Browsing by Author "Matthew, J. Cummings"

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    Detection of urine lipoarabinomannan is associated with proinflammatory innate immune activation, impaired host defense, and organ dysfunction in adults with severe HIV-associated tuberculosis in Uganda
    (JAIDS Journal of Acquired Immune Deficiency Syndromes, 2023) Matthew, J. Cummings; Bakamutumaho, Barnabas; Komal, Jain; Adam Price; Owor, Nicholas; Kayiwa, John; Namulondo, Joyce; Byaruhanga, Timothy; Muwanga, Moses; Nsereko, Christopher; Nayiga, Irene; Kyebambe, Stephen; Xiaoyu, Che; Stephen, Sameroff; Rafal, Tokarz; Wai, Wong; Thomas, S. Postler; Michelle, H. Larsen; W. Ian, Lipkin; Lutwama, Julius J.; Max, R. O’Donnell
    Background: The immunopathology of disseminated HIV-associated tuberculosis (HIV/TB), a leading cause of critical illness and death among persons living with HIV in sub-Saharan Africa, is incompletely understood. Reflective of hematogenously disseminated TB, detection of lipoarabinomannan (LAM) in urine is associated with greater bacillary burden and poor outcomes in adults with HIV/TB. Methods: We determined the relationship between detection of urine TB-LAM, organ dysfunction, and host immune responses in a prospective cohort of adults hospitalized with severe HIV/TB in Uganda. Generalized additive models were used to analyze the association between urine TB-LAM grade and concentrations of 14 soluble immune mediators. Whole-blood RNA-sequencing data were used to compare transcriptional profiles between patients with high- vs. low-grade TB-LAM results. Results: Among 157 hospitalized persons living with HIV, 40 (25.5%) had positive urine TB-LAM testing. Higher TB-LAM grade was associated with more severe physiologic derangement, organ dysfunction, and shock. Adjusted generalized additive models showed that higher TB-LAM grade was significantly associated with higher concentrations of mediators reflecting proinflammatory innate and T-cell activation and chemotaxis (IL-8, MIF, MIP-1β/CCL4, and sIL-2Ra/sCD25). Transcriptionally, patients with higher TB-LAM grades demonstrated multifaceted impairment of antibacterial defense including reduced expression of genes encoding cytotoxic and autophagy-related proteins and impaired cross-talk between innate and cell-mediated immune effectors. Conclusions: Our findings add to emerging data suggesting pathobiological relationships between LAM, TB dissemination, innate cell activation, and evasion of host immunity in severe HIV/TB. Further translational studies are needed to elucidate the role for immunomodulatory therapies, in addition to optimized anti-TB treatment, in this often critically ill population.
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    Development of a Novel Clinicomolecular Risk Index to Enhance Mortality Prediction and Immunological Stratification of Adults Hospitalized with Sepsis in Sub-Saharan Africa: A Pilot Study from Uganda
    (The American Journal of Tropical Medicine and Hygiene, 2023) Matthew, J. Cummings; Bakamutumaho, Barnabas; Komal, Jain; Adam, Price; Owor, Nicholas; Kayiwa, John; Namulondo, Joyce; Byaruhanga, Timothy; Muwanga, Moses; Nsereko, Christopher; Stephen, Sameroff; W. Ian, Lipkin; Lutwama, Julius J.; Max, R. O’Donnell
    The global burden of sepsis is concentrated in sub-Saharan Africa (SSA), where epidemic HIV and unique pathogen diversity challenge the effective management of severe infections. In this context, patient stratification based on biomarkers of a dysregulated host response may identify subgroups more likely to respond to targeted immunomodulatory therapeutics. In a prospective cohort of adults hospitalized with suspected sepsis in Uganda, we applied machine learning methods to develop a prediction model for 30-day mortality that integrates physiology-based risk scores with soluble biomarkers reflective of key domains of sepsis immunopathology. After model evaluation and internal validation, whole-blood RNA sequencing data were analyzed to compare biological pathway enrichment and inferred immune cell profiles between patients assigned differential model-based risks of mortality. Of 260 eligible adults (median age, 32 years; interquartile range, 26–43 years; 59.2% female, 53.9% living with HIV), 62 (23.8%) died by 30 days after hospital discharge. Among 14 biomarkers, soluble tumor necrosis factor receptor 1 (sTNFR1) and angiopoietin 2 (Ang-2) demonstrated the greatest importance for mortality prediction in machine learning models. A clinicomolecular model integrating sTNFR1 and Ang-2 with the Universal Vital Assessment (UVA) risk score optimized 30-day mortality prediction across multiple performance metrics. Patients assigned to the high-risk, UVA-based clinicomolecular subgroup exhibited a transcriptional profile defined by proinflammatory innate immune and necroptotic pathway activation, T-cell exhaustion, and expansion of key immune cell subsets including regulatory and gamma-delta T cells. Clinicomolecular stratification of adults with suspected sepsis in Uganda enhanced 30-day mortality prediction and identified a high-risk subgroup with a therapeutically targetable immunological profile. Further studies are needed to advance pathobiologically informed sepsis management in SSA.
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    Severe COVID-19 in Uganda across Two Epidemic Phases: A Prospective Cohort Study
    (The American journal of tropical medicine and hygiene, 2021) Bakamutumaho, Barnabas; Matthew, J. Cummings; Owor, Nicholas; Kayiwa, John; Namulondo, Joyce; Byaruhanga, Timothy; Muwanga, Moses; Nsereko, Christopher; Rwamutwe, Emmanuel; Mutonyi, Roselyn; Achan, Josephine; Wanyenze, Lucy; Ndazarwe, Alice; Nakanjako, Ruth; Natuhwera, Richard; Nsangi, Annet; Bosa, Henry Kyobe; Ocom, Felix; Max, R. O’Donnell; Kikaire, Bernard; Lutwama, Julius J.
    Among a prospective cohort of children and adults admitted to a national COVID-19 treatment unit in Uganda from March to December 2020, we characterized the epidemiology of and risk factors for severe illness. Across two epidemic phases differentiated by varying levels of community transmission, the proportion of patients admitted with WHO-defined severe COVID-19 ranged from 5% (7/146; 95% CI: 2–10) to 33% (41/124; 95% CI: 25–42); 21% (26/124; 95% CI: 14–29%) of patients admitted during the peak phase received oxygen therapy. Severe COVID-19 was associated with older age, male sex, and longer duration of illness before admission. Coinfection with HIV was not associated with illness severity; malaria or tuberculosis coinfection was rare. No patients died during admission. Despite low mortality, hospital incidence of severe COVID-19 during the first epidemic peak in Uganda was substantial. Improvements in vaccine deployment and acute care capacity, including oxygen delivery, are urgently needed to prevent and manage severe COVID-19 in sub-Saharan Africa.
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    Stratifying Sepsis in Uganda Using Rapid Pathogen Diagnostics and Clinical Data: A Prospective
    (The American Journal of Tropical Medicine and Hygiene, 2021) Matthew, J. Cummings; Bakamutumaho, Barnabas; Owor, Nicholas; Kayiwa, John; Namulondo, Joyce; Byaruhanga, Timothy; Muwanga, Moses; Nsereko, Christopher; Baldwin, Matthew R.; Lutwama, Julius J.; Max, R. O’Donnell
    The global burden of sepsis is concentrated in sub-Saharan Africa, where extensive pathogen diversity and limited laboratory capacity challenge targeted antimicrobial management of life-threatening infections. In this context, established and emerging rapid pathogen diagnostics may stratify sepsis patients into subgroups with prognostic and therapeutic relevance. In a prospective cohort of adults (age $18 years) hospitalized with suspected sepsis in Uganda, we stratified patients using rapid diagnostics for HIV, tuberculosis (TB), malaria, and influenza, and compared clinical characteristics and 30-day outcomes across these pathogen-driven subgroups. From April 2017 to August 2019, 301 adults were enrolled (median age, 32 years [interquartile range, 26–42 years]; female, n 5 178 [59%]). A total of 157 patients (53%) were HIV infected. Sixty-one patients (20%) tested positive for malaria, 52 (17%), for TB (including 49 of 157 [31%] HIV-infected patients), and 17 (6%), for influenza. Co-infection was identified in 33 (11%) patients. The frequency of multi-organ failure, including shock and acute respiratory failure, was greatest among patients with HIV-associated TB. Mortality at 30 days was 19% among patients with malaria, 40% among patients with HIV-associated TB, 32% among HIV-infected patients without microbiological evidence of TB, 6% among patients with influenza, and 11% among patients without a pathogen identified. Despite improvements in anti-retroviral delivery, the burden of sepsis in Uganda remains concentrated among young, HIV-infected adults, with a high incidence of severe HIV-associated TB. In parallel with improvements in acute-care capacity, use of rapid pathogen diagnostics may enhance triage and antimicrobial management during emergency care for sepsis in sub-Saharan Africa, and could be used to enrich study populations when trialing pathogen-specific treatment strategies in the region. enhance triage and antimicrobial management during emergency care for sepsis in sub-Saharan Africa, and could be used to enrich study populations when trialing pathogen-specific treatment strategies in the region.