Max R. O’Donnell

Treatment outcomes for extensively drug-resistant tuberculosis and HIV co-infection.

Sputum culture conversion was poorly predictive of successful treatment.

Extensively drug-resistant tuberculosis (XDR-TB) among health care workers in South Africa.

Objective  To determine the clinical profile and outcomes of health care workers (HCWs) with extensively drug resistant tuberculosis (XDR‐TB) in the Eastern and Western Cape Provinces of South Africa.

Extensively Drug-Resistant Tuberculosis in Women, KwaZulu-Natal, South Africa

To determine whether women in KwaZulu-Natal, South Africa, with drug-resistant tuberculosis (TB) were more likely than men to have extensively drug-resistant TB, we reviewed 4,514 adults admitted during 2003–2008 for drug-resistant TB. Female sex independently predicted extensively drug-resistant TB, even after we controlled for HIV infection. This association needs further study.

Primary Capreomycin Resistance Is Common and Associated With Early Mortality in Patients With Extensively Drug-Resistant Tuberculosis in KwaZulu-Natal, South Africa.

Background:Capreomycin is a key antimycobacterial drug in treatment of extensively drug-resistant tuberculosis (XDR-TB). Drug-susceptibility testing (DST) for capreomycin is not routinely performed in newly diagnosed XDR-TB in South Africa. We performed this study to assess the prevalence, clinical significance, and molecular epidemiology of capreomycin resistance in newly diagnosed patients with XDR-TB in KwaZulu-Natal, South Africa. Methods:Retrospective cohort study of consecutive patients with XDR-TB admitted to a TB referral hospital without previous XDR-TB treatment. A subset of isolates had extended DST (including capreomycin), mutational analysis, and IS6110 restriction fragment length polymorphism assays. Results:A total of 216 eligible patients with XDR-TB were identified. The majority were treated with capreomycin (72%), were young (median age: 35.5 years), and were female (56%). One hundred five (76%) were HIV+, and 109 (66%) were on antiretroviral therapy. A subset of 52 patients had full DST. A total of 47/52 (90.4%) patients with XDR-TB were capreomycin resistant. Capreomycin-resistant patients experienced worse mortality and culture conversion than capreomycin susceptible, although this difference was not statistically significant. The A1401G mutation in the rrs gene was associated with capreomycin resistance. The majority of capreomycin-resistant strains were F15/LAM4/KZN lineage (80%), and clustering was common in these isolates (92.5%). Conclusions:Capreomycin resistance is common in patients with XDR-TB in KwaZulu-Natal, is predominantly because of ongoing province-wide transmission of a highly resistant strain, and is associated with high mortality. Capreomycin should be included in routine DST in all patients with XDR-TB. New drug regimens that do not include injectable agents should be operationally tested as empiric treatment in XDR-TB.

Precision Surveillance for Viral Respiratory Pathogens: Virome Capture Sequencing for the Detection and Genomic Characterization of Severe Acute Respiratory Infection in Uganda

Abstract Background Precision public health is a novel set of methods to target disease prevention and mitigation interventions to high-risk subpopulations. We applied a precision public health strategy to syndromic surveillance for severe acute respiratory infection (SARI) in Uganda by combining spatiotemporal analytics with genomic sequencing to detect and characterize viral respiratory pathogens with epidemic potential. Methods Using a national surveillance network we identified patients with unexplained, influenza-negative SARI from 2010 to 2015. Spatiotemporal analyses were performed retrospectively to identify clusters of unexplained SARI. Within clusters, respiratory viruses were detected and characterized in naso- and oropharyngeal swab samples using a novel oligonucleotide probe capture (VirCapSeq-VERT) and high-throughput sequencing platform. Linkage to conventional epidemiologic strategies further characterized transmission dynamics of identified pathogens. Results Among 2901 unexplained SARI cases, 9 clusters were detected, accounting for 301 (10.4%) cases. Clusters were more likely to occur in urban areas and during biannual rainy seasons. Within detected clusters, we identified an unrecognized outbreak of measles-associated SARI; sequence analysis implicated cocirculation of endemic genotype B3 and genotype D4 likely imported from England. We also detected a likely nosocomial SARI cluster associated with a novel picobirnavirus most closely related to swine and dromedary viruses. Conclusions Using a precision approach to public health surveillance, we detected and characterized the genomics of vaccine-preventable and zoonotic respiratory viruses associated with clusters of severe respiratory infections in Uganda. Future studies are needed to assess the feasibility, scalability, and impact of applying similar approaches during real-time public health surveillance in low-income settings.

Emergence, Epidemiology, and Transmission Dynamics of 2009 Pandemic A/H1N1 Influenza in Kampala, Uganda, 2009–2015

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.

Transmission dynamics of influenza in two major cities of Uganda

In this paper, we report the epidemic characteristics of the three co-circulating influenza viruses (i.e., A/H1N1, A/H3N2, and B) in two tropical African cities-Kampala and Entebbe, Uganda-over an eight-year period (2008-2015). Using wavelet methods, we show that influenza epidemics recurred annually during the study period. In most months, two or more influenza viruses co-circulated at the same time. However, the epidemic timing differed by influenza (sub)type. Influenza A/H3N2 caused epidemics approximately every 2 years in both cities and tended to alternate with A/H1N1 or B. Influenza A/H1N1 and B produced smaller but more frequent epidemics and biennial epidemics of these two viruses tended to be synchronous. In addition, epidemics of A/H3N2 were more synchronized in the two cities (located ca.37 km apart) than that of A/H1N1 or influenza B.

Discordance between Tuberculin Skin Test and Interferon Gamma Release Assayis Associated with Previous Latent Tuberculosis Infection Treatment

Background: The performance of Interferon gamma release assays (IGRA) in drug users and the impact of previous latent tuberculosis infection (LTBI) treatment on discordance of IGRA and tuberculin skin test (TST) are unclear. Objective: To determine the prevalence and incidence of LTBI using TST and Quantiferon Gold In-Tube test (QFT-G-IT) in a cohort of persons with hepatitis C virus (HCV) and drug use history. Design: Eligible participants had baseline TST and QFT-G-IT assay and were retested with QFT-G-IT after 12 months to assess prevalence and incidence of LTBI. Results: Of 193 HCV-infected persons enrolled, 162 (84%) were HIV infected; 132 (81%) were on anti-retroviral therapy and 131 (81%) had a CD4 count >200. 190 (98%) had a history of drug use; only 19 (10%) were active intravenous drug users. 55 (28.5%) had LTBI based on TST results and 13 (7%) were diagnosed with LTBI based on QFT-G-IT. 46/193 persons (23.8%) had positive TST with negative QFT-G-IT test. History of LTBI treatment was a strong predictor of this discordance (OR=41.5; 95%CI 16.2-106.7; p<0.0001). No QFT-G-IT conversions were detected among the 101 initially QFT-G-IT negative patients retested at one year (95% CI: 0-3.6%). Conclusions: Intravenous drug users who are not actively using drugs have a low prevalence and incidence of LTBI by IGRA. Previous LTBI treatment is associated with a positive TST and a concurrent negative QFT-G-IT.

Unfinished business: severe acute respiratory infection in sub-Saharan Africa.

Dear Editor, We read with interest the results of the Intensive Care Global Study on Severe Acute Respiratory Infection (IC-GLOSSARI), which provide valuable insight into the epidemiology and management of critically ill SARI patients in North and South America, Europe, and Asia [1]. As the authors acknowledge, the study population was limited to patients in intensive care units in highand middle-income countries. Specifically, there were no study sites in sub-Saharan Africa, a large, geographically distinct region that accounts for a substantial proportion of global mortality from acute respiratory infections and hosts several emerging infectious disease “hotspots” [2]. Although surveillance for influenza-associated severe respiratory infections in sub-Saharan Africa has expanded considerably over the past decade, the contribution of other viral and bacterial pathogens to SARIrelated hospitalizations and deaths in the region remains unclear [3]. As available data suggest that influenza-negative SARI cases in sub-Saharan Africa may experience higher mortality, increased capacity for multiplexed respiratory diagnostics is urgently needed to support molecular epidemiologic studies in the region and enhance global health security through surveillance for emerging and re-emerging pathogens [3]. In developed countries, IC-GLOSSARI and similar studies have identified populations at risk for poor outcomes from influenza and other severe respiratory infections [1]. In contrast, little is known about the clinical epidemiology of patients at highest risk for SARI-related morbidity and mortality in sub-Saharan Africa and whether co-morbidities highly prevalent in the region, namely HIV infection, tuberculosis, and malaria, are consistently associated with poor outcomes [3]. Closing such data gaps is imperative, both to develop targeted vaccination and clinical management guidelines and inform pandemic preparedness through resource-allocation planning. Finally, in their editorial accompanying the publication of IC-GLOSSARI, Dr. Martin-Loeches and colleagues highlight clinical limitations of the broad SARI case-definition but acknowledge its potential utility as a triage tool in low-income countries [4]. We believe this is an important point that deserves emphasis. In subSaharan Africa, where intensive care facilities are scarce, patients with severe respiratory infections are predominantly cared for on hospital wards where poorly standardized triage practices challenge prompt identification and treatment of critical illness [5]. However, at four sentinel surveillance sites in Uganda, we have observed health care workers translating SARI case-identification into syndromic management, with hospitalized patients meeting SARI case-definitions prioritized for further evaluation (pulse oximetry, chest radiography) and basic, emergent interventions (supplemental oxygen, anti-microbials). While epidemiologic studies and improvements in diagnostic capacity are ongoing, we believe that utilization of SARI case-definitions has potential to improve clinical management and outcomes now for severely ill patients in sub-Saharan Africa and other resource-limited settings.