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In Uganda, children with febrile illness are often treated with antibiotics even though most have self-limiting, likely viral, infections. C-reactive protein (CRP) measurement can help identify those who are more likely to have a bacterial infection and therefore need antibiotic treatment. Implementation of a CRP rapid diagnostic test (RDT) at the point-of-care in resource-constrained settings with minimal laboratory infrastructure could reduce unnecessary antibiotic use. In this study, we evaluated the performance of three semi-quantitative CRP RDTs (Actim, BTNX, Duo) against a reference CRP assay requiring an electrically powered analyzer (Afinion). While both tests demonstrated substantial agreement with Afinion, Actim had slightly higher agreement than BTNX. The sensitivity was higher for the BTNX test, whereas the Actim test had a higher specificity, at cut-offs of 40 mg/L and 80 mg/L. At a cut-off of 20 mg/L, Duo demonstrated substantial agreement with the Afinion test as well. Our results demonstrate the reliability of CRP RDTs when compared to a reference standard. CRP RDTs without the need for a laboratory-based analyzer are promising tools for optimizing antibiotic use in low-resource settings.

BackgroundResistance to antibiotics is rising and threatens future antibiotic effectiveness. 'Antibiotic targeting' ensures patients who may benefit from antibiotics receive them, while being safely withheld from those who may not. Point-of-care tests may assist with antibiotic targeting by allowing primary care clinicians to establish if symptomatic patients have a viral, bacterial, combined, or no infection. However, because organisms can be harmlessly carried, it is important to know if the presence of the virus/bacteria is related to the illness for which the patient is being assessed. One way to do this is to look for associations with more severe/prolonged symptoms and test results. Previous research to answer this question for acute respiratory tract infections has given conflicting results with studies has not having enough participants to provide statistical confidence.AimTo undertake a synthesis of IPD from both randomised controlled trials (RCTs) and observational cohort studies of respiratory tract infections (RTI) in order to investigate the prognostic value of microbiological data in addition to, or instead of, clinical symptoms and signs.MethodsA systematic search of Cochrane Central Register of Controlled Trials, Ovid Medline and Ovid Embase will be carried out for studies of acute respiratory infection in primary care settings. The outcomes of interest are duration of disease, severity of disease, repeated consultation with new/worsening illness and complications requiring hospitalisation. Authors of eligible studies will be contacted to provide anonymised individual participant data. The data will be harmonised and aggregated. Multilevel regression analysis will be conducted to determine key outcome measures for different potential pathogens and whether these offer any additional information on prognosis beyond clinical symptoms and signs.Trial registrationPROSPERO Registration number: CRD42023376769.

Public health surveillance systems likely underestimate the true prevalence and incidence of SARS-CoV-2 infection due to limited access to testing and the high proportion of subclinical infections in community-based settings. This ongoing prospective, observational study aimed to generate accurate estimates of the prevalence and incidence of, and risk factors for, SARS-CoV-2 infection among residents of a central North Carolina county. From this cohort, we collected survey data and nasal swabs every two weeks and venous blood specimens every month. Nasal swabs were tested for the presence of SARS-CoV-2 virus (evidence of active infection), and serum specimens for SARS-CoV-2-specific antibodies (evidence of prior infection). As of June 23, 2021, we have enrolled a total of 153 participants from a county with an estimated 76,285 total residents. The anticipated study duration is at least 24 months, pending the evolution of the pandemic. Study data are being shared on a monthly basis with North Carolina state health authorities and future analyses aim to compare study data to state-wide metrics over time. Overall, the use of a probability-based sampling design and a well-characterized cohort will enable collection of critical data that can be used in planning and policy decisions for North Carolina and may be informative for other states with similar demographic characteristics.

As the field of global child health increasingly focuses on inpatient and emergency care, there is broad recognition of the need for comprehensive, accurate data to guide decision-making at both patient and system levels. Limited financial and human resources present barriers to reliable and detailed clinical documentation at hospitals in low-and-middle-income countries (LMICs). Kamuzu Central Hospital (KCH) is a tertiary referral hospital in Malawi where the paediatric ward admits up to 3000 children per month. To improve availability of robust inpatient data, we collaboratively designed an acute care database on behalf of PACHIMAKE, a consortium of Malawi and US-based institutions formed to improve paediatric care at KCH. We assessed the existing health information systems at KCH, reviewed quality care metrics, engaged clinical providers and interviewed local stakeholders who would directly use the database or be involved in its collection. Based on the information gathered, we developed electronic forms collecting data at admission, follow-up and discharge for children admitted to the KCH paediatric wards. The forms record demographic information, basic medical history, clinical condition and pre-referral management; track diagnostic processes, including laboratory studies, imaging modalities and consults; and document the final diagnoses and disposition obtained from clinical files and corroborated through review of existing admission and death registries. Our experience with the creation of this database underscores the importance of fully assessing existing health information systems and involving all stakeholders early in the planning process to ensure meaningful and sustainable implementation.

The pathogenesis of immunodeficiency due to human immunodeficiency virus (HIV)-1 is incompletely understood, but immune activation is believed to play a central role. Immunomodulatory agents that decrease immune activation may be useful in the treatment of HIV-1 infection.A randomized, double blind, placebo-controlled pilot study of leflunomide for 28 days was performed in participants with HIV-1 infection who were not receiving antiretroviral therapy. Participants randomized to leflunomide were subsequently treated with cholestyramine until leflunomide levels were below detection limit.Treatment with leflunomide was well tolerated with mostly low-grade adverse events. Leflunomide administration reduced cycling of CD4 T cells (by ex vivo bromodeoxyuridine uptake and Ki67 expression) and decreased expression of activation markers (HLA-DR/CD38 co-expression) on CD8 T cells in peripheral blood. In addition, decreased expression of HIV-1 co-receptors was observed in both CD4 and CD8 T cells in the leflunomide group. There were no significant changes in naïve and memory T cell subsets, apoptosis of T cells or markers of microbial translocation.Leflunomide was effective in reducing immune activation in the setting of chronic HIV-1 infection suggesting that targeting immune activation with immunomodulatory agents may be a feasible strategy.ClinicalTrials.gov NCT00101374.

Abstract Background The COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to evolve as a global health crisis. Although highly effective vaccines have been developed, non-pharmaceutical interventions remain critical to controlling disease transmission. One such intervention—rapid, at-home antigen self-testing—can ease the burden associated with facility-based testing programs and improve testing access in high-risk communities. However, its impact on SARS-CoV-2 community transmission has yet to be definitively evaluated, and the socio-behavioral aspects of testing in underserved populations remain unknown. Methods As part of the Rapid Acceleration of Diagnostics–Underserved Populations (RADx-UP) program funded by the National Institutes of Health, we are implementing a public health intervention titled “Say Yes! COVID Test” (SYCT) involving at-home self-testing using a SARS-CoV-2 rapid antigen assay in North Carolina (Greenville, Pitt County) and Tennessee (Chattanooga City, Hamilton County). The intervention is supported by a multifaceted communication and community engagement strategy to ensure widespread awareness and uptake, particularly in marginalized communities. Participants receive test kits either through online orders or via local community distribution partners. To assess the impact of this intervention on SARS-CoV-2 transmission, we will conduct a non-randomized, ecological study using community-level outcomes. Specifically, we will evaluate trends in SARS-CoV-2 cases and hospitalizations, SARS-CoV-2 viral load in wastewater, and population mobility in each community before, during, and after the SYCT intervention. Individuals who choose to participate in SYCT will also have the option to enroll in an embedded prospective cohort substudy gathering participant-level data to evaluate behavioral determinants of at-home self-testing and socio-behavioral mechanisms of SARS-CoV-2 community transmission. Discussion This is the first large-scale, public health intervention implementing rapid, at-home SARS-CoV-2 self-testing in the United States. The program consists of a novel combination of an at-home testing program, a broad communications and community engagement strategy, an ecological study to assess impact, and a research substudy of the behavioral aspects of testing. The findings from the SYCT project will provide insights into innovative methods to mitigate viral transmission, advance the science of public health communications and community engagement, and evaluate emerging, novel assessments of community transmission of disease.

ABSTRACT Pediatric acute respiratory illness (ARI) is one of the most common reasons for evaluation at peripheral health centers in sub-Saharan Africa and is frequently managed based on clinical syndrome alone. Although most ARI episodes are likely caused by self-limited viral infections, the majority are treated with antibiotics. This overuse contributes to the development of antimicrobial resistance. To evaluate the preliminary feasibility and potential impact of adding pathogen-specific and clinical biomarker diagnostic testing to existing clinical management algorithms, we conducted a prospective, observational cohort study of 225 children presenting with malaria-negative, febrile ARI to the outpatient department of a semi-urban peripheral health facility in southwestern Uganda from October 2019 to January 2020. In addition to routine clinical evaluation, we performed influenza and Streptococcus pneumoniae antigen testing and measured levels of C-reactive protein, procalcitonin, and lactate in the clinic’s laboratory, and conducted a follow-up assessment by phone 7 days later. Almost one-fifth of participants (40/225) tested positive for influenza. Clinical biomarker measurements were low with C-reactive protein of >40 mg/L in only 11% (13/222) of participants and procalcitonin >0.25 ng/mL in only 13% (16/125). All but two children received antibiotic treatment; only 3% (7/225) were admitted. At follow-up, 59% (118/201) of caregivers reported at least one persistent symptom, but fever had resolved for all children. Positive influenza testing was associated with persistent symptoms. In summary, we demonstrate that simple, rapid pathogen-specific testing and biomarker measurement are possible in resource-limited settings and could improve syndromic management and, in turn, antibiotic stewardship. IMPORTANCE Globally, respiratory illness is one of the most common reasons that children seek care. It is often treated inappropriately with antibiotics, which can drive the development of antibiotic resistance. In resource-rich settings, testing for specific pathogens or measurement of clinical biomarkers, such as procalcitonin and C-reactive protein, is often employed to help determine which children should receive antibiotics. However, there are limited data on the use of these tests in resource-constrained, outpatient contexts in sub-Saharan Africa. We enrolled children with respiratory illness presenting to a clinic in southwestern Uganda and performed testing for influenza, Streptococcus pneumoniae, C-reactive protein, and procalcitonin on-site. Almost all children received antibiotics. We demonstrate that employing clinical algorithms that include influenza and clinical biomarker testing could significantly decrease antibiotic prescriptions. Our study therefore provides preliminary data to support the feasibility and potential utility of diagnostics to improve management of respiratory illness in resource-constrained settings.

Public health surveillance systems likely underestimate the true prevalence and incidence of SARS-CoV-2 infection due to limited access to testing and the high proportion of subclinical infections in community-based settings. This ongoing prospective, observational study aimed to generate accurate estimates of the prevalence and incidence of, and risk factors for, SARS-CoV-2 infection among residents of a central North Carolina county. From this cohort, we collected survey data and nasal swabs every two weeks and venous blood specimens every month. Nasal swabs were tested for the presence of SARS-CoV-2 virus (evidence of active infection), and serum specimens for SARS-CoV-2-specific antibodies (evidence of prior infection). As of June 23, 2021, we have enrolled a total of 153 participants from a county with an estimated 76,285 total residents. The anticipated study duration is at least 24 months, pending the evolution of the pandemic. Study data are being shared on a monthly basis with North Carolina state health authorities and future analyses aim to compare study data to state-wide metrics over time. Overall, the use of a probability-based sampling design and a well-characterized cohort will enable collection of critical data that can be used in planning and policy decisions for North Carolina and may be informative for other states with similar demographic characteristics.

Abstract Background Death audits have been used to describe pediatric mortality in under-resourced settings, where record keeping is often a challenge. This information provides the cornerstone for the foundation of quality improvement initiatives. Malawi, located in sub-Saharan Africa, currently has an Under-5 mortality rate of 64/1000. Kamuzu Central Hospital, in the capital city Lilongwe, is a busy government referral hospital, which admits up to 3000 children per month. A study published in 2013 reported mortality rates as high as 9%. This is the first known audit of pediatric death files conducted at this hospital. Methods A retrospective chart review on all pediatric deaths that occurred at Kamuzu Central Hospital (excluding deaths in the neonatal nursery) during a 13-month period was done using a standardized death audit form. A descriptive analysis was completed, including patient demographics, HIV and nutritional status, and cause of death. Modifiable factors were identified that may have contributed to mortality, including a lack of vital sign collection, poor documentation, and delays in the procurement or results of tests, studies, and specialist review. Results Seven hundred forty three total pediatric deaths were recorded and 700 deceased patient files were reviewed. The mortality rate by month ranged from a low of 2.2% to a high of 4.4%. Forty-four percent of deaths occurred within the first 24 h of admission, and 59% occurred within the first 48 h. The most common causes of death were malaria, malnutrition, HIV-related illnesses, and sepsis. Conclusions The mortality rate for this pediatric referral center has dramatically decreased in the 6 years since the last published mortality data, but remains high. Areas identified for continued development include improved record keeping, improved patient assessment and monitoring, and more timely and reliable provision of testing and treatment. This study demonstrates that in low-resource settings, where reliable record keeping is often difficult, death audits are useful tools to describe the sickest patient population and determine factors possibly contributing to mortality that may be amenable to quality improvement interventions.

ABSTRACT The region encompassing the Pacific Northwest (PNW), Vancouver Island, Oregon, and Washington has been the location of an ongoing Cryptococcus gattii outbreak since the 1990s, and there is evidence that the outbreak is expanding along the West Coast into California. Here we report a clinical case of a 69-year-old, HIV-negative man from North Carolina who was diagnosed with a fungal brain mass by magnetic resonance imaging (MRI) and pathology. He had traveled to Seattle and Vancouver 3 years earlier and to Costa Rica 4 months prior to presentation. Phenotypic evidence showed that the fungal mass isolated from the patient’s brain represented C. gattii. In agreement with the phenotypic results, multilocus sequence typing (MLST) provided genotypic evidence that assigned the infecting organism within the C. gattii species complex and to the C. deuterogattii VGIIa clade. Whole-genome sequencing revealed >99.99% identity with the C. deuterogattii reference strain R265, indicating that the infecting strain is derived from the highly clonal outbreak strains in the PNW. We conclude that the patient acquired the C. gattii infection during his travel to the region 3 years prior and that the infection was dormant for an extended period of time before causing disease. The patient tested positive for anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibodies, supporting earlier reports that implicate these autoantibodies as a risk factor associated with C. gattii infection. IMPORTANCE Mortality rates associated with C. gattii infections are estimated to be between 13% and 33%, depending on an individual’s predisposition, and C. gattii has caused at least 39 deaths in the PNW region. There have been four other international travel cases reported in patients from Europe and Asia with travel history to the PNW, but this report describes the first North American traveler who acquired C. deuterogattii infection presenting within the United States and the first case of a C. deuterogattii outbreak infection associated with anti-GM-CSF autoantibodies. Early and accurate diagnoses are important for disease prevention and treatment and for control of infectious diseases. Continual reporting of C. deuterogattii infections is necessary to raise awareness of the ongoing outbreak in the PNW and to alert travelers and physicians to the areas of endemicity with potential risks.

Abstract Background Ehrlichiosis is a potentially fatal tick-borne disease that can progress to involve the central nervous system (CNS) (i.e., neuro-ehrlichiosis), particularly in cases where diagnosis and treatment are delayed. Despite a six-fold national increase in the incidence of ehrlichiosis over the past 20 years, recent data on the prevalence and manifestations of neuro-ehrlichiosis are lacking. Methods We conducted a retrospective chart review of all patients tested for ehrlichiosis at University of North Carolina Health facilities between 2018 and 2021 and identified patients who met epidemiological criteria for ehrlichiosis as established by the Council of State and Territorial Epidemiologists and employed by the Centers for Disease Control and Prevention. We estimated the prevalence of neurological symptoms and described the spectrum of neurological manifestations in acute ehrlichiosis, documenting select patient cases in more detail in a case series. Results Out of 55 patients with confirmed or probable ehrlichiosis, five patients (9.1%) had neurologic symptoms, which is notably lower than previous estimates. Neurological presentations were highly variable and included confusion, amnesia, seizures, focal neurological deficits mimicking ischemic vascular events, and an isolated cranial nerve palsy, though all patients had unremarkable neuroimaging at time of presentation. All but one patient had risk factors for severe ehrlichiosis (i.e., older age, immunosuppression). Conclusions Neuro-ehrlichiosis may lack unifying patterns in clinical presentation that would otherwise aid in diagnosis. Clinicians should maintain a high index of suspicion for neuro-ehrlichiosis in patients with acute febrile illness, diverse neurological symptoms, and negative neuroimaging in lone star tick endemic regions.

Abstract Background The spatial distribution and burden of dengue in sub-Saharan Africa remains highly uncertain, despite high levels of ecological suitability. The goal of this study was to describe the epidemiology of dengue among a cohort of febrile children presenting to outpatient facilities located in areas of western Uganda with differing levels of urbanicity and malaria transmission intensity. Methods Eligible children were first screened for malaria using rapid diagnostic tests. Children with a negative malaria result were tested for dengue using a combination NS1/IgM/IgG rapid test (SD Bioline Dengue Duo). Confirmatory testing by RT-PCR was performed in a subset of participants. Antigen-capture ELISA was performed to estimate seroprevalence. Results Only 6 of 1416 (0.42%) children had a positive dengue rapid test, while none of the RT-PCR results were positive. ELISA testing demonstrated reactive IgG antibodies in 28 (2.2%) participants with the highest prevalence seen at the urban site in Mbarara (19 of 392, 4.9%, p

Conducting collaborative and comprehensive epidemiological research on neonatal sepsis in low- and middle-income countries (LMICs) is challenging due to a lack of diagnostic tests. This prospective study protocol aims to obtain epidemiological data on bacterial sepsis in newborns and young infants at Kamuzu Central Hospital in Lilongwe, Malawi. The main goal is to determine if the use of whole blood transcriptome host immune response signatures can help in the identification of infants who have sepsis of bacterial causes. The protocol includes a detailed clinical assessment with vital sign measurements, strict aseptic blood culture protocol with state-of-the-art microbial analyses and RNA-sequencing and metagenomics evaluations of host responses and pathogens, respectively. We also discuss the directions of a brief analysis plan for RNA sequencing data. This study will provide robust epidemiological data for sepsis in neonates and young infants in a setting where sepsis confers an inordinate burden of disease.