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Biomedical subjects

Christopher C Whalen

Publications and source records attributed to Christopher C Whalen.

At least 19 recordsLinked to original sources
PubMed2006

Predictive value of plasma HIV RNA level on rate of CD4 T-cell decline in untreated HIV infection.

CONTEXT: Plasma human immunodeficiency virus (HIV) RNA level predicts HIV disease progression, but the extent to which it explains the variability in rate of CD4 cell depletion is poorly characterized. OBJECTIVE: To estimate the proportion of variability in rate of CD4 cell loss predicted by presenting plasma HIV RNA levels in untreated HIV-infected persons. DESIGN: Repeated-measures analyses of 2 multicenter cohorts, comprising observations beginning on May 12, 1984, and ending on August 26, 2004. Analyses were conducted between August 2004 and March 2006. SETTING: Two cohorts of HIV-infected persons: patients followed up at 4 US teaching medical institutions or participating in either the Research in Access to Care for the Homeless Cohort (REACH) or the San Francisco Men's Health Study (SFMHS) cohorts and participants in the Multicenter AIDS Cohort Study (MACS) cohort. PARTICIPANTS: Antiretroviral treatment-naive, chronically HIV-infected persons (n = 1289 and n = 1512 for each of the 2 cohorts) untreated during the observation period (> or =6 months) and with at least 1 HIV RNA level and 2 CD4 cell counts available. Approximately 35% were nonwhite, and 35% had risk factors other than male-to-male sexual contact. MAIN OUTCOME MEASURES: The extent to which presenting plasma HIV RNA level could explain the rate of model-derived yearly CD4 cell loss, as estimated by the coefficient of determination (R2). RESULTS: In both cohorts, higher presenting HIV RNA levels were associated with greater subsequent CD4 cell decline. In the study cohort, median model-estimated CD4 cell decrease among participants with HIV RNA levels of 500 or less, 501 to 2000, 2001 to 10,000, 10,001 to 40,000, and more than 40,000 copies/mL were 20, 39, 48, 56, and 78 cells/microL, respectively. Despite this trend across broad categories of HIV RNA levels, only a small proportion of CD4 cell loss variability (4%-6%) could be explained by presenting plasma HIV RNA level. Analyses using multiple HIV RNA measurements or restricting to participants with high HIV RNA levels improved this correlation minimally (R2, 0.09), and measurement error was estimated to attenuate these associations only marginally (deattenuated R2 in the 2 cohorts, 0.05 and 0.08, respectively). CONCLUSIONS: Presenting HIV RNA level predicts the rate of CD4 cell decline only minimally in untreated persons. Other factors, as yet undefined, likely drive CD4 cell losses in HIV infection. These findings have implications for treatment decisions in HIV infection and for understanding the pathogenesis of progressive immune deficiency.

Adult↗
PubMed2006

Oropharyngeal colonization by Streptococcus pneumoniae among HIV-infected adults in Uganda: assessing prevalence and antimicrobial susceptibility.

OBJECTIVES: To evaluate characteristics of Streptococcus pneumoniae associated with oropharyngeal colonization in the Ugandan adult HIV population. METHODS: We conducted a cross-sectional study at the outpatient HIV clinic at the Joint Clinical Research Centre in Kampala, Uganda between July 2004 and February 2005. Six hundred HIV-infected individuals were interviewed and had oropharyngeal specimens collected. Pneumococci were isolated from these specimens and antimicrobial susceptibility patterns determined using standard microdilution methods. Serotypes of the pneumococcal isolates were evaluated by capsular swelling reaction with commercial antisera. RESULTS: The prevalence of oropharyngeal colonization with pneumococci was 18% (108/600). Thirty-two different pneumococcal serotypes were identified, and the most common were serotypes 3 (14.7%), 19F (6.4%), 23F (6.4%), and 16 (5.5%). Seventy-two percent of the isolates were penicillin (PCN) intermediate (MICs 0.12-1 microg/mL), the remainder all being PCN susceptible, and >99% were trimethoprim-sulfamethoxazole (TMP-SMX) resistant. Novel PCN intermediate serotypes included 7, 11, 16, 20, 22, 24, and 34. Only one isolate was resistant to macrolides, and resistance to other antibiotics was rare. CONCLUSIONS: HIV-infected adults in Uganda are colonized with pneumococci that exhibit a high degree of TMP-SMX and PCN non-susceptibility, with several unique PCN non-susceptible serotypes that are not included in current vaccine preparations.

Adult↗
PubMed2006

Delayed-type hypersensitivity skin test reactivity and survival in HIV-infected patients in Uganda: should anergy be a criterion to start antiretroviral therapy in low-income countries?

Access to antiretroviral (ARV) drugs is improving in sub-Saharan Africa but still constrained by several clinical and logistical obstacles. There is a need to develop affordable markers to guide initiation of treatment. We present a prospective cohort study of 779 patients participating in a TB prophylaxis trial. We performed separate analyses for anergic and nonanergic subjects. Prognostic factors for anergic and nonanergic subjects differed between groups. Individuals with anergy and constitutional symptoms were at the highest risk of death. Incident tuberculosis and CD4 < 200 cells/muL at enrollment were the strongest risk factors for death. HIV disease is associated with substantial morbidity and mortality in this population. The burden caused by tuberculosis is particularly high. Anergy is a strong and independent predictor of death. World Health Organization criteria to start ARV may be strengthened with the addition of DTH testing, an inexpensive and readily available tool in sub-Saharan Africa.

Adolescent↗
PubMed2006

Immune correlates of acute Mycobacterium tuberculosis infection in household contacts in Kampala, Uganda.

To determine immunologic and epidemiologic correlates of acute Mycobacterium tuberculosis infection in household contacts of infectious tuberculosis cases, we performed a prospective, community-based cohort study of index cases and their household contacts in Kampala, Uganda. Contacts were evaluated for tuberculin skin test (TST) conversion over two years. Interferon-gamma expression was measured using a whole blood assay after stimulating with M. tuberculosis culture-filtrate. In 222 contacts with a TST less than 5 mm at baseline, the one-year rate of TST conversion was 27%. The TST conversion was associated with the infectiousness of the index case and proximity of contact. Interferon-gamma levels at baseline were greater among TST converters compared with those who did not convert. The risk of TST conversion increased four-fold as the baseline interferon-gamma increased 10-fold, but only in contacts with BCG vaccination. In household contacts of tuberculosis, interferon-gamma responses to non-specific mycobacterial antigens may be used to make an early diagnosis of tuberculosis infection, especially in resource-limited settings where bacille Calmette-Guérin vaccination is commonly used.

Acute Disease↗
PubMed2006

Factors affecting infection or reinfection with Schistosoma haematobium in coastal Kenya: survival analysis during a nine-year, school-based treatment program.

Urinary schistosomiasis remains a significant burden for Africa and the Middle East. Success of regional control strategies will depend, in part, on what influence local environmental and behavioral factors have on individual risk for primary infection and/or reinfection. Based on experience in a multi-year (1984-1992), school-based Schistosoma haematobium control program in Coast Province, Kenya, we examined risk for infection outcomes as a function of age, sex, pretreatment morbidity, treatment regimen, water contact, and residence location, with the use of life tables and Cox proportional-hazards analysis. After adjustment, location of residence, age less than 12 years, pretreatment hematuria, and incomplete treatment were the significant independent predictors of infection, whereas sex and frequency of water contact were not. We conclude that local physical features and age-related factors play a predominant role in S. haematobium transmission in this setting. In large population-based control programs, treatment allocation strategies may need to be tailored to local conditions on a village-by-village basis.

Adolescent↗
PubMed2005

Evidence for a major gene influence on tumor necrosis factor-alpha expression in tuberculosis: path and segregation analysis.

OBJECTIVE: Tuberculosis (TB) is a growing global public health problem. Several studies suggest a role for host genetics in disease susceptibility, but studies to date have been inconsistent and a comprehensive genetic model has not emerged. A limitation of previous genetic studies is that they only analyzed the binary trait TB, which does not reflect disease heterogeneity. Furthermore, these studies have not accounted for the influence of shared environment within households on TB risk, which may spuriously inflate estimates of heritability. METHODS: We conducted a household contact study in a TB-endemic community in Uganda. Antigen-induced tumor necrosis factor-alpha (TNFalpha) expression, a key component of the underlying immune response to TB, was used as an endophenotype for TB. RESULTS: Path analysis, conducted to assess the effect of shared environment, suggested that TNFalpha is heritable (narrow sense heritability = 34-66%); the effect of shared environment is minimal (1-14%), but gene-environment interaction may be involved. Segregation analysis of TNFalpha suggested a major gene model that explained one-third of the phenotypic variance, and provided putative evidence of natural selection acting on this phenotype. CONCLUSION: Our data further support TNFalpha as an endophenotype for TB, as it may increase power to detect disease-predisposing loci.

Adolescent↗
PubMed2005

Vdelta2+ gammadelta T cell function in Mycobacterium tuberculosis- and HIV-1-positive patients in the United States and Uganda: application of a whole-blood assay.

BACKGROUND: Vgamma9(+)Vdelta2(+) gammadelta T cells (Vdelta 2(+) T cells) are activated by Mycobacterium tuberculosis and secrete interferon (IFN)-gamma. Vdelta 2(+) T cells recognize phosphoantigens, such as bromohydrin pyrophosphate (BrHPP), and link innate and adaptive immunity. METHODS: A whole-blood assay was developed that used IFN-gamma secretion in response to BrHPP as a measurement of Vdelta2(+) T cell function. RESULTS: Peak IFN-gamma levels were detected after stimulating whole blood with BrHPP for 7-9 days. IFN- gamma production in whole blood in response to BrHPP paralleled IFN-gamma production and Vdelta2(+) T cell expansion of peripheral-blood mononuclear cells. The assay was used to evaluate Vdelta2(+) T cell function in subjects in the United States (n = 24) and Uganda (n = 178) who were or were not infected with M. tuberculosis and/or human immunodeficiency virus (HIV) type 1. When 50 micromol/L BrHPP was used, 100% of healthy subjects produced IFN-gamma. The Vdelta2(+) T cell response was independent of the tuberculin skin test response. In Uganda, Vdelta2(+) T cell responses were decreased in patients with tuberculosis (n = 73) compared with responses in household contacts (n = 105). HIV-1-positive household contacts had lower responses than did HIV-1-negative household contacts. HIV-1-positive patients with tuberculosis had the lowest V delta 2(+) T cell responses. CONCLUSIONS: Tuberculosis and HIV-1 infection are associated with decreased Velta2(+) T cell function. Decreased Vdelta2(+) T cell function may contribute to increased risk for tuberculosis in HIV-1-positive patients.

Adolescent↗
PubMed2005

Immunoadjuvant prednisolone therapy for HIV-associated tuberculosis: a phase 2 clinical trial in Uganda.

Background. Human immunodeficiency virus (HIV)-infected patients with tuberculosis (TB) respond to effective antituberculous therapy, but their prognosis remains poor. Mounting evidence from clinical studies supports the concept of copathogenesis in which immune activation that is triggered by TB and mediated by cytokines stimulates viral replication and worsens HIV infection, especially when immune function is preserved.Methods. We performed a phase 2, randomized, double-blind, placebo-controlled clinical trial in Kampala, Uganda, to determine whether immunoadjuvant prednisolone therapy in HIV-infected patients with TB who have CD4(+) T cell counts >/=200 cells/ mu L is safe and effective at increasing CD4(+) T cell counts.Results. Short-term prednisolone therapy reduced levels of immune activation and tended to produce higher CD4(+) T cell counts. Although prednisolone therapy was associated with a more rapid clearance of Mycobacterium tuberculosis from the sputum, it was also associated with a transient increase in HIV RNA levels, which receded when prednisolone therapy was discontinued. The intervention worsened underlying hypertension and caused fluid retention and hyperglycemia.Conclusion. The benefits of prednisolone therapy on immune activation and CD4(+) T cell counts do not outweigh the risks of adverse events in HIV-infected patients with TB and preserved immune function.

AIDS-Related Opportunistic Infections↗
PubMed2004

Burden of tuberculosis in Kampala, Uganda.

OBJECTIVE: To determine the prevalence and incidence of tuberculosis in one of Uganda's poor peri-urban areas. METHODS: Multi-stage sampling was used to select a sample of households whose members were evaluated for presence of signs and/or symptoms of active tuberculosis; history of tuberculosis treatment; and relevant demographic, socioeconomic, and household environment characteristics. Patients with suspected tuberculosis underwent standardized evaluation for active disease. FINDINGS: A sample of 263 households with 1142 individuals was evaluated. Nineteen people were classified as having had tuberculosis during the one-year reference period (May 2001-April 2002): nine (47%) cases already had been diagnosed through the health care system, while 10 cases (53%) were diagnosed through the survey. The prevalences for all forms of tuberculosis and for sputum smear-positive tuberculosis were 14.0 (95% confidence interval (CI) 7.8-20.3) and 4.4 (CI = 0.83-7.89) per thousand, respectively. The incidences for all forms of tuberculosis and for sputum smear-positive tuberculosis were 9.2 (CI = 3.97-14.4) and 3.7 (CI = 0.39-6.95) per thousand per year, respectively. CONCLUSION: The rate of tuberculosis in this peri-urban community was exceptionally high and may be underestimated by current surveillance systems. The need for interventions aimed at reducing tuberculosis transmission in this, and other similar communities with high case rates, is urgent.

Housing↗
PubMed2004

High prevalence of antiretroviral resistance in treated Ugandans infected with non-subtype B human immunodeficiency virus type 1.

This study examined the emergence and prevalence of drug-resistant mutations in reverse transcriptase and protease coding regions in human immunodeficiency virus type 1 (HIV-1)-infected Ugandans treated with antiretroviral drugs (ARV). Genotypic resistance testing was performed on 50 and 16 participants who were enrolled in a cross-sectional and longitudinal observational cohort, respectively. The majority of the 113 HIV-1 PR-RT sequences were classified as subtypes A and D. Drug resistance mutations were prevalent in 52% of ARV-experienced individuals, and 17 of 27 ARV-resistant isolates had three mutations or more in reverse transcriptase. Resistance mutations in protease were less prevalent but only 17 of the 50 patients were receiving a protease inhibitor upon sample collection. Mutations conferring drug resistance were also selected in 3 of 16 participants in the longitudinal cohort, i.e., less than 8 months after the initiation of ARV treatment. Rapid emergence of ARV resistance was associated with poor adherence to treatment regimens, which was related to treatment costs. ARV resistance did, however, appear at a slightly higher prevalence in HIV-1 subtype D (21 of 33) than subtype A (7 of 25) infected individuals. Overall, this observational study suggests that ARV-resistant HIV-1 isolates are emerging rapidly in ARV-treated individual in Uganda and possibly other developing countries.

Adult↗
PubMed2004

Effectiveness of nevirapine and zidovudine in a pilot program for the prevention of mother-to-child transmission of HIV-1 in Uganda.

BACKGROUND: Single dose nevirapine and a short course of zidovudine (AZT) are now administered in most hospitals in Uganda to prevent mother-to-child transmission (MTCT) of HIV. The effectiveness of these antiretroviral (ARV) regimens has been shown in the clinical trials but has not been demonstrated outside the clinical trials setting in this country. OBJECTIVES: The study evaluated the effectiveness of short course ARV regimens in a pilot program to prevent mother-to-child transmission of HIV and determined the risk factors for perinatal transmission. METHODS: Cross-sectional study design was used to compare perinatal transmission rates of HIV in two sets of mothers: ARV-treated mothers and ARV-untreated mothers. RESULTS: 109 treated and 90 naïve mother-infant pairs were recruited. HIV transmission rates were similar in the nevirapine (10/61) and AZT (8/48) groups (16.4% vs. 16.7%) respectively but higher in the naive group (43/90 48%, p= 0.0001). ARV therapy offers a protective effect against MTCT of HIV (Adjusted Odds Ratio 0.22 95%CI 0.09, 0.54) but mothers in Stage 1 and 2 of disease were more likely to benefit from this intervention than mothers in Stage 3 and 4. CONCLUSION: In this community-based observational study, ARV reduces the risk of perinatal transmission of HIV but does not eliminate the risk completely. Early screening of asymptomatic pregnant women will identify a group of mothers more likely to benefit from the intervention.

Anti-HIV Agents↗
PubMed2003

Heritability analysis of cytokines as intermediate phenotypes of tuberculosis.

Numerous studies have provided support for genetic susceptibility to tuberculosis (TB); however, heterogeneity in disease expression has hampered previous genetic studies. The purpose of this work was to investigate possible intermediate phenotypes for TB. A set of cytokine profiles, including antigen-stimulated whole-blood assays for interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta, and the ratio of IFN to TNF, were analyzed in 177 pedigrees from a community in Uganda with a high prevalence of TB. The heritability of these variables was estimated after adjustment for covariates, and TNF-alpha, in particular, had an estimated heritability of 68%. A principal component analysis of IFN-gamma, TNF-alpha, and TGF-beta reflected the immunologic model of TB. In this analysis, the first component explained >38% of the variation in the data. This analysis illustrates the value of such intermediate phenotypes in mapping susceptibility loci for TB and demonstrates that this area deserves further research.

Adolescent↗
PubMed2003

Cefotaxime-resistant bacteria colonizing older people admitted to an acute care hospital.

OBJECTIVES: To determine the frequency of fecal colonization by cefotaxime-resistant gram-negative bacilli in older patients living in the community and in long-term care facilities (LTCFs) admitted to an acute care hospital. DESIGN: Case-control, point prevalence study. SETTING: Hospital. PARTICIPANTS: One hundred forty-three patients aged 65 and older. MEASUREMENTS: Rectal swab cultures, antibiotic drug sensitivity, beta lactamase isolation, and clonal identity. RESULTS: Of the 190 surveillance cultures obtained from 143 patients, 26 cefotaxime-resistant gram-negative isolates from 22 patients were recovered. The prevalence rate of cefotaxime-resistant isolates on admission was 13.3% (19/143). A logistic regression model using cefotaxime colonization as the dependent variable found that multiple comorbidities, admission to a surgical service, and having a diagnosis of infection on presentation and a transfusion history were factors associated with the presence of colonization. These four clinical items accurately classified 74% of patients colonized. Antibiotic use and nursing home residence were not associated with the presence of colonization by cefotaxime-resistant organisms. Twelve of the cefotaxime-resistant isolates (46%) were identified as Pseudomonas aeruginosa, and 14 (54%) were other gram-negative bacilli. In six of the 14 isolates that were not P. aeruginosa (36%), it was possible to demonstrate the presence of an AmpC beta-lactamase related to the CMY-2 beta-lactamase, a plasmid-borne cephalosporinase. CONCLUSION: These data raise awareness that there are community- and LTCF-dwelling older patients colonized with gram-negative enteric bacilli resistant to third-generation cephalosporins on admission to the hospital. The "reservoir of resistant bacteria" in older people is no longer confined to LTCFs.

Aged↗
PubMed2002

Investigation of the relationships between immune-mediated inhibition of mycobacterial growth and other potential surrogate markers of protective Mycobacterium tuberculosis immunity.

Tuberculosis (TB) vaccine development is hindered by the lack of clear surrogate markers of protective human immunity to Mycobacterium tuberculosis. This study evaluated the hypothesis that immune-mediated inhibition of mycobacterial growth would more directly correlate with protective TB immunity than other immunologic responses. Bacille Calmette-Guérin (BCG) vaccination, known to induce partial protection against TB, was used as a model system to investigate mechanistic relationships among different parameters of antigen-specific immunity. Effects of primary and booster intradermal BCG vaccinations were assessed in 3 distinct assays of mycobacterial inhibition. Correlations between vaccine-induced growth inhibition and other immune responses were analyzed. BCG significantly enhanced all antigen-specific responses. Peak responses occurred at 2 months after boosting. Statistical analyses suggested that each assay measured unique aspects of mycobacterial immunity. Despite previous evidence that type 1 immune responses are essential for TB immunity, interferon-gamma production did not correlate with mycobacterial inhibition. These results have important implications for TB vaccine development.

BCG Vaccine↗