Clinical and Epidemiological Aspects of Diphtheria: A Systematic Review and Pooled Analysis.

BACKGROUND: Diphtheria, once a major cause of childhood morbidity and mortality, all but disappeared following introduction of diphtheria vaccine. Recent outbreaks highlight the risk diphtheria poses when civil unrest interrupts vaccination and healthcare access. Lack of interest over the last century resulted in knowledge gaps about diphtheria's epidemiology, transmission, and control. METHODS: We conducted 9 distinct systematic reviews on PubMed and Scopus (March-May 2018). We pooled and analyzed extracted data to fill in these key knowledge gaps. RESULTS: We identified 6934 articles, reviewed 781 full texts, and included 266. From this, we estimate that the median incubation period is 1.4 days. On average, untreated cases are colonized for 18.5 days (95% credible interval [CrI], 17.7-19.4 days), and 95% clear Corynebacterium diphtheriae within 48 days (95% CrI, 46-51 days). Asymptomatic carriers cause 76% (95% confidence interval, 59%-87%) fewer cases over the course of infection than symptomatic cases. The basic reproductive number is 1.7-4.3. Receipt of 3 doses of diphtheria toxoid vaccine is 87% (95% CrI, 68%-97%) effective against symptomatic disease and reduces transmission by 60% (95% CrI, 51%-68%). Vaccinated individuals can become colonized and transmit; consequently, vaccination alone can only interrupt transmission in 28% of outbreak settings, making isolation and antibiotics essential. While antibiotics reduce the duration of infection, they must be paired with diphtheria antitoxin to limit morbidity. CONCLUSIONS: Appropriate tools to confront diphtheria exist; however, accurate understanding of the unique characteristics is crucial and lifesaving treatments must be made widely available. This comprehensive update provides clinical and public health guidance for diphtheria-specific preparedness and response.

Asymptomatic SARS-CoV-2 Infection and COVID-19 Mortality During an Outbreak Investigation in a Skilled Nursing Facility.

BACKGROUND: Outbreaks of coronavirus disease 2019 (COVID-19) have been reported in nursing homes and assisted living facilities; however, the extent of asymptomatic and presymptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in this high-risk population remains unclear. METHODS: We conducted an investigation of the first known outbreak of SARS-CoV-2 at a skilled nursing facility (SNF) in Illinois on 15 March 2020 and followed residents for 30 days. We tested 126/127 residents for SARS-CoV-2 via reverse-transcription polymerase chain reaction and performed symptom assessments. We calculated the point prevalence of SARS-CoV-2 and assessed symptom onset over 30-day follow-up to determine: (1) the proportion of cases who were symptomatic, presymptomatic, and asymptomatic and (2) incidence of symptoms among those who tested negative. We used the Kaplan-Meier method to determine the 30-day probability of death for cases. RESULTS: Of 126 residents tested, 33 had confirmed SARS-CoV-2 on 15 March. Nineteen (58%) had symptoms at the time of testing, 1 (3%) developed symptoms over follow-up, and 13 (39%) remained asymptomatic. Thirty-five residents who tested negative on 15 March developed symptoms over follow-up; of these, 3 were re-tested and 2 were positive. The 30-day probability of death among cases was 29%. CONCLUSIONS: SNFs are particularly vulnerable to SARS-CoV-2, and residents are at risk of severe outcomes. Attention must be paid to preventing outbreaks in these and other congregate care settings. Widespread testing and infection control are key to help prevent COVID-19 morbidity and mortality in these high-risk populations.

Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis.

The American Thoracic Society, Centers for Disease Control and Prevention, and Infectious Diseases Society of America jointly sponsored the development of this guideline for the treatment of drug-susceptible tuberculosis, which is also endorsed by the European Respiratory Society and the US National Tuberculosis Controllers Association. Representatives from the American Academy of Pediatrics, the Canadian Thoracic Society, the International Union Against Tuberculosis and Lung Disease, and the World Health Organization also participated in the development of the guideline. This guideline provides recommendations on the clinical and public health management of tuberculosis in children and adults in settings in which mycobacterial cultures, molecular and phenotypic drug susceptibility tests, and radiographic studies, among other diagnostic tools, are available on a routine basis. For all recommendations, literature reviews were performed, followed by discussion by an expert committee according to the Grading of Recommendations, Assessment, Development and Evaluation methodology. Given the public health implications of prompt diagnosis and effective management of tuberculosis, empiric multidrug treatment is initiated in almost all situations in which active tuberculosis is suspected. Additional characteristics such as presence of comorbidities, severity of disease, and response to treatment influence management decisions. Specific recommendations on the use of case management strategies (including directly observed therapy), regimen and dosing selection in adults and children (daily vs intermittent), treatment of tuberculosis in the presence of HIV infection (duration of tuberculosis treatment and timing of initiation of antiretroviral therapy), as well as treatment of extrapulmonary disease (central nervous system, pericardial among other sites) are provided. The development of more potent and better-tolerated drug regimens, optimization of drug exposure for the component drugs, optimal management of tuberculosis in special populations, identification of accurate biomarkers of treatment effect, and the assessment of new strategies for implementing regimens in the field remain key priority areas for research. See the full-text online version of the document for detailed discussion of the management of tuberculosis and recommendations for practice.

Executive Summary: Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis.

The American Thoracic Society, Centers for Disease Control and Prevention, and Infectious Diseases Society of America jointly sponsored the development of this guideline for the treatment of drug-susceptible tuberculosis, which is also endorsed by the European Respiratory Society and the US National Tuberculosis Controllers Association. Representatives from the American Academy of Pediatrics, the Canadian Thoracic Society, the International Union Against Tuberculosis and Lung Disease, and the World Health Organization also participated in the development of the guideline. This guideline provides recommendations on the clinical and public health management of tuberculosis in children and adults in settings in which mycobacterial cultures, molecular and phenotypic drug susceptibility tests, and radiographic studies, among other diagnostic tools, are available on a routine basis. For all recommendations, literature reviews were performed, followed by discussion by an expert committee according to the Grading of Recommendations, Assessment, Development and Evaluation methodology. Given the public health implications of prompt diagnosis and effective management of tuberculosis, empiric multidrug treatment is initiated in almost all situations in which active tuberculosis is suspected. Additional characteristics such as presence of comorbidities, severity of disease, and response to treatment influence management decisions. Specific recommendations on the use of case management strategies (including directly observed therapy), regimen and dosing selection in adults and children (daily vs intermittent), treatment of tuberculosis in the presence of HIV infection (duration of tuberculosis treatment and timing of initiation of antiretroviral therapy), as well as treatment of extrapulmonary disease (central nervous system, pericardial among other sites) are provided. The development of more potent and better-tolerated drug regimens, optimization of drug exposure for the component drugs, optimal management of tuberculosis in special populations, identification of accurate biomarkers of treatment effect, and the assessment of new strategies for implementing regimens in the field remain key priority areas for research. See the full-text online version of the document for detailed discussion of the management of tuberculosis and recommendations for practice.

Times to key events in Zika virus infection and implications for blood donation: a systematic review.

OBJECTIVE: To estimate the timing of key events in the natural history of Zika virus infection. METHODS: In February 2016, we searched PubMed, Scopus and the Web of Science for publications containing the term Zika. By pooling data, we estimated the incubation period, the time to seroconversion and the duration of viral shedding. We estimated the risk of Zika virus contaminated blood donations. FINDINGS: We identified 20 articles on 25 patients with Zika virus infection. The median incubation period for the infection was estimated to be 5.9 days (95% credible interval, CrI: 4.4-7.6), with 95% of people who developed symptoms doing so within 11.2 days (95% CrI: 7.6-18.0) after infection. On average, seroconversion occurred 9.1 days (95% CrI: 7.0-11.6) after infection. The virus was detectable in blood for 9.9 days (95% CrI: 6.9-21.4) on average. Without screening, the estimated risk that a blood donation would come from an infected individual increased by approximately 1 in 10 000 for every 1 per 100 000 person-days increase in the incidence of Zika virus infection. Symptom-based screening may reduce this rate by 7% (relative risk, RR: 0.93; 95% CrI: 0.89-0.99) and antibody screening, by 29% (RR: 0.71; 95% CrI: 0.28-0.88). CONCLUSION: Neither symptom- nor antibody-based screening for Zika virus infection substantially reduced the risk that blood donations would be contaminated by the virus. Polymerase chain reaction testing should be considered for identifying blood safe for use in pregnant women in high-incidence areas.

Impact of GeneXpert MTB/RIF on patients and tuberculosis programs in a low-burden setting. a hypothetical trial.

RATIONALE: Guidelines recommend routine nucleic-acid amplification testing in patients with presumed tuberculosis (TB), but these tests have not been widely adopted. GeneXpert MTB/RIF (Xpert), a novel, semiautomated TB nucleic-acid amplification test, has renewed interest in this technology, but data from low-burden countries are limited. OBJECTIVES: We sought to estimate Xpert's potential clinical and public health impact on empiric treatment, contact investigation, and housing in patients undergoing TB evaluation. METHODS: We performed a prospective, cross-sectional study with 2-month follow-up comparing Xpert with standard strategies for evaluating outpatients for active pulmonary TB at the San Francisco Department of Public Health TB Clinic between May 2010 and June 2011. We calculated the diagnostic accuracy of standard algorithms for initial empiric TB treatment, contact investigation, and housing in reference to three Mycobacterium tuberculosis sputum cultures, as compared with that of a single sputum Xpert test. We estimated the incremental diagnostic value of Xpert, and the hypothetical reductions in unnecessary treatment, contact investigation, and housing if Xpert were adopted to guide management decisions. MEASUREMENTS AND MAIN RESULTS: A total of 156 patients underwent Xpert testing. Fifty-nine (38%) received empiric TB treatment. Thirteen (8%) had culture-positive TB. Xpert-guided management would have hypothetically decreased overtreatment by 94%, eliminating a median of 44 overtreatment days (interquartile range, 43-47) per patient and 2,169 total overtreatment days (95% confidence interval, 1,938-2,400) annually, without reducing early detection of TB patients. We projected similar benefits for contact investigation and housing. CONCLUSIONS: Xpert could greatly reduce the frequency and impact of unnecessary empiric treatment, contact investigation, and housing, providing substantial patient and programmatic benefits if used in management decisions.

Impact of GeneXpert MTB/RIF assay on triage of respiratory isolation rooms for inpatients with presumed tuberculosis: a hypothetical trial.

BACKGROUND: Placing inpatients with presumed active pulmonary tuberculosis in respiratory isolation pending results of serial sputum acid-fast bacilli (AFB) smear microscopy is standard practice in high-income countries. However, this diagnostic strategy is slow and yields few tuberculosis diagnoses. We sought to determine if replacing microscopy with the GeneXpert MTB/RIF (Xpert) nucleic acid amplification assay could reduce testing time and usage of isolation rooms. METHODS: We prospectively followed inpatients at San Francisco General Hospital undergoing tuberculosis evaluation. We performed smear microscopy and Xpert testing on concentrated sputum, and calculated diagnostic accuracy for both strategies in reference to serial sputum mycobacterial culture. We measured turnaround time for microscopy and estimated hypothetical turnaround times for Xpert on concentrated and unconcentrated sputum. We compared median and total isolation times for microscopy to those estimated for the 2 Xpert strategies. RESULTS: Among 139 patients with 142 admissions, median age was 54 years (interquartile range [IQR], 43-60 years); 32 (23%) patients were female, and 42 (30%) were HIV seropositive. Serial sputum smear microscopy and a single concentrated sputum Xpert had identical sensitivity (89%; 95% confidence interval [CI], 52%-100%) and similar specificity (99% [95% CI, 96%-100%] vs 100% [95% CI, 97%-100%]). A single concentrated sputum Xpert could have saved a median of 35 hours (IQR, 24-36 hours) in unnecessary isolation compared with microscopy, and a single unconcentrated sputum Xpert, 45 hours (IQR, 35-46 hours). CONCLUSIONS: Replacing serial sputum smear microscopy with a single sputum Xpert could eliminate most unnecessary isolation for inpatients with presumed tuberculosis, greatly benefiting patients and hospitals.

Sex differences in tuberculosis infection and disease among people with HIV.

OBJECTIVES: Worldwide, adult men experience an excess burden of tuberculosis (TB) disease compared to women, but few studies have examined sex differences in TB among people with HIV. In this study, we aimed to investigate sex differences in TB infection and disease among people with HIV in Rio de Janeiro, Brazil. DESIGN: Analysis of data from a randomized controlled trial and retrospective cohort study. METHODS: We analyzed data from two studies conducted between 2005 and 2017. The THRio Study (2005-2012) evaluated increasing tuberculin skin testing (TST) and TB preventive therapy (TPT) and UnivART (2010-2017) was a virtual cohort study of people with HIV and TB with data from four national electronic registries. RESULTS: Among 4,606 people with HIV in THRio, 2,992 (65.0%) had a TST placed and read, of whom 312/1,865 (17%) males and 203/1,127 (18%) females (p = 0.37) had prevalent TB infection. TB disease incidence was higher among males compared to females overall (IRR 1.33, 95% CI 1.04-1.69), among males compared to females who did not receive TPT (IRR 1.30, 95% CI 1.01-1.67), and among males compared to females on ART (IRR 1.64, 95% CI 1.17-2.29). Among 54,957 people with HIV in UnivART, TB disease incidence rates were higher among males than females overall (IRR 1.28, 95% CI 1.18-1.39), among males compared to females on ART (IRR 1.58, 95% CI 1.40-1.77), and among males compared to females not on ART (IRR 1.11, 95% CI 0.99-1.25). CONCLUSIONS: In this medium TB and HIV burden setting, TB disease incidence was higher among males than females with HIV, despite similar prevalence of TB infection.

Remdesivir use and antimicrobial stewardship restrictions during the coronavirus disease 2019 (COVID-19) pandemic in the United States: A cross-sectional survey.

Deploying therapeutics for coronavirus disease 2019 (COVID-19) has proved challenging due to evolving evidence, supply shortages, and conflicting guideline recommendations. We conducted a survey on remdesivir use and the role of stewardship. Use differs significantly from guidelines. Hospitals with remdesivir restrictions were more guideline concordant. Formulary restrictions can be important for pandemic response.

Antimicrobial stewardship and drug formulary restrictions during COVID-19: what is restricted and who decides?

COVID-19 therapies were challenging to deploy due to evolving literature and conflicting guidelines. Antimicrobial stewardship can help optimize drug use. We conducted a survey to understand the role of stewardship and formulary restrictions during the pandemic. Restrictions for COVID-19 therapies were common and approval by infectious disease physicians often required.

Number Needed to Screen for Tuberculosis Disease Among Children: A Systematic Review.

CONTEXT: Improving detection of pediatric tuberculosis (TB) is critical to reducing morbidity and mortality among children. OBJECTIVE: We conducted a systematic review to estimate the number of children needed to screen (NNS) to detect a single case of active TB using different active case finding (ACF) screening approaches and across different settings. DATA SOURCES: We searched 4 databases (PubMed, Embase, Scopus, and the Cochrane Library) for articles published from November 2010 to February 2020. STUDY SELECTION: We included studies of TB ACF in children using symptom-based screening, clinical indicators, chest x-ray, and Xpert. DATA EXTRACTION: We indirectly estimated the weighted mean NNS for a given modality, location, and population using the inverse of the weighted prevalence. We assessed risk of bias using a modified AXIS tool. RESULTS: We screened 27 221 titles and abstracts, of which we included 31 studies of ACF in children < 15 years old. Symptom-based screening was the most common screening modality (weighted mean NNS: 257 [range, 5-undefined], 19 studies). The weighted mean NNS was lower in both inpatient (216 [18-241]) and outpatient (67 [5-undefined]) settings (107 [5-undefined]) compared with community (1117 [28-5146]) and school settings (464 [118-665]). Risk of bias was low. LIMITATIONS: Heterogeneity in the screening modalities and populations make it difficult to draw conclusions. CONCLUSIONS: We identified a potential opportunity to increase TB detection by screening children presenting in health care settings. Pediatric TB case finding interventions should incorporate evidence-based interventions and local contextual information in an effort to detect as many children with TB as possible.

Lessons learned: Development of COVID-19 clinical staging models at a large urban research institution.

Background/Objective: The University of Illinois at Chicago (UIC), along with many academic institutions worldwide, made significant efforts to address the many challenges presented during the COVID-19 pandemic by developing clinical staging and predictive models. Data from patients with a clinical encounter at UIC from July 1, 2019 to March 30, 2022 were abstracted from the electronic health record and stored in the UIC Center for Clinical and Translational Science Clinical Research Data Warehouse, prior to data analysis. While we saw some success, there were many failures along the way. For this paper, we wanted to discuss some of these obstacles and many of the lessons learned from the journey. Methods: Principle investigators, research staff, and other project team members were invited to complete an anonymous Qualtrics survey to reflect on the project. The survey included open-ended questions centering on participants' opinions about the project, including whether project goals were met, project successes, project failures, and areas that could have been improved. We then identified themes among the results. Results: Nine project team members (out of 30 members contacted) completed the survey. The responders were anonymous. The survey responses were grouped into four key themes: Collaboration, Infrastructure, Data Acquisition/Validation, and Model Building. Conclusion: Through our COVID-19 research efforts, the team learned about our strengths and deficiencies. We continue to work to improve our research and data translation capabilities.

Viral suppression among adults with HIV receiving routine dolutegravir-based antiretroviral therapy and 3 months weekly isoniazid-rifapentine.

OBJECTIVE: We aimed to evaluate safety of 3 months weekly isoniazid-rifapentine (3HP) for tuberculosis (TB) prevention when co-administered with dolutegravir-based antiretroviral therapy (TLD), and compare viral suppression among those initiating TLD + 3HP vs. TLD alone. DESIGN/METHODS: We analyzed data from an ongoing Phase 3 randomized trial comparing TB screening strategies among adults with CD4 + ≤350 cells/µl initiating routine antiretroviral therapy (ART) in Kampala, Uganda. TB screen-negative participants without contraindications are referred for self-administered 3HP. HIV viral load is routinely measured at 6 and 12 months. Here, we included TB-negative participants who initiated TLD with or without 3HP. We determined the number who discontinued 3HP due to drug toxicity. In addition, we assessed viral suppression at 6 and 12 months and used log-binomial regression to assess risk of viremia at 6 months for participants who initiated TLD + 3HP vs. TLD alone. RESULTS: Of 453 participants initiating TLD (287 [63.4%] female, median age 30 years [interquartile range (IQR) 25-37], median pre-ART CD4 + cell count 188 cells/µl [IQR 86-271]), 163 (36.0%) initiated 3HP. Of these, 154 (94.5%) completed 3HP and one (0.6%) had treatment permanently discontinued due to a possible 3HP-related adverse event. At 6 months, for participants who received TLD + 3HP, risk of viremia >50 copies/ml was 1.51 [95% confidence interval (CI) 1.07-2.14] times that of participants who received TLD alone. There was no difference in viral suppression between those who received TLD + 3HP vs. TLD alone at 12 months. CONCLUSIONS: Co-administration of TLD + 3HP was well tolerated. However, those who received TLD + 3HP were less likely to achieve viral suppression within six-months compared to those who received TLD alone.

Contextualizing and optimizing novel strategies to improve the latent TB continuum of care: Insights from people living with HIV and health care providers in Brazil.

Tuberculosis (TB) causes 1 in 3 deaths among people living with HIV (PLHIV). Diagnosing and treating latent tuberculosis infection (LTBI) is critical to reducing TB incidence and mortality. Blood-based screening tests (e.g., QuantiFERON-TB Gold Plus (QFT+)) and shorter-course TB preventive therapy (TPT) regimens such as 3HP (3 months weekly isoniazid-rifapentine) hold significant promise to improve TB outcomes. We qualitatively explored barriers and solutions to optimizing QFT+ and 3HP among PLHIV in three cities in Brazil. We conducted 110 in-depth interviews with PLHIV, health care providers (HCP) and key informants (KI). Content analysis was conducted including the use of case summaries and comparison of themes across populations and contexts. LTBI screening and treatment practices were dependent on HCP's perceptions of whether they were critical to improving TB outcomes. Many HCP lacked a strong understanding of LTBI and perceived the current TPT regimen as complicated. HCP reported that LTBI screening and treatment were constrained by clinic staffing challenges. While PLHIV generally expressed willingness to consider any test or treatment that doctors recommended, they indicated HCP rarely discussed LTBI and TPT. TB testing and treatment requests were constrained by structural factors including financial and food insecurity, difficulties leaving work for appointments, stigma and family responsibilities. QFT+ and 3HP were viewed by all participants as tools that could significantly improve the LTBI cascade by avoiding complexities of TB skin tests and longer LTBI treatment courses. QFT+ and 3HP were perceived to have challenges, including the potential to increase workload on over-burdened health systems if not implemented alongside improved supply chains, staffing, and training, and follow-up initiatives. Multi-level interventions that increase understanding of the importance of LTBI and TPT among HCP, improve patient-provider communication, and streamline clinic-level operations related to QFT+ and 3HP are needed to optimize their impact among PLHIV and reduce TB mortality.

Characteristics of Pregnant Women With Syphilis and Factors Associated With Congenital Syphilis at a Chicago Hospital.

Background: Congenital syphilis incidence has more than tripled in recent years, in parallel with the resurgence of syphilis among reproductive-aged women. An understanding of risk factors associated with maternal syphilis infection can guide prevention of congenital syphilis through prenatal diagnosis and treatment. We aimed to describe factors associated with maternal syphilis and congenital syphilis at a public medical center in Chicago, Illinois. Methods: Maternal syphilis diagnoses were identified using a database for local health department reporting. Medical records were reviewed for infant congenital syphilis diagnoses, sociodemographic information, medical history, and other behavioral factors. Maternal characteristics associated with congenital syphilis were assessed using logistic regression. Results: Of 106 maternal syphilis diagnoses between 2014 and 2018, 76 (72%) had a known pregnancy outcome; of these, 8 (11%) delivered an infant with congenital syphilis. Women with psychiatric illness and noninjection substance use each had a >5-fold increased odds of having an infant with congenital syphilis. Cases with congenital syphilis were more likely to have late or scant prenatal care and initiated treatment nearly 3 months later in pregnancy. None were human immunodeficiency virus positive or reported incarceration, intravenous substance use, sex work, or having sex with men who have sex with men. Conclusions: Maternal psychiatric illness and substance use may have complicated prenatal care and delayed syphilis treatment, describing a population in need of public health intervention. Women experiencing such barriers to care may benefit from closer follow-up after a prenatal syphilis diagnosis to prevent congenital transmission.

A systematic review and meta-analysis of active case finding for tuberculosis in India.

Background: Active case finding (ACF) for tuberculosis (TB) is the cornerstone case-finding strategy in India's national TB policy. However, ACF strategies are highly diverse and pose implementation challenges in routine programming. We reviewed the literature to characterise ACF in India; assess the yield of ACF for different risk groups, screening locations, and screening criteria; and estimate losses to follow-up (LTFU) in screening and diagnosis. Methods: We searched PubMed, EMBASE, Scopus, and the Cochrane library to identify studies with ACF for TB in India from November 2010 to December 2020. We calculated 1) weighted mean number needed to screen (NNS) stratified by risk group, screening location, and screening strategy; and 2) the proportion of screening and pre-diagnostic LTFU. We assessed risk of bias using the AXIS tool for cross-sectional studies. Findings: Of 27,416 abstracts screened, we included 45 studies conducted in India. Most studies were from southern and western India and aimed to diagnose pulmonary TB at the primary health level in the public sector after screening. There was considerable heterogeneity in risk groups screened and ACF methodology across studies. Of the 17 risk groups identified, the lowest weighted mean NNS was seen in people with HIV (21, range 3-89, n=5), tribal populations (50, range 40-286, n=3), household contacts of people with TB (50, range 3-undefined, n=12), people with diabetes (65, range 21-undefined, n=3), and rural populations (131, range 23-737, n=5). ACF at facility-based screening (60, range 3-undefined, n=19) had lower weighted mean NNS than at other screening locations. Using the WHO symptom screen (135, 3-undefined, n=20) had lower weighted mean NNS than using criteria of abnormal chest x-ray or any symptom. Median screening and pre-diagnosis loss-to-follow-up was 6% (IQR 4.1%, 11.3%, range 0-32.5%, n=12) and 9.5% (IQR 2.4%, 34.4%, range 0-86.9%, n=27), respectively. Interpretation: For ACF to be impactful in India, its design must be based on contextual understanding. The narrow evidence base available currently is insufficient for effectively targeting ACF programming in a large and diverse country. Achieving case-finding targets in India requires evidence-based ACF implementation. Funding: WHO Global TB Programme.

Transaminitis prevalence among HIV-infected adults eligible for tuberculosis preventive therapy.

OBJECTIVE: To assess the prevalence of severe transaminitis precluding tuberculosis (TB) preventive therapy (TPT) initiation for people with HIV (PWH) in a high TB/HIV burden setting. DESIGN/METHODS: We conducted a secondary analysis of data from a prospective cohort study of PWH with pre-antiretroviral therapy (ART) CD4 + counts 350 cells/µl or less undergoing systematic TB screening from two HIV clinics in Uganda. For this analysis, we excluded patients with culture-confirmed TB and patients without aspartate transaminase (AST) or alanine transaminase (ALT) levels measured within three months of enrollment. We compared the proportion of patients with any transaminitis (AST or ALT greater than one times the upper limit of normal ULN) and severe transaminitis (AST or ALT >3 times ULN) for patients screening negative for TB by symptoms and for those screening negative by C-reactive protein (CRP). We also assessed the proportion of patients with transaminitis by self-reported alcohol consumption. RESULTS: Among 313 participants [158 (50%) women, median age 34 years (IQR 27-40)], 75 (24%) had any transaminitis and six (2%) had severe transaminitis. Of 32 of 313 (10%) who screened negative for TB by symptoms, none had severe transaminitis. In contrast, six-times more PWH screened negative for TB by CRP (194 of 313; 62%), of whom only four (2.1%) had severe transaminitis. Differences in the proportion with any and severe transaminitis according to alcohol consumption were not statistically significant. CONCLUSION: Prevalence of severe transaminitis was low among PWH without culture-confirmed TB in this setting, and is therefore, unlikely to be a major barrier to scaling-up TPT.

Tuberculosis screening improves preventive therapy uptake (TB SCRIPT) trial among people living with HIV in Uganda: a study protocol of an individual randomized controlled trial.

BACKGROUND: People living with HIV (PLHIV) have an increased risk of developing active tuberculosis (TB). To reduce the burden of TB among PLHIV, the World Health Organization (WHO) recommends systematic TB screening followed by (1) confirmatory TB testing for all who screen positive and (2) TB preventive therapy (TPT) for all TPT-eligible PLHIV who screen negative. Symptom-based screening remains the standard of care in most high TB burden settings, including Uganda. Despite having high sensitivity for active TB among antiretroviral-naïve PLHIV, symptom screening has poor specificity; as such, many high-risk PLHIV without active TB are not referred for TPT. C-reactive protein (CRP) is a promising alternative strategy for TB screening that has comparable sensitivity and higher specificity than symptom screening, and was endorsed by WHO in 2021. However, the impact of CRP-based TB screening on TB burden for PLHIV remains unclear. METHODS: TB SCRIPT (TB Screening Improves Preventive Therapy Uptake) is a phase 3, multi-center, single-blinded, individual (1:1) randomized controlled trial evaluating the effectiveness of CRP-based TB screening on clinical outcomes of PLHIV. The trial aims to compare the effectiveness of a TB screening strategy based on CRP levels using a point-of-care (POC) assay on 2-year TB incidence and all-cause mortality (composite primary trial endpoint) and prevalent TB case detection and uptake of TPT (intermediate outcomes), relative to symptom-based TB screening (current practice). DISCUSSION: This study will be critical to improving selection of eligible PLHIV for TPT and helping guide the scale-up and integration of TB screening and TPT activities. This work will enable the field to improve TB screening by removing barriers to TPT initiation among eligible PLHIV, and provide randomized evidence to inform and strengthen WHO guidelines. TRIAL REGISTRATION: ClinicalTrials.gov NCT04557176. Registered on September 21, 2020.

Elevated Mortality Among People Experiencing Homelessness With COVID-19.

We reviewed publicly available data from major US health jurisdictions to compare severe acute respiratory syndrome coronavirus 2 case fatality rates in people experiencing homelessness with the general population. The case fatality rate among people experiencing homelessness was 1.3 times (95% CI, 1.1-1.5) that of the general population, suggesting that people experiencing homelessness should be prioritized for vaccination.