemiologic Trends of Caliciviruses Associated with Outbreaks of Acute Gastroenteritis in the United States, 2000–2004

Abstract: Between July 2000 and June 2004, fecal specimens from 270 outbreaks of acute gastroenteritis were sent to the Centers for Disease Control and Prevention by local or state health departments for calicivirus testing. Of the 226 outbreaks that met the criteria for inclusion in the present study, caliciviruses were detected in 184 (81%) by reverse-transcription polymerase chain reaction and nucleotide sequencing. Nursing homes, retirement centers, and hospitals were the most frequently reported settings, and person-to-person contact was the most common mode of transmission, followed by foodborne spread. Overall, genogroup II norovirus (NoV) strains were the most abundant (79%), followed by genogroup I NoV strains (19%) and sapovirus (2%). Nucleotide-sequence analysis indicated a great diversity of NoV strains and implicated the emergence of one particular sequence variant in outbreaks occurring between July 2002 and June 2003. The public health impact of caliciviruses will not be fully appreciated, nor will interventions be completely evaluated, until methods to detect these viruses are more routinely used.

Human cytomegalovirus infection is associated with increased proportions of NK cells that express the CD94/NKG2C receptor in aviremic HIV-1-positive patients.

Abstract: In healthy blood donors, serological positivity for human cytomegalovirus (HCMV) is associated with an increased proportion of NK cells bearing the CD94/NKG2C NK cell receptor (NKR). The expression of the activating CD94/NKG2C NKR and of the inhibitory CD94/NKG2A NKR was studied in a cohort of 45 aviremic human immunodeficiency virus type 1 (HIV-1)-positive patients receiving highly active antiretroviral therapy. The proportions of NKG2C+ NK cells were significantly increased in HIV-1-positive patients (mean +/- SD, 25.9% +/- 23.0%), compared with those in 31 healthy individuals (mean +/- SD, 16.1% +/- 20.7%). Yet, the association vanished when HCMV serological status was considered in a multivariate regression model. These results support the conclusion that changes in the NKR repertoire in HIV1-positive patients are related to a concomitant HCMV infection.

Two-year prospective study of the humoral immune response of patients with severe acute respiratory syndrome.

Abstract: In a cohort study of 56 convalescent patients with severe acute respiratory syndrome (SARS), titers of immunoglobulin G (IgG) antibodies and neutralizing antibodies (NAbs) against SARS-associated coronavirus were assessed at regular intervals (at 1, 4, 7, 10, 16, and 24 months after the onset of disease) by use of enzyme-linked immunosorbent assay and neutralization assay. IgG antibody and NAb titers were highly correlated, peaking at month 4 after the onset of disease and decreasing thereafter. IgG antibodies remained detectable in all patients until month 16, and they became undetectable in 11.8% of patients at month 24. The finding that NAbs remained detectable throughout follow-up is reassuring in terms of protection provided against reinfection; however, NAb titers decreased markedly after month 16.

Postexposure Protection of Guinea Pigs against a Lethal Ebola Virus Challenge Is Conferred by RNA Interference

Abstract: : Background. Ebola virus (EBOV) infection causes a frequently fatal hemorrhagic fever (HF) that is refractory to treatment with currently available antiviral therapeutics. RNA interference represents a powerful, naturally occurring biological strategy for the inhibition of gene expression and has demonstrated utility in the inhibition of viral replication. Here, we describe the development of a potential therapy for EBOV infection that is based on small interfering RNAs (siRNAs). Methods. Four siRNAs targeting the polymerase (L) gene of the Zaire species of EBOV (ZEBOV) were either complexed with polyethylenimine (PEI) or formulated in stable nucleic acid-lipid particles (SNALPs). Guinea pigs were treated with these siRNAs either before or after lethal ZEBOV challenge. Results. Treatment of guinea pigs with a pool of the L gene-specific siRNAs delivered by PEI polyplexes reduced plasma viremia levels and partially protected the animals from death when administered shortly before the ZEBOV challenge. Evaluation of the same pool of siRNAs delivered using SNALPs proved that this system was more efficacious, as it completely protected guinea pigs against viremia and death when administered shortly after the ZEBOV challenge. Additional experiments showed that 1 of the 4 siRNAs alone could completely protect guinea pigs from a lethal ZEBOV challenge. Conclusions. Further development of this technology has the potential to yield effective treatments for EBOV HF as well as for diseases caused by other agents that are considered to be biological threats.

Distribution of Amantadine-Resistant H5N1 Avian Influenza Variants in Asia

Abstract: We examined the distribution of genetic mutations associated with resistance to the M2 ion channel–blocking adamantane derivatives, amantadine and rimantadine, among H5N1 viruses isolated in Vietnam, Thailand, Cambodia, Indonesia, Hong Kong, and China. More than 95% of the viruses isolated in Vietnam and Thailand contained resistance mutations, but resistant mutants were less commonly isolated in Indonesia (6.3% of isolates) and China (8.9% of isolates), where human infection was recently reported. The dual mutation motif Leu26Ile–Ser31Asn (leucinerisoleucine at aa 26 and serinerasparagine at aa 31) was found almost exclusively in all resistant isolates from Vietnam, Thailand, and Cambodia, suggesting the biological selection of these mutations. Avian influenza H5N1 viruses have caused repeated disease outbreaks in poultry in Asia since 2003. Outbreaks have occurred most recently in central Asia and parts of Europe [1]. Long-term endemicity of H5N1 viruses in Asia has led to the evolution of multiple genetic and antigenic sublineages, and regular control measures may be ineffective in the eradication of H5N1 viruses from poultry [2, 3]. Human infection has

Etiologies of Nongonococcal Urethritis: Bacteria, Viruses, and the Association with Orogenital Exposure

Abstract: Background. The purpose of the present study was to determine pathogens and behaviors associated with nongonococcal urethritis (NGU) and the usefulness of the urethral smear in predicting the presence of pathogens. Methods. We conducted a case-control study of men with and without symptoms of NGU. Sexual practices were measured by questionnaire. First-stream urine was tested for Chlamydia trachomatis, Mycoplasma genitalium, Ureaplasma parvum, U. urealyticum, herpes simplex virus (HSV)–1, HSV-2, adenoviruses, and Gardnerella vaginalis by polymerase chain reaction. Results. C. trachomatis (20%), M. genitalium (9%), adenoviruses (4%), and HSV-1 (2%) were more common in cases with NGU ( ) after age and sexual risk were adjusted for ( ); U. urealyticum, U. parvum, n p 329 P .01 and G. vaginalis were not. Infection with adenoviruses or HSV-1 was associated with distinct clinical features, oral sex, and male partners, whereas infection with M. genitalium or C. trachomatis was associated with unprotected vaginal sex. Oral sex was associated with NGU in which no pathogen was detected ( ). Fewer than 5 P .001 polymorphonuclear leukocytes (PMNLs) per high-power field (HPF) on urethral smear were present in 32%, 37%, 38%, and 44% of cases with C. trachomatis, M. genitalium, adenoviruses, and HSV, respectively. Conclusion. We identified adenoviruses and HSV-1 as significant causes of NGU with distinct clinical and behavioral characteristics and highlighted the association between insertive oral sex and NGU. A urethral PMNL count of 5 PMNLs/HPF is not sufficiently sensitive to exclude pathogens in men with urethral symptoms.

Premature Induction of an Immunosuppressive Regulatory T Cell Response during Acute Simian Immunodeficiency Virus Infection

Abstract: Here we report the results of an investigation into the possibility that one mechanism responsible for the establishment of persistent human immunodeficiency virus infection is an early regulatory T (Treg) cell response that blunts virus-specific responses. Using the simian immunodeficiency virus (SIV)-infected rhesus macaque model, we show that, indeed, viral replication and immune activation in lymphatic tissue drive a premature immunosuppressive response, with dramatic increases in the frequencies of CD4+CD25+FOXP3+ Treg cells, transforming growth factor- beta 1+ cells, interleukin-10+ cells, and indoleamine 2,3-dioxygenase+CD3+ cells. When we compared SIV infection with rhesus cytomegalovirus (RhCMV) infection, we found that the frequency of Treg cells paralleled the magnitude of immune activation during both infections but that the magnitude of immune activation and of the Treg cell response were lower and peaked much later during RhCMV infection. Importantly, the frequency of Treg cells inversely correlated with the magnitude of the SIV-specific cytotoxic T lymphocyte response. We conclude that an early Treg cell response during acute SIV infection may contribute to viral persistence by prematurely limiting the antiviral immune response before infection is cleared.

Recovery of drug-resistant influenza virus from immunocompromised patients: a case series.

Abstract: Influenza virus with resistance to antiviral drugs emerges with increased frequency in immunocompromised patients and can limit the benefit of M2 and neuraminidase (NA) inhibitors. We document 3 cases of influenza in severely immunocompromised patients from whom virus variants with molecular markers of resistance to anti-influenza drugs were recovered. Virus variants recovered from 2 patients had mutations in the M2, NA (with a previously recognized Glu119Val NA substitution), and hemagglutinin genes. We describe a novel Asp198Asn NA mutation in an influenza B virus and its decreased susceptibility to both oseltamivir and zanamivir. Influenza causes significant morbidity and mortality in patients with compromised immune systems. Influenza virus infection in transplant recipients is associated with a higher rate of pulmonary complications (particularly viral pneumonia), extrapulmonary manifestations, an increased risk of graft dysfunction and rejection, and high attributable mortality [1]. In addition, transplant recipients have prolonged shedding of influenza virus, often despite antiviral therapy [2], which promotes the emergence of antiviral resistance [3]. This is a wellrecognized problem with the use of the M2 inhibitors amantadine and rimantadine [1] but is an uncommon

Vaccines for Seasonal and Pandemic Influenza

Abstract: Seasonal influenza continues to have a huge annual impact in the United States, accounting for tens of millions of illnesses, hundreds of thousands of excess hospitalizations, and tens of thousands of excess deaths. Vaccination remains the mainstay for the prevention of influenza. In the United States, 2 types of influenza vaccine are currently licensed: trivalent inactivated influenza vaccine and live attenuated influenza vaccine. Both are safe and effective in the populations for which they are approved for use. Children, adults <65 years of age, and the elderly all receive substantial health benefits from vaccination. In addition, vaccination appears to be cost-effective, if not cost saving, across the age spectrum. Despite long-standing recommendations for the routine vaccination of persons in high-priority groups, US vaccination rates remain too low across all age groups. Important issues to be addressed include improving vaccine delivery to current and expanded target groups, ensuring timely availability of adequate vaccine supply, and development of even more effective vaccines. Development of a vaccine against potentially pandemic strains is an essential part of the strategy to control and prevent a pandemic outbreak. The use of existing technologies for influenza vaccine production would be the most straightforward approach, because these technologies are commercially available and licensing would be relatively simple. Approaches currently being tested include subvirion inactivated vaccines and cold-adapted, live attenuated vaccines. Preliminary results have suggested that, for some pandemic antigens, particularly H5, subvirion inactivated vaccines are poorly immunogenic, for reasons that are not clear. Data from evaluation of live pandemic vaccines are pending. Second-generation approaches designed to provide improved immune responses at lower doses have focused on adjuvants such as alum and MF59, which are currently licensed for influenza or other vaccines. Additional experimental approaches are required to achieve the ultimate goal for seasonal and pandemic influenza prevention--namely, the ability to generate broadly cross-reactive and durable protection in humans.