NRU :: Browsing by Author "Lutwama, Julius J."

Browsing by Author "Lutwama, Julius J."

Now showing 1 - 20 of 23

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.
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.
Discovery and Characterization of Bukakata orbivirus (Reoviridae:Orbivirus), a Novel Virus from a Ugandan Bat
(Viruses, 2019) Fagre, Anna C.; Lee, Justin S.; Kityo, Robert M.; Bergren, Nicholas A.; Mossel, Eric C.; Nakayiki, Teddy; Nalikka, Betty; Nyakarahuka, Luke; Gilbert, Amy T.; Kerbis Peterhans, Julian; Crabtree, Mary B.; Towner, Jonathan S.; Amman, Brian R.; Sealy, Tara K.; Schuh, Amy J.; Nichol, Stuart T.; Lutwama, Julius J.; Miller, Barry R.; Kading, Rebekah C.
While serological and virological evidence documents the exposure of bats to medicallyimportant arboviruses, their role as reservoirs or amplifying hosts is less well-characterized. We describe a novel orbivirus (Reoviridae:Orbivirus) isolated from an Egyptian fruit bat (Rousettus aegyptiacus leachii) trapped in 2013 in Uganda and named Bukakata orbivirus. This is the fifth orbivirus isolated from a bat, however genetic information had previously only been available for one bat-associated orbivirus. We performed whole-genome sequencing on Bukakata orbivirus and three other bat-associated orbiviruses (Fomede, Ife, and Japanaut) to assess their phylogenetic relationship within the genus Orbivirus and develop hypotheses regarding potential arthropod vectors. Replication kinetics were assessed for Bukakata orbivirus in three different vertebrate cell lines. Lastly, qRT-PCR and nested PCR were used to determine the prevalence of Bukakata orbivirus RNA in archived samples from three populations of Egyptian fruit bats and one population of cave-associated soft ticks in Uganda. Complete coding sequences were obtained for all ten segments of Fomede, Ife, and Japanaut orbiviruses and for nine of the ten segments for Bukakata orbivirus. Phylogenetic analysis placed Bukakata and Fomede in the tick-borne orbivirus clade and Ife and Japanaut within the Culicoides/phlebotomine sandfly orbivirus clade. Further, Bukakata and Fomede appear to be serotypes of the Chobar Gorge virus species. Bukakata orbivirus replicated to high titers (106–107 PFU/mL) in Vero, BHK-21 [C-13], and R06E (Egyptian fruit bat) cells. Preliminary screening of archived bat and tick samples do not support Bukakata orbivirus presence in these collections, however additional testing is warranted given the phylogenetic associations observed. This study provided complete coding sequence for several bat-associated orbiviruses and in vitro characterization of a bat-associated orbivirus. Our results indicate that bats may play an important role in the epidemiology of viruses in the genus Orbivirus and further investigation is warranted into vector-host associations and ongoing surveillance efforts.
Early cases of SARS-CoV-2 infection in Uganda: epidemiology and lessons learned from risk-based testing approaches – March-April 2020
(Globalization and Health, 2020) Migisha, Richard; Kwesiga, Benon; Mirembe, Bernadette B.; Amanya, Geofrey; Kabwama, Steven N.; Kadobera, Daniel; Bulage, Lilian; Nsereko, Godfrey; Wadunde, Ignatius; Tindyebwa, Tonny; Lubwama, Bernard; Kagirita, Atek A.; Kayiwa, John T.; Lutwama, Julius J.; Boore, Amy L.; Harris, Julie R.; Kyobe Bosa, Henry
On March 13, 2020, Uganda instituted COVID-19 symptom screening at its international airport, isolation and SARS-CoV-2 testing for symptomatic persons, and mandatory 14-day quarantine and testing of persons traveling through or from high-risk countries. On March 21, 2020, Uganda reported its first SARS-CoV-2 infection in a symptomatic traveler from Dubai. By April 12, 2020, 54 cases and 1257 contacts were identified. We describe the epidemiological, clinical, and transmission characteristics of these cases. Methods: A confirmed case was laboratory-confirmed SARS-CoV-2 infection during March 21–April 12, 2020 in a resident of or traveler to Uganda. We reviewed case-person files and interviewed case-persons at isolation centers. We identified infected contacts from contact tracing records. Results: Mean case-person age was 35 (±16) years; 34 (63%) were male. Forty-five (83%) had recently traveled internationally (‘imported cases’), five (9.3%) were known contacts of travelers, and four (7.4%) were community cases. Of the 45 imported cases, only one (2.2%) was symptomatic at entry. Among all case-persons, 29 (54%) were symptomatic at testing and five (9.3%) were pre-symptomatic. Among the 34 (63%) case-persons who were ever symptomatic, all had mild disease: 16 (47%) had fever, 13 (38%) reported headache, and 10 (29%) reported cough. Fifteen (28%) case-persons had underlying conditions, including three persons with HIV. An average of 31 contacts (range, 4–130) were identified per case-person. Five (10%) case-persons, all symptomatic, infected one contact each. Conclusion: The first 54 case-persons with SARS-CoV-2 infection in Uganda primarily comprised incoming air travelers with asymptomatic or mild disease. Disease would likely not have been detected in these persons without the targeted testing interventions implemented in Uganda. Transmission was low among symptomatic persons and nonexistent from asymptomatic persons. Routine, systematic screening of travelers and at-risk persons, and thorough contact tracing will be needed for Uganda to maintain epidemic control
Ebola Hemorrhagic Fever Associated with Novel Virus Strain, Uganda, 2007–2008
(Emerging infectious diseases, 2010) Wamala, Joseph F.; Lukwago, Luswa; Malimbo, Mugagga; Nguku, Patrick; Yoti, Zabulon; Musenero, Monica; Amone, Jackson; Mbabazi, William; Nanyunja, Miriam; Zaramba, Sam; Opio, Alex; Lutwama, Julius J.; Talisuna, Ambrose O.; Okware, Sam I.
During August 2007–February 2008, the novel Bundibugyo ebola virus species was identified during an outbreak of Ebola viral hemorrhagic fever in Bundibugyo district, western Uganda. To characterize the outbreak as a requisite for determining response, we instituted a caseseries investigation. We identified 192 suspected cases, of which 42 (22%) were laboratory positive for the novel species; 74 (38%) were probable, and 77 (40%) were negative. Laboratory confirmation lagged behind outbreak verification by 3 months. Bundibugyo ebola virus was less fatal (case fatality rate 34%) than Ebola viruses that had caused previous outbreaks in the region, and most transmission was associated with handling of dead persons without appropriate protection (adjusted odds ratio 3.83, 95% confidence interval 1.78–8.23). Our study highlights the need for maintaining a high index of suspicion for viral hemorrhagic fevers among healthcare workers, building local capacity for laboratory confirmation of viral hemorrhagic fevers, and institutionalizing standard precautions.
Emergence, Epidemiology, and Transmission Dynamics of 2009 Pandemic A/H1N1 Influenza in Kampala, Uganda, 2009–2015
(The American journal of tropical medicine and hygiene, 2018) Cummings, Matthew J.; Bakamutumaho, Barnabas; Yang, Wan; Wamala, Joseph F.; Kayiwa, John; Owor, Nicholas; Namagambo, Barbara; Byaruhanga, Timothy; Lutwama, Julius J.; Shaman, Jeffrey; O’Donnell, Max R.
In sub-Saharan Africa, little is known about the epidemiology of pandemic-prone influenza viruses in urban settings. Using data from a prospective sentinel surveillance network, we characterized the emergence, epidemiology, and transmission dynamics of 2009 pandemic A/H1N1 influenza (H1N1pdm09) in Kampala, Uganda. After virus introduction via international air travel from England in June 2009, we estimated the basic reproductive number in Kampala to be 1.06–1.13, corresponding to attack rates of 12–22%. We subsequently identified 613 cases of influenza in Kampala from 2009 to 2015, of which 191 (31.2%) were infected with H1N1pdm09. Patients infected with H1N1pdm09 were more likely to be older adult (ages 35–64) males with illness onset during rainy season months. Urban settings in sub-Saharan Africa are vulnerable to importation and intense transmission of pandemic-prone influenza viruses. Enhanced surveillance and influenza pandemic preparedness in these settings is needed.
Genetic Diversity of Bundibugyo Ebolavirus from Uganda and the Democratic Republic of Congo
(bioRxiv, 2021) Omara, Isaac Emmanuel; Kiwuwa-Muyingo, Sylvia; Balinandi, Stephen; Nyakarahuka, Luke; Kiconco, Jocelyn; Kayiwa, John Timothy; Mboowa, Gerald; Jjingo, Daudi; Lutwama, Julius J.
The Ebolavirus is one of the deadliest viral pathogens which was first discovered in the year 1976 during two consecutive outbreaks in the Democratic Republic of Congo and Sudan. Six known strains have been documented. The Bundibugyo Ebolavirus in particular first emerged in the year 2007 in Uganda. This outbreak was constituted with 116 human cases and 39 laboratory confirmed deaths. After 5 years, it re-emerged and caused an epidemic for the first time in the Democratic Republic of Congo in the year 2012 as reported by the WHO. Here, 36 human cases with 13 laboratory confirmed deaths were registered. Despite several research studies conducted in the past, there is still scarcity of knowledge available on the genetic diversity of Bundibugyo Ebolavirus. We undertook a research project to provide insights into the unique variants of Bundibugyo Ebolavirus that circulated in the two epidemics that occurred in Uganda and the Democratic Republic of Congo
Infection control during filoviral hemorrhagic fever outbreaks: preferences of community members and health workers in Masindi, Uganda
(Transactions of the Royal Society of Tropical Medicine and Hygiene, 2010-01-01) Raabe, Vanessa N.; Mutyaba, Imaam; Lutwama, Julius J.; Geisslera, Wenzel; Borchert, Matthias
Interviews were conducted with health workers and community members in Masindi, Uganda on improving the acceptability of infection control measures used during an Ebola outbreak. Measures that promote cultural sensitivity and transparency of control activities were preferred and should be employed in future control efforts. We suggest assessing the practicality of body bags with viewing windows, and face shields with or without chin protectors, in future outbreaks.
Influenza-associated pneumonia hospitalizations in Uganda, 2013-2016
(PLoS ONE, 2019) Emukule, Gideon O.; Namagambo, Barbara; Owor, Nicholas; Bakamutumaho, Barnabas; Kayiwa, John T.; Namulondo, Joyce; Byaruhanga,Timothy; Tempia, Stefano; Sandra, S. Chaves; Lutwama, Julius J.
Background Influenza is an important contributor to acute respiratory illness, including pneumonia, and results in substantial morbidity and mortality globally. Understanding the local burden of influenza-associated severe disease can inform decisions on allocation of resources toward influenza control programs. Currently, there is no national influenza vaccination program in Uganda. Methods In this study, we used data on pneumonia hospitalizations that were collected and reported through the Health Management Information System (HMIS) of the Ministry of Health, Uganda, and the laboratory-confirmed influenza positivity data from severe acute respiratory illness (SARI) surveillance in three districts (Wakiso, Mbarara, and Tororo) to estimate the age-specific incidence of influenza-associated pneumonia hospitalizations from January 2013 through December 2016. Results The overall estimated mean annual rate of pneumonia hospitalizations in the three districts was 371 (95% confidence interval [CI] 323–434) per 100,000 persons, and was highest among children aged <5 years (1,524 [95% CI 1,286–1,849]) compared to persons aged ≥5 years (123 [95% CI 105–144]) per 100,000 persons. The estimated mean annual rate of influenza-associated pneumonia hospitalization was 34 (95% CI 23–48) per 100,000 persons (116 [95% CI 78–165] and 16 [95% CI 6–28] per 100,000 persons among children aged <5 years and those ≥5 years, respectively). Among children aged <5 years, the rate of hospitalized influenza-associated pneumonia was highest among those who were <2 years old (178 [95% CI 109–265] per 100,000 persons). Over the period of analysis, the estimated mean annual number of hospitalized influenza-associated pneumonia cases in the three districts ranged between 672 and 1,436, of which over 70% represent children aged <5 years. Conclusions The burden of influenza-associated pneumonia hospitalizations was substantial in Uganda, and was highest among young children aged <5 years. Influenza vaccination may be considered, especially for very young children.
Intervention To Stop Transmission of Imported Pneumonic Plague — Uganda, 2019
(Morbidity and Mortality Weekly Report, 2019) Apangu, Titus; Acayo, Sarah; Atiku, Linda A.; Apio, Harriet,; Candini, Gordian; Okoth, Felix; Kaggwa Basabose, John; Ojosia, Lawrence; Ajoga, Sam; Mongiba, Grace; Makoba Wetaka, Milton; Kayiwa, Joshua; Balinandi, Stephen; Schwartz, Amy; Yockey, Brook; Sexton, Christopher; Dietrich, Elizabeth A.; Pappert, Ryan; Petersen, Jeannine M.; Mead, Paul S.; Lutwama, Julius J.; Kugeler, Kiersten J.
Plague, an acute zoonosis caused by Yersinia pestis, isendemic in the West Nile region of northwestern Uganda andneighboring northeastern Democratic Republic of the Congo(DRC) (1–4). The illness manifests in multiple clinical forms,including bubonic and pneumonic plague. Pneumonic plagueis rare, rapidly fatal, and transmissible from person to person via respiratory droplets. On March 4, 2019, a patient withsuspected pneumonic plague was hospitalized in West Nile,Uganda, 4 days after caring for her sister, who had come toUganda from DRC and died shortly thereafter, and 2 daysafter area officials received a message from a clinic in DRCwarning of possible plague. The West Nile-based Uganda Virus Research Institute (UVRI) plague program, together withlocal health officials, commenced a multipronged responseto suspected person-to-person transmission of pneumonicplague, including contact tracing, prophylaxis, and education.Plague was laboratoryconfirmed, and no additionaltransmission occurred in Uganda. This event transpired inthe context of heightened awareness of cross-border disease spread caused by ongoing Ebola virus disease transmission in DRC, approximately 400 km to the south. Building expertise in areas of plague endemicity can provide the rapid detection and effective response needed to mitigate epidemic spread and minimize mortality. Cross-border agreements can improve ability to respond effectively.
Intervention To Stop Transmission of Imported Pneumonic Plague — Uganda, 2019
(, 69(9),, 2020) Apangu, Titus; Acayo, Sarah; Atiku, Linda A.; Apio, Harriet; Candini, Gordian; Okoth, Felix; Basabose, John Kaggwa; Ojosia, Lawrence; Ajoga, Sam; Mongiba, Grace; Wetaka, Milton Makoba; Kayiwa, Joshua; Balinand, Stephen; Schwartz, Amy; Yockey, Brook; Sexton, Christopher; Dietrich, Elizabeth A.; Pappert, Ryan; Petersen, Jeannine M.; Mead, Paul S.; Lutwama, Julius J.; Kugeler, Kiersten J.
A plague is an acute zoonosis that occurs on several continents and can manifest in different clinical forms. Pneumonic plague is highly fatal and directly transmissible from person to person via infectious respiratory droplets. Importation of pneumonic plague from the Democratic Republic of the Congo into an area of Uganda with effective public health response capabilities resulted in prompt action to halt transmission. Despite multiple high-risk exposures, only a single transmission event occurred. Building expertise in areas of plague endemicity can provide the rapid detection and response needed to mitigate the epidemic spread and minimize mortality. Cross-border agreements can improve ability to respond effectively
Knowledge and Attitude towards Ebola and Marburg Virus Diseases in Uganda Using Quantitative and Participatory Epidemiology Techniques
(PLoS neglected tropical diseases, 2017) Nyakarahuka, Luke; Skjerve, Eystein; Nabadda, Daisy; Sitali, Doreen Chilolo; Mumba, Chisoni; Mwiine, Frank N.; Lutwama, Julius J.; Balinandi, Stephen; Shoemaker, Trevor; Kankya, Clovice
Uganda has reported five (5) Ebola virus disease outbreaks and three (3) Marburg virus disease outbreaks from 2000 to 2016. Peoples’ knowledge and attitude towards Ebola and Marburg virus disease impact on control and prevention measures especially during outbreaks. We describe knowledge and attitude towards Ebola and Marburg virus outbreaks in two affected communities in Uganda to inform future outbreak responses and help in the design of health education and communication messages.The study was a community survey done in Luweero, Ibanda and Kamwenge districts that have experienced outbreaks of Ebola and Marburg virus diseases. Quantitative data were collected using a structured questionnaire and triangulated with qualitative participatory epidemiology techniques to gain a communities’ knowledge and attitude towards Ebola and Marburg virus disease.Out of 740 respondents, 48.5% (359/740) were categorized as being knowledgeable about Ebola and Marburg virus diseases, whereas 60.5% (448/740) were having a positive attitude towards control and prevention of Ebola and Marburg virus diseases. The mean knowledge and attitude percentage scores were 54.3 (SD = 23.5, 95%CI = 52.6–56.0) and 69.9 (SD = 16.9, 95%CI = 68.9–71.1) respectively. People educated beyond primary school were more likely to be knowledgeable about Ebola and Marburg virus disease than those who did not attain any formal education (OR = 3.6, 95%CI = 2.1–6.1). Qualitative data revealed that communities describe Ebola and Marburg virus diseases as very severe diseases with no cure and they believe the diseases spread so fast. Respondents reported fear and stigma suffered by survivors, their families and the broader community due to these diseases.Communities in Uganda affected by filovirus outbreaks have moderate knowledge about these diseases and have a positive attitude towards practices to prevent and control Ebola and Marburg viral diseases. The public health sector should enhance this community knowledge gap to empower them more by supplying educational materials for epidemic preparedness in future using appropriate communication channels as proposed by the communities.
Morphological and molecular identification of ixodid tick species (Acari: Ixodidae) infesting cattle in Uganda
(Parasitology Research, 2020) Balinandi, Stephen; Chitimia-Dobler, Lidia; Grandi, Giulio; Nakayiki, Teddy; Kabasa, William; Bbira, Johnson; Lutwama, Julius J.; Bakkes, Deon K.; Malmberg, Maja; Mugisha, Lawrence
In Uganda, the role of ticks in zoonotic disease transmission is not well described, partly, due to limited available information on tick diversity. This study aimed to identify the tick species that infest cattle. Between September and November 2017, ticks (n = 4362) were collected from 5 districts across Uganda (Kasese, Hoima, Gulu, Soroti, and Moroto) and identified morphologically at Uganda Virus Research Institute. Morphological and genetic validation was performed in Germany on representative identified specimens and on all unidentified ticks. Ticks were belonging to 15 species: 8 Rhipicephalus species (Rhipicephalus appendiculatus, Rhipicephalus evertsi evertsi, Rhipicephalus microplus, Rhipicephalus decoloratus, Rhipicephalus afranicus, Rhipicephalus pulchellus, Rhipicephalus simus, and Rhipicephalus sanguineus tropical lineage); 5 Amblyomma species (Amblyomma lepidum, Amblyomma variegatum, Amblyomma cohaerens, Amblyomma gemma, and Amblyomma paulopunctatum); and 2 Hyalomma species (Hyalomma rufipes and Hyalomma truncatum). The most common species were R. appendiculatus (51.8%), A. lepidum (21.0%), A. variegatum (14.3%), R. evertsi evertsi (8.2%), and R. decoloratus (2.4%). R. afranicus is a new species recently described in South Africa and we report its presence in Uganda for the first time. The sequences of R. afranicus were 2.4% divergent from those obtained in Southern Africa. We confirm the presence of the invasive R. microplus in two districts (Soroti and Gulu). Species diversity was highest in Moroto district (p = 0.004) and geographical predominance by specific ticks was observed (p = 0.001). The study expands the knowledge on tick fauna in Uganda and demonstrates that multiple tick species with potential to transmit several tick-borne diseases including zoonotic pathogens are infesting cattle.
Multidimensional analysis of the host response reveals prognostic and pathogen-driven immune subtypes among adults with sepsis in Uganda
(Critical Care, 2022) Cummings, Matthew J.; Bakamutumaho, Barnabas; Adam, Price; Owor, Nicholas; Kayiwa, John; Namulondo, Joyce; Byaruhanga, Timothy; Muwanga, Moses; Nsereko, Christopher; Stephen, Samerof; Rafal, Tokarz; Wai, Wong; Shivang, S. Shah; Michelle, H. Larsen; Lipkin, W. Ian; Lutwama, Julius J.; Max, R. O’Donnell
Background The global burden of sepsis is concentrated in sub-Saharan Africa, where severe infections disproportionately affect young, HIV-infected adults and high-burden pathogens are unique. In this context, poor understanding of sepsis immunopathology represents a crucial barrier to development of locally-effective treatment strategies. We sought to determine inter-individual immunologic heterogeneity among adults hospitalized with sepsis in a sub-Saharan African setting, and characterize associations between immune subtypes, infecting pathogens, and clinical outcomes. Methods Among a prospective observational cohort of 288 adults hospitalized with suspected sepsis in Uganda, we applied machine learning methods to 14 soluble host immune mediators, reflective of key domains of sepsis immunopathology (innate and adaptive immune activation, endothelial dysfunction, fibrinolysis), to identify immune subtypes in randomly-split discovery (N = 201) and internal validation (N = 87) sub-cohorts. In parallel, we applied similar methods to whole-blood RNA-sequencing data from a consecutive subset of patients (N = 128) to identify transcriptional subtypes, which we characterized using biological pathway and immune cell-type deconvolution analyses. Results Unsupervised clustering consistently identified two immune subtypes defined by differential activation of pro-inflammatory innate and adaptive immune pathways, with transcriptional evidence of concomitant CD56(-)/CD16( +) NK-cell expansion, T-cell exhaustion, and oxidative-stress and hypoxia-induced metabolic and cell-cycle reprogramming in the hyperinflammatory subtype. Immune subtypes defined by greater pro-inflammatory immune activation, T-cell exhaustion, and metabolic reprogramming were consistently associated with a high-prevalence of severe and often disseminated HIV-associated tuberculosis, as well as more extensive organ dysfunction, worse functional outcomes, and higher 30-day mortality. Conclusions Our results highlight unique host- and pathogen-driven features of sepsis immunopathology in sub-Saharan Africa, including the importance of severe HIV-associated tuberculosis, and reinforce the need to develop more biologically-informed treatment strategies in the region, particularly those incorporating immunomodulation.
Neutralizing antibodies against flaviviruses, Babanki virus, and Rift Valley fever virus in Ugandan bats
(Infection Ecology & Epidemiology, 2018) Kading, Rebekah C.; Kityo, Robert M.; Mossel, Eric C.; Borland, Erin M.; Nakayiki, Teddie; Nalikka, Betty; Nyakarahuka, Luke; Ledermann, Jeremy P.; Panella, Nicholas A.; Gilbert, Amy T.; Crabtree, Mary B.; Kerbis Peterhans, Julian; Towner, Jonathan S.; Amman, Brian R.; Sealy, Tara K.; Nichol, Stuart T.; Powers, Ann M.; Lutwama, Julius J.; Miller, Barry R.
A number of arboviruses have previously been isolated from naturally-infected East African bats, however the role of bats in arbovirus maintenance is poorly understood. The aim of this study was to investigate the exposure history of Ugandan bats to a panel of arboviruses. Materials and methods: Insectivorous and fruit bats were captured from multiple locations throughout Uganda during 2009 and 2011–2013. All serum samples were tested for neutralizing antibodies against West Nile virus (WNV), yellow fever virus (YFV), dengue 2 virus (DENV-2), Zika virus (ZIKV), Babanki virus (BBKV), and Rift Valley fever virus (RVFV) by plaque reduction neutralization test (PRNT). Sera from up to 626 bats were screened for antibodies against each virus. Results and Discussion: Key findings include the presence of neutralizing antibodies against RVFV in 5/52 (9.6%) of little epauletted fruit bats (Epomophorus labiatus) captured from Kawuku and 3/54 (5.6%) Egyptian rousette bats from Kasokero cave. Antibodies reactive to flaviviruses were widespread across bat taxa and sampling locations. Conclusion: The data presented demonstrate the widespread exposure of bats in Uganda to arboviruses, and highlight particular virus-bat associations that warrant further investigation.
Rapid establishment of a frontline field laboratory in response to an imported outbreak of Ebola virus disease in western Uganda, June 2019
(PLOS Neglected Tropical Diseases, 2021) Schuh, Amy J.; Kyondo, Jackson; Graziano, James; Balinandi, Stephen; Kainulainen, Markus H.; Tumusiime, Alex; Nyakarahuka, Luke; Mulei, Sophia; Baluku, Jimmy; Lonergan, William; Mayer, Oren; Masereka, Rastus; Masereka, Fredrick; Businge, Esther; Gatare, Alphonse; Kabyanga, Loice; Muhindo, Samuel; Mugabe, Raymond; Makumbi, Issa; Kayiwa, Joshua; Makoba Wetaka, Milton; Brown, Vance; Ojwang, Joseph; Nelson, Lisa; Millard, Monica; Nichol, Stuart T.; Montgomery, Joel M.; Taboy, Celine H.; Lutwama, Julius J.; Klena, John D.
The Democratic Republic of the Congo (DRC) declared an Ebola virus disease (EVD) outbreak in North Kivu in August 2018. By June 2019, the outbreak had spread to 26 health zones in northeastern DRC, causing >2,000 reported cases and >1,000 deaths. On June 10, 2019, three members of a Congolese family with EVD-like symptoms traveled to western Uganda’s Kasese District to seek medical care. Shortly thereafter, the Viral Hemorrhagic Fever Surveillance and Laboratory Program (VHF program) at the Uganda Virus Research Institute (UVRI) confirmed that all three patients had EVD. The Ugandan Ministry of Health declared an outbreak of EVD in Uganda’s Kasese District, notified the World Health Organization, and initiated a rapid response to contain the outbreak. As part of this response, UVRI and the United States Centers for Disease Control and Prevention, with the support of Uganda’s Public Health Emergency Operations Center, the Kasese District Health Team, the Superintendent of Bwera General Hospital, the United States Department of Defense’s Makerere University Walter Reed Project, and the United States Mission to Kampala’s Global Health Security Technical Working Group, jointly established an Ebola Field Laboratory in Kasese District at Bwera General Hospital, proximal to an Ebola Treatment Unit (ETU). The laboratory consisted of a rapid containment kit for viral inactivation of patient specimens and a GeneXpert Instrument for performing Xpert Ebola assays. Laboratory staff tested 76 specimens from alert and suspect cases of EVD; the majority were admitted to the ETU (89.3%) and reported recent travel to the DRC (58.9%). Although no EVD cases were detected by the field laboratory, it played an important role in patient management and epidemiological surveillance by providing diagnostic results in <3 hours. The integration of the field laboratory into Uganda’s National VHF Program also enabled patient specimens to be referred to Entebbe for confirmatory EBOV testing and testing for other hemorrhagic fever viruses that circulate in Uganda.
Risk factors for Crimean-Congo Haemorrhagic Fever (CCHF) virus exposure in farming communities in Uganda
(Journal of Infection, 2022) Atim, Stella A.; Ashraf, Shirin; Ademun, Anna R.; Nakayiki, Teddy; Balinandi, Stephen; Nakanjako, Gladys; Abaasa, Andrew; Odongo, Steven; Esau, Martin; Kaleebu, Pontiano; Lutwama, Julius J.; Masembe, Charles; Lambe, Teresa; Tweyongyere, Robert
Crimean-Congo Haemorrhagic Fever (CCHF) is an emerging human-health threat causing sporadic outbreaks in livestock farming communities. However, the full extent and the risks associated with exposure of such communities has not previously been well-described. We collected blood samples from 800 humans, 666 cattle, 549 goats and 32 dogs in districts within and outside Ugandan cattle corridor in a cross-sectional survey, and tested for CCHFV-specific IgG antibodies using Enzyme-Linked Immunosorbent Assays. Sociodemographic and epidemiological data were recorded using structured questionnaire. Ticks were collected to identify circulating nairoviruses by metagenomic sequencing. CCHFV seropositivity was in 221/800 (27·6%) in humans, 612/666 (91·8%) in cattle, 413/549 (75·2%) in goats and 18/32 (56·2%) in dogs. Human seropositivity was associated with livestock farming (AOR=5·68, p<0·0001), age (AOR=2·99, p=0·002) and collecting/eating engorged ticks (AOR=2·13, p=0·004). In animals, seropositivity was higher in cattle versus goats (AOR=2·58, p<0·0001), female sex (AOR=2·13, p=0·002) and heavy tick infestation (>50 ticks: AOR=3·52, p=0·004). CCHFV was identified in multiple tick pools of Rhipicephalus appendiculatus.
Severe COVID-19 in Uganda across Two Epidemic Phases: A Prospective Cohort Study
(The American journal of tropical medicine and hygiene, 2021) Bakamutumaho, Barnabas; Cummings, Matthew J.; Owor, Nicholas; Kayiwa, John; Namulondo, Joyce; Byaruhanga, Timothy; Muwanga, Moses; Nsereko, Christopher; Mutonyi, Roselyn; Achan, Josephine; wanyenze, Lucy; Ndazarwe, Alice; Nakanjako, Ruth; Natuhwera, Richard; Nsangi, Annet; Bosa, Henry Kyobe; Ocom, Felix; 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.
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.
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.

Browsing by Author "Lutwama, Julius J."

Results Per Page

Sort Options