Browsing by Author "Okware, Brenda"

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    Clinical and epidemiological characteristics of individuals resistant to M. tuberculosis infection in a longitudinal TB household contact study in Kampala, Uganda
    (BioMed Central, 2014) Ma, Ningning; Zalwango, Sarah; Malone, LaShaunda L; Nsereko, Mary; Wampande, Eddie M; Thiel, Bonnie A; Okware, Brenda; Igo Jr., Robert P; Joloba3, Moses L.; Mupere, Ezekiel; Mayanja-Kizza, Harriet; Boom, Henry; Stein, Catherine M
    Background: Despite sustained exposure to a person with pulmonary tuberculosis (TB), some M. tuberculosis (Mtb) exposed individuals maintain a negative tuberculin skin test (TST). Our objective was to characterize these persistently negative TST (PTST-) individuals and compare them to TST converters (TSTC) and individuals who are TST positive at study enrollment. Methods: During a TB household contact study in Kampala, Uganda, PTST-, TSTC, and TST + individuals were identified. PTST- individuals maintained a negative TST over a 2 year observation period despite prolonged exposure to an infectious tuberculosis (TB) case. Epidemiological and clinical characteristics were compared, a risk score developed by another group to capture risk for Mtb infection was computed, and an ordinal regression was performed. Results: When analyzed independently, epidemiological risk factors increased in prevalence from PTST- to TSTC to TST+. An ordinal regression model suggested age (p < 0.01), number of windows (p < 0.01) and people (p = 0.07) in the home, and sleeping in the same room (p < 0.01) were associated with PTST- and TSTC. As these factors do not exist in isolation, we examined a risk score, which reflects an accumulation of risk factors. This compound exposure score did not differ significantly between PTST-, TSTC, and TST+, except for the 5–15 age group (p = 0.009). Conclusions: Though many individual factors differed across all three groups, an exposure risk score reflecting a collection of risk factors did not differ for PTST-, TSTC and TST + young children and adults. This is the first study to rigorously characterize the epidemiologic risk profile of individuals with persistently negative TSTs despite close exposure to a person with TB. Additional studies are needed to characterize possible epidemiologic and host factors associated with this phenotype.
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    Contact Investigation for Active Tuberculosis Among Child Contacts in Uganda
    (Oxford University Press, 2013) Jaganath, Devan; Zalwango, Sarah; Okware, Brenda; Nsereko, Mary; Kisingo, Hussein; Malone, LaShaunda; Lancioni, Christina; Okwera, Alphonse; Joloba, Moses; Mayanja-Kizza, Harriet; Boom, Henry; Stein, Catherine; Mupere, Ezekiel
    Background. Tuberculosis is a large source of morbidity and mortality among children. However, limited studies characterize childhood tuberculosis disease, and contact investigation is rarely implemented in high-burden settings. In one of the largest pediatric tuberculosis contact investigation studies in a resource-limited setting, we assessed the yield of contact tracing on childhood tuberculosis and indicators for disease progression in Uganda. Methods. Child contacts aged <15 years in Kampala, Uganda, were enrolled from July 2002 to June 2009 and evaluated for tuberculosis disease via clinical, radiographic, and laboratory methods for up to 24 months. Results. Seven hundred sixty-one child contacts were included in the analysis. Prevalence of tuberculosis in our child population was 10%, of which 71% were culture-confirmed positive. There were no cases of disseminated tuberculosis, and 483 of 490 children (99%) started on isoniazid preventative therapy did not develop disease. Multivariable testing suggested risk factors including human immunodeficiency virus (HIV) status (odds ratio [OR], 7.90; P < .001), and baseline positive tuberculin skin test (OR, 2.21; P = .03); BCG vaccination was particularly protective, especially among children aged ≤5 years (OR, 0.23; P < .001). Adult index characteristics such as sex, HIV status, and extent or severity of disease were not associated with childhood disease. Conclusions. Contact tracing for children in high-burden settings is able to identify a large percentage of culture-confirmed positive tuberculosis cases before dissemination of disease, while suggesting factors for disease progression to identify who may benefit from targeted screening.
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    Long-term Stability of Resistance to Latent Mycobacterium tuberculosis Infection in Highly Exposed Tuberculosis Household Contacts in Kampala, Uganda
    (Clinical Infectious Diseases, 2019) Stein, Catherine M.; Nsereko, Mary; Malone, LaShaunda L.; Okware, Brenda; Kisingo, Hussein; Nalukwago, Sophie; Chervenak, Keith; Mayanja-Kizza, Harriet; Hawn, Thomas R.; Boom, W. Henry
    Resistance to latent Mycobacterium tuberculosis (M.tb) infection, identified by persistently negative tuberculin skin tests (TST) and interferon-gamma release assays (IGRA), after close contact with pulmonary tuberculosis (TB) patients has not been extensively characterized. Stability of this “resistance” beyond 2 years from exposure is unknown. Methods. 407 of 657 eligible human immunodeficiency virus (HIV)-negative adults from a TB household contact study with persistently negative TST (PTST−) or with stable latent M.tb infection (LTBI) were retraced 9.5 years (standard deviation = 3.2) later. Asymptomatic retraced contacts underwent 3 IGRAs and follow-up TST, and their M.tb infection status classified as definite/ possible/probable. Results. Among PTST− with a definite classification, 82.7% were concordantly TST−/ quantiferon-TB Gold− (QFT−), and 16.3% converted to TST+/QFT+ LTBI. Among original LTBI contacts, 83.6% remained LTBI, and 3.9% reverted their TST and were QFT−. Although TST and QFT concordance was high (κ = 0.78), 1.0% of PTST and 12.5% of original LTBI contacts could not be classified due to discordant TST and QFT results. Epidemiological variables did not differ between retraced PTST− and LTBI contacts. Conclusion. Resistance to LTBI, defined by repeatedly negative TST and IGRA, in adults who have had close contact with pulmonary TB patients living in TB-endemic areas, is a stable outcome of M.tb exposure. Repeated longitudinal measurements with 2 different immune assays and extended follow-up provide enhanced discriminatory power to identify this resister phenotype and avoid misclassification. Resisters may use immune mechanisms to control aerosolized M.tb that differ from those used by persons who develop “classic” LTBI.
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    Resistance and Susceptibility to Mycobacterium tuberculosis Infection and Disease in Tuberculosis Households in Kampala, Uganda
    (Oxford University Press, 2017) Stein, Catherine M.; Zalwango, Sarah; Malone, LaShaunda L.; Thiel, Bonnie; Mupere, Ezekiel; Nsereko, Mary; Okware, Brenda; Kisingo, Hussein; Lancioni, Christina L.; Bark, Charles M.; Whalen, Christopher C.; Joloba, Moses L.; Boom, W. Henry; Mayanja-Kizza, Harriet
    Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a major public health problem. Household contact studies identify children and adults along the spectrum from Mtb exposure to disease. In the Kawempe Community Health Study (conducted in Kampala, Uganda), 872 culture-confirmed pulmonary TB cases and their 2,585 contacts were enrolled during 2002–2012 and followed for up to 2 years each. Risk factors identified by time-to-event analysis for secondary TB differed among children, women, and men. Younger age (P = 0.0061), human immunodeficiency virus (HIV) (P = 0.0002), thinness (P = 0.01), absent bacille Calmette-Guérin vaccination (P = 0.002), and epidemiologic risk score (P < 0.0001) were risks for children. For women, risks were HIV (P < 0.0001), thinness (World Health Organization criteria; P < 0.0001), and epidemiologic risk score (P = 0.003). For men, HIV (P = 0.0007) and low body mass index (P = 0.008) resulted in faster progression to TB. Tuberculin skin testing (TST) identified contacts with Mtb infection and those with persistently negative TST. Risks for faster time to Mtb infection were identified, and included age (P = 0.0007), baseline TST induration (P < 0.0001), and epidemiologic risk score (P < 0.0001) only in children. Those with persistently negative TST comprised 10% of contacts but had no unique epidemiologic characteristics among adults. The burden of Mtb infection and disease is high in TB households, and risk factors for progression from exposure to infection and disease differ among children, women, and men.
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    Sulfamethoxazole Susceptibility of Mycobacterium tuberculosis Isolates from HIV-Infected Ugandan Adults with Tuberculosis Taking Trimethoprim-Sulfamethoxazole Prophylaxis
    (Antimicrob Agents Chemother, 2015) Ogwang, Sam; Good, Caryn E.; Okware, Brenda; Nsereko, Mary; Jacobs, Michael R.; Boom, W. Henry; Bark, Charles M.
    Alternative drugs are urgently needed to treat multidrug-resistant (MDR) tuberculosis (TB). Given the difficulties of new drug development, repurposing currently licensed antibiotics is practical and efficient. Trimethoprim-sulfamethoxazole (SXT) is a fixed-dose drug combination used worldwide as treatment and prophylaxis for multiple infections. Sulfamethoxazole (SMX) is in the sulfonamide class of antibiotics, which were explored as an anti-TB treatment in the mid-20th century with early studies showing potential value for the treatment of pulmonary and miliary TB (1–5). More recently, Forgacs et al. reported defervescence of a patient with pulmonary TB who was initially treated with SXT alone and also demonstrated in vitro susceptibility to SXT in 43 of 44 Mycobacterium tuberculosis isolates (6). These drug susceptibility results were independently confirmed in laboratory strains (7, 8) and in patient isolates demonstrating SMX to be the active agent with MICs within achievable serum levels (9, 10). In addition, Alsaad and colleagues reported the use of SXT as part of a combination regimen used to treat 10 patients with MDR-TB in the Netherlands (11). They also reported M. tuberculosis susceptibility to SXT in 17 of 18 patients with TB-HIV coinfection; however, only 1 was taking SXT prior to TB diagnosis (12). Given the development of drug resistance when active TB is treated with a single drug, there is concern for resistance to SMX among TBHIV- coinfected patients taking SXT prophylaxis. To address this concern, we performed drug susceptibility testing (DST) on M. tuberculosis isolates obtained from pretreatment sputum specimens of HIV-infected patients taking SXT prophylaxis at the time of diagnosis of active TB. Sputum isolates used for
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    Tuberculosis case finding in first-degree relative contacts not living with index tuberculosis cases in Kampala, Uganda
    (Dove Medical Press Limited,, 2015) Chheng, Phalkun; Nsereko, Mary; Malone, LaShaunda L.; Okware, Brenda; Zalwango, Sarah; Joloba, Moses; Boom, Henry W.; Mupere, Ezekiel; Stein, Catherine M.
    To assess the prevalence of pulmonary tuberculosis among first-degree relative (FDR) contacts not living with tuberculosis (TB) cases. Methods: A cross-sectional analysis of household contacts living with an index TB case and FDR contacts living outside of households in Kampala, Uganda, is presented.Results: A total of 177 contacts (52 FDRs and 125 index household contacts) of 31 TB cases were examined. Compared with index household contacts, FDR contacts were older, more likely to be TB symptomatic (50% vs 33%), had a higher percentage of abnormal chest X-rays (19% vs 11%), sputum smear positive (15% vs 5%), and many similar epidemiologic risk factors, including HIV infection (13% vs 10%). Contact groups had similar pulmonary tuberculosis prevalence: 9.6% in FDR vs 10.4% in index household contacts and similar Mycobacterium tuberculosis infection: 62% in FDR vs 61% in index households.Conclusion: TB is common among FDR contacts. High TB prevalence justifies targeting FDRs during household contact investigations. Combining TB active-case finding among FDR contacts with household contact investigation in low-income setting is feasible. This should be part of national TB control program strategies for increasing TB case-detection rates and reducing community TB transmission and death.