Efficiency of Field Laboratories for Ebola Virus Disease Outbreak during Chronic Insecurity, Eastern Democratic Republic of the Congo, 2018-2020.

During the 10th outbreak of Ebola virus disease in the Democratic Republic of the Congo, the Institut National de Recherche Biomédicale strategically positioned 13 decentralized field laboratories with dedicated equipment to quickly detect cases as the outbreak evolved. The laboratories were operated by national staff, who quickly handed over competencies and skills to local persons to successfully manage future outbreaks. Laboratories analyzed ≈230,000 Ebola diagnostic samples under stringent biosafety measures, documentation, and database management. Field laboratories diversified their activities (diagnosis, chemistry and hematology, survivor follow-up, and genomic sequencing) and shipped 127,993 samples from the field to a biorepository in Kinshasa under good conditions. Deploying decentralized and well-equipped laboratories run by local personnel in at-risk countries for Ebola virus disease outbreaks is an efficient response; all activities are quickly conducted in the field.

Sensitivity and Specificity of Rapid Diagnostic Tests for Hepatitis C Virus With or Without HIV Coinfection: A Multicentre Laboratory Evaluation Study.

BACKGROUND: Hepatitis C virus (HCV) screening is critical to HCV elimination efforts. Simplified diagnostics are required for low-resource settings and difficult-to-reach populations. This retrospective study assessed performance of rapid diagnostic tests (RDTs) for detection of HCV antibodies. METHODS: Two lots of 13 RDTs were evaluated at 3 laboratories using archived plasma samples from 4 countries (Nigeria, Georgia, Cambodia, and Belgium). HCV status was determined using 3 reference tests according to a composite algorithm. Sensitivity and specificity were evaluated in HIV-infected and HIV-uninfected populations. Operational characteristics were also assessed. RESULTS: In total, 1710 samples met inclusion criteria. In HIV-uninfected samples (n = 384), the majority of RDTs had sensitivity ≥98% in 1 or both lots and most RDTs had specificity ≥99%. In HIV-infected samples (n = 264), specificity remained high but sensitivity was markedly lower than in HIV-uninfected samples; only 1 RDT reached >95%. The majority of HIV-infected samples for which sensitivity was low did not have detectable HCV viral load/core antigen. Interreader variability, lot-to-lot variability, and rate of invalid runs were low for all RDTs (<2%). CONCLUSIONS: HCV RDTs should be evaluated in the intended target population, as sensitivity can be impacted by population factors such as HIV status. CLINICAL TRIALS REGISTRATION: NCT04033887.

Postmortem Surveillance for Ebola Virus Using OraQuick Ebola Rapid Diagnostic Tests, Eastern Democratic Republic of the Congo, 2019-2020.

After a pilot study, we tested 443 cadavers using OraQuick Ebola rapid diagnostic tests during surveillance after the 10th Ebola outbreak in the Democratic Republic of the Congo. No false negative and 2% false-positive results were reported. Quickly returning results and engaging the community enabled timely public health actions.

Transmission of NS5A-Inhibitor Resistance-Associated Substitutions Among Men Who Have Sex With Men Recently Infected with Hepatitis C Virus Genotype 1a.

The transmission of direct-acting antiviral resistance-associated substitutions (RAS) could hamper hepatitis C virus (HCV) cure rates and elimination efforts. A phylogenetic analysis of 87 men who have sex with men recently infected with HCV genotype 1a placed one-third (28/87) in a large cluster, in which 96% harbored NS5A M28V RAS.

Evaluation of Convalescent Plasma for Ebola Virus Disease in Guinea.

BACKGROUND: In the wake of the recent outbreak of Ebola virus disease (EVD) in several African countries, the World Health Organization prioritized the evaluation of treatment with convalescent plasma derived from patients who have recovered from the disease. We evaluated the safety and efficacy of convalescent plasma for the treatment of EVD in Guinea. METHODS: In this nonrandomized, comparative study, 99 patients of various ages (including pregnant women) with confirmed EVD received two consecutive transfusions of 200 to 250 ml of ABO-compatible convalescent plasma, with each unit of plasma obtained from a separate convalescent donor. The transfusions were initiated on the day of diagnosis or up to 2 days later. The level of neutralizing antibodies against Ebola virus in the plasma was unknown at the time of administration. The control group was 418 patients who had been treated at the same center during the previous 5 months. The primary outcome was the risk of death during the period from 3 to 16 days after diagnosis with adjustments for age and the baseline cycle-threshold value on polymerase-chain-reaction assay; patients who had died before day 3 were excluded. The clinically important difference was defined as an absolute reduction in mortality of 20 percentage points in the convalescent-plasma group as compared with the control group. RESULTS: A total of 84 patients who were treated with plasma were included in the primary analysis. At baseline, the convalescent-plasma group had slightly higher cycle-threshold values and a shorter duration of symptoms than did the control group, along with a higher frequency of eye redness and difficulty in swallowing. From day 3 to day 16 after diagnosis, the risk of death was 31% in the convalescent-plasma group and 38% in the control group (risk difference, -7 percentage points; 95% confidence interval [CI], -18 to 4). The difference was reduced after adjustment for age and cycle-threshold value (adjusted risk difference, -3 percentage points; 95% CI, -13 to 8). No serious adverse reactions associated with the use of convalescent plasma were observed. CONCLUSIONS: The transfusion of up to 500 ml of convalescent plasma with unknown levels of neutralizing antibodies in 84 patients with confirmed EVD was not associated with a significant improvement in survival. (Funded by the European Union's Horizon 2020 Research and Innovation Program and others; ClinicalTrials.gov number, NCT02342171.).

Rational use of Xpert testing in patients with presumptive TB: clinicians should be encouraged to use the test-treat threshold.

BACKGROUND: A recently published Ugandan study on tuberculosis (TB) diagnosis in HIV-positive patients with presumptive smear-negative TB, which showed that out of 90 patients who started TB treatment, 20% (18/90) had a positive Xpert MTB/RIF (Xpert) test, 24% (22/90) had a negative Xpert test, and 56% (50/90) were started without Xpert testing. Although Xpert testing was available, clinicians did not use it systematically. Here we aim to show more objectively the process of clinical decision-making. First, we estimated that pre-test probability of TB, or the prevalence of TB in smear-negative HIV infected patients with signs of presumptive TB in Uganda, was 17%. Second, we argue that the treatment threshold, the probability of disease at which the utility of treating and not treating is the same, and above which treatment should be started, should be determined. In Uganda, the treatment threshold was not yet formally established. In Rwanda, the calculated treatment threshold was 12%. Hence, one could argue that the threshold was reached without even considering additional tests. Still, Xpert testing can be useful when the probability of disease is above the treatment threshold, but only when a negative Xpert result can lower the probability of disease enough to cross the treatment threshold. This occurs when the pre-test probability is lower than the test-treat threshold, the probability of disease at which the utility of testing and the utility of treating without testing is the same. We estimated that the test-treatment threshold was 28%. Finally, to show the effect of the presence or absence of arguments on the probability of TB, we use confirming and excluding power, and a log10 odds scale to combine arguments. CONCLUSION: If the pre-test probability is above the test-treat threshold, empirical treatment is justified, because even a negative Xpert will not lower the post-test probability below the treatment threshold. However, Xpert testing for the diagnosis of TB should be performed in patients for whom the probability of TB was lower than the test-treat threshold. Especially in resource constrained settings clinicians should be encouraged to take clinical decisions and use scarce resources rationally.

Electrolyte and Metabolic Disturbances in Ebola Patients during a Clinical Trial, Guinea, 2015.

By using data from a 2015 clinical trial on Ebola convalescent-phase plasma in Guinea, we assessed the prevalence of electrolyte and metabolic abnormalities at admission and their predictive value to stratify patients into risk groups. Patients underwent testing with a point-of-care device. We used logistic regression to construct a prognostic model and summarized the predictive value with the area under the receiver operating curve. Abnormalities were common among patients, particularly hypokalemia, hypocalcemia, hyponatremia, raised creatinine, high anion gap, and anemia. Besides age and PCR cycle threshold value, renal dysfunction, low calcium levels, and low hemoglobin levels were independently associated with increased risk for death. A prognostic model using all 5 factors was highly discriminatory (area under the receiver operating curve 0.95; 95% CI 0.90-0.99) and enabled the definition of risk criteria to guide targeted care. Most patients had a very low (<5%) or very high (>80%) risk for death.

Design and analysis considerations in the Ebola_Tx trial evaluating convalescent plasma in the treatment of Ebola virus disease in Guinea during the 2014-2015 outbreak.

The Ebola virus disease outbreak in 2014-2015 led to a huge caseload with a high case fatality rate. No specific treatments were available beyond supportive care for conditions such as dehydration and shock. Evaluation of treatment with convalescent plasma from Ebola survivors was identified as a priority. We evaluated this intervention in an emergency setting, where randomization was unacceptable. The original trial design was an open-label study comparing patients receiving convalescent plasma and supportive care to patients receiving supportive care alone. The comparison group comprised patients recruited at the start of the trial before convalescent plasma became available, as well as patients presenting during the trial for whom there was insufficient blood group-compatible plasma or no staffing capacity to provide additional transfusions. However, during the trial, convalescent plasma was available to treat all new patients. The design was changed to use a comparator group comprising patients previously treated at the same Ebola treatment center prior to the start of the trial. In the analysis, it was planned to adjust for any differences in prognostic variables between intervention and comparison groups, specifically baseline polymerase chain reaction cycle threshold and age. In addition, adjustment was planned for other potential confounders, identified in the analysis, such as patient presenting symptoms and time to treatment seeking. Because plasma treatment started up to 3 days after diagnosis and we could not define a similar time-point for the comparator group, patients who died before the third day after confirmation of diagnosis were excluded from both intervention and comparison groups in a per-protocol analysis. Some patients received additional experimental treatments soon after plasma treatment, and these were excluded. We also analyzed mortality including all patients from the time of confirmed diagnosis, irrespective of whether those in the trial series actually received plasma, as an intention-to-treat analysis. Per-protocol and intention-to-treat approaches gave similar conclusions. An important caveat in the interpretation of the findings is that it is unlikely that all potential sources of confounding, such as any variation in supportive care over time, were eliminated. Protocols and electronic data capture systems have now been extensively field-tested for emergency evaluation of treatment with convalescent plasma. Ongoing studies seek to quantify the level of neutralizing antibodies in different plasma donations to determine whether this influences the response and survival of treated patients.

Evaluation of centralised and decentralised models of care during the 2020 Ebola Virus Disease outbreak in Equateur Province, Democratic Republic of the Congo: A brief report.

Background: Traditionally in the Democratic Republic of the Congo (DRC), centralised Ebola treatment centres (ETCs) have been set exclusively for Ebola virus disease (EVD) case management during outbreaks. During the 2020 EVD outbreak in DRC's Equateur Province, existing health centres were equipped as decentralised treatment centres (DTC) to improve access for patients with suspected EVD. Between ETCs and DTCs, we compared the time from symptom onset to admission and diagnosis among patients with suspected EVD. Methods: This was a cohort study based on analysis of a line-list containing demographic and clinical information of patients with suspected EVD admitted to any EVD health facility during the outbreak. Results: Of 2359 patients with suspected EVD, 363 (15%) were first admitted to a DTC. Of 1996 EVD-suspected patients initially admitted to an ETC, 72 (4%) were confirmed as EVD-positive. Of 363 EVD-suspected patients initially admitted to a DTC, 6 (2%) were confirmed and managed as EVD-positive in the DTC. Among all EVD-suspected patients, the median (interquartile range) duration between symptom onset and admission was 2 (1-4) days in a DTC compared to 4 (2-7) days in an ETC (p<0.001). Similarly, time from symptom onset to admission was significantly shorter among EVD-suspected patients ultimately diagnosed as EVD-negative. Conclusions: Since <5% of the EVD-suspected patients admitted were eventually diagnosed with EVD, there is a need for better screening to optimise resource utilization and outbreak control. Only one in seven EVD-suspected patients were admitted to a DTC first, as the DTCs were piloted in a limited and phased manner. However, there is a case to be made for considering decentralized care especially in remote and hard-to-reach areas in places like the DRC to facilitate early access to care, contain viral shedding by patients with EVD and ensure no disrupted provision of non-EVD services.

Mild and moderate COVID-19 during Alpha, Delta and Omicron pandemic waves in urban Maputo, Mozambique, December 2020-March 2022: A population-based surveillance study.

In sub-Saharan Africa, reported COVID-19 numbers have been lower than anticipated, even when considering populations' younger age. The extent to which risk factors, established in industrialised countries, impact the risk of infection and of disease in populations in sub-Saharan Africa, remains unclear. We estimated the incidence of mild and moderate COVID-19 in urban Mozambique and analysed factors associated with infection and disease in a population-based surveillance study. During December 2020-March 2022, 1,561 households (6,049 participants, median 21 years, 54.8% female, 7.3% disclosed HIV positive) of Polana Caniço, Maputo, Mozambique, were visited biweekly to report respiratory symptoms, anosmia, or ageusia, and self-administer a nasal swab for SARS-CoV-2 testing. Every three months, dried blood spots of a subset of participants (1,412) were collected for detection of antibodies against SARS-CoV-2 spike glycoprotein and nucleocapsid protein. Per 1000 person-years, 364.5 (95%CI 352.8-376.1) respiratory illness episodes were reported, of which 72.2 (95%CI 60.6-83.9) were COVID-19. SARS-CoV-2 seroprevalence rose from 4.8% (95%CI 1.1-8.6%) in December 2020 to 34.7% (95%CI 20.2-49.3%) in June 2021, when 3.0% were vaccinated. Increasing age, chronic lung disease, hypertension, and overweight increased risk of COVID-19. Older age increased the risk of SARS-CoV-2 seroconversion. We observed no association between socio-economic status, behaviour and COVID-19 or SARS-CoV-2 seroconversion. Active surveillance in an urban population confirmed frequent COVID-19 underreporting, yet indicated that the large majority of cases were mild and non-febrile. In contrast to reports from industrialised countries, social deprivation did not increase the risk of infection nor disease.