Laparoscopic-Assisted Transvaginal Cholecystectomy - the US Military Experience With Long-Term Follow Up.

Objectives: We present our initial clinical experience applying Natural Orifice Transluminal Endoscopic Surgical (NOTES) technique to perform cholecystectomy in ten patients at a military institution. Methods: A posterior colpotomy was created to accommodate a single site working port used to facilitate dissection and gallbladder mobilization under direct visualization via an infraumbilical port. The specimen was retrieved through the vagina and the colpotomy was closed with absorbable suture under direct visualization. Long-term follow up was performed over the phone to assess quality of life with 2 widely used health-related quality of life (HRQoL) surveys including RAND-36 Health Item Survey (Version 1.0),1 and the Female Sexual Function Index (FSFI).2. Results: Ten women underwent a laparoscopic-assisted transvaginal cholecystectomy (TVC) with 7 available for long-term follow-up. The average age was 28.9 years (20-37) and the indications for surgery included symptomatic cholelithiasis (9) and biliary dyskinesia (1). The mean operative time was 129 mins (95-180), and median blood loss was 34 ml (5-400). There were no conversions and the average length of stay was 9.98 hours (2.4-28.8). Pain (analogue scale 1-10) on postoperative day three was minimal (mean 2.3) and was limited to the infraumbilical incision. On average patients returned to work by postoperative day six and resumed normal daily activities at seven days. Immediate postoperative complications included one incident of postoperative urinary retention requiring bladder catheterization. One intra-operative cholangiogram was successfully performed due to elevated preoperative liver enzymes without significant findings. Long-term complications included one asymptomatic incisional hernia repair at the infraumbilical port site. The RAND-36 survey demonstrated an average physical and mental health summary score of 82.2 and 63.7 with an average general health score of 63.6. The average FSFI total score was 21.8. Conclusion: TVC is safe and effective. Implementation may improve operational readiness by returning service members to normal activities more expeditiously than conventional laparoscopy.

Persistent Mycobacterium tuberculosis bioaerosol release in a tuberculosis-endemic setting.

Pioneering studies linking symptomatic disease and cough-mediated release of Mycobacterium tuberculosis (Mtb) established the infectious origin of tuberculosis (TB), simultaneously informing the pervasive notion that pathology is a prerequisite for Mtb transmission. Our prior work has challenged this assumption: by sampling TB clinic attendees, we detected equivalent release of Mtb-containing bioaerosols by confirmed TB patients and individuals not receiving a TB diagnosis, and we demonstrated a time-dependent reduction in Mtb bioaerosol positivity during six-months' follow-up, irrespective of anti-TB chemotherapy. Now, by extending bioaerosol sampling to a randomly selected community cohort, we show that Mtb release is common in a TB-endemic setting: of 89 participants, 79.8% (71/89) produced Mtb bioaerosols independently of QuantiFERON-TB Gold status, a standard test for Mtb infection; moreover, during two-months' longitudinal sampling, only 2% (1/50) were serially Mtb bioaerosol negative. These results necessitate a reframing of the prevailing paradigm of Mtb transmission and infection, and may explain the current inability to elucidate Mtb transmission networks in TB-endemic regions.

Self-transfers, Hospital Admissions and Mortality Among Children and Adolescents Lost to Follow-up From Antiretroviral Therapy Programs in the Western Cape, South Africa Between 2004 and 2019: Linkage to Provincial Records.

BACKGROUND: Pediatric programs face a high rate of loss to follow-up (LTFU) among children and adolescents living with HIV (CAHIV). We assessed true outcomes and predictors of these among CAHIV who were LTFU using linkage to the Western Cape Provincial Health Data Centre at Western Cape sites of the International epidemiology Databases to Evaluate AIDS-Southern Africa collaboration. METHODS: We examined factors associated with self-transfer, hospital admission and mortality using competing risks regression in a retrospective cohort of CAHIV initiating antiretroviral therapy <15 years old between 2004 and 2019 and deemed LTFU (no recorded visit at the original facility for ≥180 days from the last visit date before database closure and not known to have officially transferred out or deceased). RESULTS: Of the 1720 CAHIV deemed LTFU, 802 (46.6%) had self-transferred and were receiving care elsewhere within the Western Cape, 463 (26.9%) had been hospitalized and 45 (2.6%) CAHIV had died. The overall rates of self-transfer, hospitalization, mortality and LTFU were 9.4 [95% confidence interval (CI): 8.8-10.1], 5.4 (95% CI: 5.0-6.0), 0.5 (95% CI: 0.4-0.7) and 4.8 (95% CI: 4.4-5.3) per 100 person-years respectively. Increasing duration on antiretroviral therapy before LTFU was associated with self-transfers while male sex, older age at last visit (≥10 years vs. younger) were associated with hospital admission and immune suppression at last visit was associated with 5 times higher mortality. CONCLUSIONS: Nearly half of CAHIV classified as LTFU had self-transferred to another health facility, a quarter had been hospitalized and a small proportion had died.

Aerosolization of viable Mycobacterium tuberculosis bacilli by tuberculosis clinic attendees independent of sputum-Xpert Ultra status.

Potential Mycobacterium tuberculosis (Mtb) transmission during different pulmonary tuberculosis (TB) disease states is poorly understood. We quantified viable aerosolized Mtb from TB clinic attendees following diagnosis and through six months' follow-up thereafter. Presumptive TB patients (n=102) were classified by laboratory, radiological, and clinical features into Group A: Sputum-Xpert Ultra-positive TB (n=52), Group B: Sputum-Xpert Ultra-negative TB (n=20), or Group C: TB undiagnosed (n=30). All groups were assessed for Mtb bioaerosol release at baseline, and subsequently at 2 wk, 2 mo, and 6 mo. Groups A and B were notified to the national TB program and received standard anti-TB chemotherapy; Mtb was isolated from 92% and 90% at presentation, 87% and 74% at 2 wk, 54% and 44% at 2 mo and 32% and 20% at 6 mo, respectively. Surprisingly, similar numbers were detected in Group C not initiating TB treatment: 93%, 70%, 48% and 22% at the same timepoints. A temporal association was observed between Mtb bioaerosol release and TB symptoms in all three groups. Persistence of Mtb bioaerosol positivity was observed in ~30% of participants irrespective of TB chemotherapy. Captured Mtb bacilli were predominantly acid-fast stain-negative and poorly culturable; however, three bioaerosol samples yielded sufficient biomass following culture for whole-genome sequencing, revealing two different Mtb lineages. Detection of viable aerosolized Mtb in clinic attendees, independent of TB diagnosis, suggests that unidentified Mtb transmitters might contribute a significant attributable proportion of community exposure. Additional longitudinal studies with sputum culture-positive and -negative control participants are required to investigate this possibility.

Airborne transmission risks of tuberculosis and COVID-19 in schools in South Africa, Switzerland, and Tanzania: Modeling of environmental data.

The COVID-19 pandemic renewed interest in airborne transmission of respiratory infections, particularly in congregate indoor settings, such as schools. We modeled transmission risks of tuberculosis (caused by Mycobacterium tuberculosis, Mtb) and COVID-19 (caused by SARS-CoV-2) in South African, Swiss and Tanzanian secondary schools. We estimated the risks of infection with the Wells-Riley equation, expressed as the median with 2.5% and 97.5% quantiles (credible interval [CrI]), based on the ventilation rate and the duration of exposure to infectious doses (so-called quanta). We computed the air change rate (ventilation) using carbon dioxide (CO2) as a tracer gas and modeled the quanta generation rate based on reported estimates from the literature. The share of infectious students in the classroom is determined by country-specific estimates of pulmonary TB. For SARS-CoV-2, the number of infectious students was estimated based on excess mortality to mitigate the bias from country-specific reporting and testing. Average CO2 concentration (parts per million [ppm]) was 1,610 ppm in South Africa, 1,757 ppm in Switzerland, and 648 ppm in Tanzania. The annual risk of infection for Mtb was 22.1% (interquartile range [IQR] 2.7%-89.5%) in South Africa, 0.7% (IQR 0.1%-6.4%) in Switzerland, and 0.5% (IQR 0.0%-3.9%) in Tanzania. For SARS-CoV-2, the monthly risk of infection was 6.8% (IQR 0.8%-43.8%) in South Africa, 1.2% (IQR 0.1%-8.8%) in Switzerland, and 0.9% (IQR 0.1%-6.6%) in Tanzania. The differences in transmission risks primarily reflect a higher incidence of SARS-CoV-2 and particularly prevalence of TB in South Africa, but also higher air change rates due to better natural ventilation of the classrooms in Tanzania. Global comparisons of the modeled risk of infectious disease transmission in classrooms can provide high-level information for policy-making regarding appropriate infection control strategies.

Clinical utility of WHO-recommended screening tools and development and validation of novel clinical prediction models for pulmonary tuberculosis screening among outpatients living with HIV: an individual participant data meta-analysis.

BACKGROUND: The World Health Organization (WHO) recommends that outpatient people living with HIV (PLHIV) undergo tuberculosis screening with the WHO four-symptom screen (W4SS) or C-reactive protein (CRP) (5 mg·L-1 cut-off) followed by confirmatory testing if screen positive. We conducted an individual participant data meta-analysis to determine the performance of WHO-recommended screening tools and two newly developed clinical prediction models (CPMs). METHODS: Following a systematic review, we identified studies that recruited adult outpatient PLHIV irrespective of tuberculosis signs and symptoms or with a positive W4SS, evaluated CRP and collected sputum for culture. We used logistic regression to develop an extended CPM (which included CRP and other predictors) and a CRP-only CPM. We used internal-external cross-validation to evaluate performance. RESULTS: We pooled data from eight cohorts (n=4315 participants). The extended CPM had excellent discrimination (C-statistic 0.81); the CRP-only CPM had similar discrimination. The C-statistics for WHO-recommended tools were lower. Both CPMs had equivalent or higher net benefit compared with the WHO-recommended tools. Compared with both CPMs, CRP (5 mg·L-1 cut-off) had equivalent net benefit across a clinically useful range of threshold probabilities, while the W4SS had a lower net benefit. The W4SS would capture 91% of tuberculosis cases and require confirmatory testing for 78% of participants. CRP (5 mg·L-1 cut-off), the extended CPM (4.2% threshold) and the CRP-only CPM (3.6% threshold) would capture similar percentages of cases but reduce confirmatory tests required by 24, 27 and 36%, respectively. CONCLUSIONS: CRP sets the standard for tuberculosis screening among outpatient PLHIV. The choice between using CRP at 5 mg·L-1 cut-off or in a CPM depends on available resources.

Diagnostic yield of urine lipoarabinomannan and sputum tuberculosis tests in people living with HIV: a systematic review and meta-analysis of individual participant data.

BACKGROUND: Sputum is the most widely used sample to diagnose active tuberculosis, but many people living with HIV are unable to produce sputum. Urine, in contrast, is readily available. We hypothesised that sample availability influences the diagnostic yield of various tuberculosis tests. METHODS: In this systematic review and meta-analysis of individual participant data, we compared the diagnostic yield of point-of-care urine-based lipoarabinomannan tests with that of sputum-based nucleic acid amplification tests (NAATs) and sputum smear microscopy (SSM). We used microbiologically confirmed tuberculosis based on positive culture or NAAT from any body site as the denominator and accounted for sample provision. We searched PubMed, Web of Science, Embase, African Journals Online, and clinicaltrials.gov from database inception to Feb 24, 2022 for randomised controlled trials, cross-sectional studies, and cohort studies that assessed urine lipoarabinomannan point-of-care tests and sputum NAATs for active tuberculosis detection in participants irrespective of tuberculosis symptoms, HIV status, CD4 cell count, or study setting. We excluded studies in which recruitment was not consecutive, systematic, or random; provision of sputum or urine was an inclusion criterion; less than 30 participants were diagnosed with tuberculosis; early research assays without clearly defined cutoffs were tested; and humans were not studied. We extracted study-level data, and authors of eligible studies were invited to contribute deidentified individual participant data. The main outcomes were the tuberculosis diagnostic yields of urine lipoarabinomannan tests, sputum NAATs, and SSM. Diagnostic yields were predicted using Bayesian random-effects and mixed-effects meta-analyses. This study is registered with PROSPERO, CRD42021230337. FINDINGS: We identified 844 records, from which 20 datasets and 10 202 participants (4561 [45%] male participants and 5641 [55%] female participants) were included in the meta-analysis. All studies assessed sputum Xpert (MTB/RIF or Ultra, Cepheid, Sunnyvale, CA, USA) and urine Alere Determine TB LAM (AlereLAM, Abbott, Chicago, IL, USA) in people living with HIV aged 15 years or older. Nearly all (9957 [98%] of 10 202) participants provided urine, and 82% (8360 of 10 202) provided sputum within 2 days. In studies that enrolled unselected inpatients irrespective of tuberculosis symptoms, only 54% (1084 of 1993) of participants provided sputum, whereas 99% (1966 of 1993) provided urine. Diagnostic yield was 41% (95% credible interval [CrI] 15-66) for AlereLAM, 61% (95% Crl 25-88) for Xpert, and 32% (95% Crl 10-55) for SSM. Heterogeneity existed across studies in the diagnostic yield, influenced by CD4 cell count, tuberculosis symptoms, and clinical setting. In predefined subgroup analyses, all tests had higher yields in symptomatic participants, and AlereLAM yield was higher in those with low CD4 counts and inpatients. AlereLAM and Xpert yields were similar among inpatients in studies enrolling unselected participants who were not assessed for tuberculosis symptoms (51% vs 47%). AlereLAM and Xpert together had a yield of 71% in unselected inpatients, supporting the implementation of combined testing strategies. INTERPRETATION: AlereLAM, with its rapid turnaround time and simplicity, should be prioritised to inform tuberculosis therapy among inpatients who are HIV-positive, regardless of symptoms or CD4 cell count. The yield of sputum-based tuberculosis tests is undermined by people living with HIV who cannot produce sputum, whereas nearly all participants are able to provide urine. The strengths of this meta-analysis are its large size, the carefully harmonised denominator, and the use of Bayesian random-effects and mixed-effects models to predict yields; however, data were geographically restricted, clinically diagnosed tuberculosis was not considered in the denominator, and little information exists on strategies for obtaining sputum samples. FUNDING: FIND, the Global Alliance for Diagnostics.

Abacavir safety and effectiveness in young infants with HIV in South African observational cohorts.

BACKGROUND: WHO guidelines recommend abacavir in first-line antiretroviral treatment for children and neonates. However, there is no approved dose <3 months of age, and data in neonates are limited. METHODS: We included infants who initiated ART aged <3 months, between 2006 and 2019, in nine South African cohorts. In those who received abacavir or zidovudine, we described antiretroviral discontinuation rates; and 6- and 12-month viral suppression (<400 copies/mL). We compared infants aged <28 and ≥28 days, those weighing <3 and ≥3 kg. RESULTS: Overall 837/1643 infants (51%) received abacavir and 443 (27%) received zidovudine. Median (interquartile range, IQR) age was 52 days (23-71), CD4 percentage was 27.9 (19.2-38.0), and weight was 4.0 kg (3.0-4.7) at ART initiation. In those with ≥1 month's follow-up, 100/718 (14%) infants discontinued abacavir, at a median of 17.5 months (IQR 6.5-39.5). Abacavir discontinuations did not differ by age or weight category (p = 0.4 and 0.2, respectively); and were less frequent than zidovudine discontinuations (adjusted hazard ratio 0.14, 95% confidence interval 0.10-0.20). Viral suppression at 12 months occurred in 43/79 (54%) and 130/250 (52%) of those who started abacavir aged <28 and ≥28 days, respectively (p = 0.8); 11/19 (58%) and 31/60 (52%) in those who weighed <3 and ≥3 kg, respectively (p = 0.6); and 174/329 (53%) in those on abacavir versus 77/138 (56%) in those on zidovudine (adjusted odds ratio 1.8, 95% confidence interval 1.0-3.2). CONCLUSION: Our data suggest that abacavir may be used safely in infants <28 days old or who weigh <3 kg.

Pneumoproteins and biomarkers of inflammation and coagulation do not predict rapid lung function decline in people living with HIV.

Chronic obstructive pulmonary disease (COPD) is among the leading causes of death worldwide and HIV is an independent risk factor for the development of COPD. However, the etiology of this increased risk and means to identify persons with HIV (PWH) at highest risk for COPD have remained elusive. Biomarkers may reveal etiologic pathways and allow better COPD risk stratification. We performed a matched case:control study of PWH in the Strategic Timing of Antiretoviral Treatment (START) pulmonary substudy. Cases had rapid lung function decline (> 40 mL/year FEV1 decline) and controls had stable lung function (+ 20 to - 20 mL/year). The analysis was performed in two distinct groups: (1) those who were virally suppressed for at least 6 months and (2) those with untreated HIV (from the START deferred treatment arm). We used linear mixed effects models to test the relationship between case:control status and blood concentrations of pneumoproteins (surfactant protein-D and club cell secretory protein), and biomarkers of inflammation (IL-6 and hsCRP) and coagulation (d-dimer and fibrinogen); concentrations were measured within ± 6 months of first included spirometry. We included an interaction with treatment group (untreated HIV vs viral suppression) to test if associations varied by treatment group. This analysis included 77 matched case:control pairs in the virally suppressed batch, and 42 matched case:control pairs in the untreated HIV batch (n = 238 total) who were followed for a median of 3 years. Median (IQR) CD4 + count was lowest in the controls with untreated HIV at 674 (580, 838). We found no significant associations between case:control status and pneumoprotein or biomarker concentrations in either virally suppressed or untreated PWH. In this cohort of relatively young, recently diagnosed PWH, concentrations of pneumoproteins and biomarkers of inflammation and coagulation were not associated with subsequent rapid lung function decline.Trial registration: NCT00867048 and NCT01797367.

Environmental air sampling for detection and quantification of Mycobacterium tuberculosis in clinical settings: Proof of concept.

OBJECTIVE: Novel approaches are needed to understand and disrupt Mycobacterium tuberculosis transmission. In this proof-of-concept study, we investigated the use of environmental air samplings to detect and quantify M. tuberculosis in different clinic settings in a high-burden area. DESIGN: Cross-sectional, environmental sampling. SETTING: Primary-care clinic. METHODS: A portable, high-flow dry filter unit (DFU) was used to draw air through polyester felt filters for 2 hours. Samples were collected in the waiting area and TB room of a primary care clinic. Controls included sterile filters placed directly into collection tubes at the DFU sampling site, and filter samplings performed outdoors. DNA was extracted from the filters, and droplet digital polymerase chain reaction (ddPCR) was used to quantify M. tuberculosis DNA copies. Carbon dioxide (CO2) data loggers captured CO2 concentrations in the sampled areas. RESULTS: The median sampling time was 123 minutes (interquartile range [IQR], 121-126). A median of 121 (IQR, 35-243) M. tuberculosis DNA copies were obtained from 74 clinic samplings, compared to a median of 3 (IQR, 1-33; P < .001) obtained from 47 controls. At a threshold of 320 DNA copies, specificity was 100%, and 18% of clinic samples would be classified as positive. CONCLUSIONS: This proof-of-concept study suggests that the potential for airborne M. tuberculosis detection based on M. tuberculosis DNA copy yield to enable the identification of high-risk transmission locations. Further optimization of the M. tuberculosis extraction technique and ddPCR data analysis would improve detection and enable robust interpretation of these data.

Health systems and health equity: Advancing the agenda.

Despite a compelling body of evidence and decades of policy recommendations, deep inequities in health persist with historically marginalized groups. Operationalizing strategies to achieve equity in health and health care continues to remain elusive to health systems. We propose several focus areas; attention to semantics and concepts, building knowledge of health inequities, redesigning care and transforming cultures, to advance health equity work by health system nurse leaders and clinical nurses. Health equity frameworks, traditionally applied in population and public health, are also discussed to tackle health equity issues and formulate, implement and evaluate solutions to inequities. Examples illustrate ongoing work in our health system in targeted areas and challenges in advancing health equity work. Future efforts by health system nurse leaders should concentrate on technology for point of care health screening and data acquisition, data-driven decisions, and organizational performance measures to narrow health equity gaps.

Neighbourhood risk factors of recurrent tuberculosis in Cape Town: a cohort study using geocoded notification data.

BACKGROUND: Individuals with a history of tuberculosis (TB) disease are at higher risk of developing a subsequent episode than those without. Considering the role of social and environmental factors in tuberculosis, we assessed neighbourhood-level risk factors associated with recurrent tuberculosis in Cape Town, South Africa. METHODS: This cohort consisted of patients who completed treatment for their first drug-sensitive TB episode between 2003 and 2015. Addresses were geocoded at neighbourhood level. Data on neighbourhood-level factors were obtained from the Census 2011 (household size, population density) and the City of Cape Town (Socio-Economic Index). Neighbourhood-level TB burden was calculated annually by dividing the number of notified TB episodes by the population in that neighbourhood. Multilevel survival analysis was performed with the outcome recurrent TB, defined as a second episode of TB, and controlling for individual-level risk factors (age, gender and time since first episode in years). Follow-up ended at the second episode, or on 31 December 2015, whichever came first. RESULTS: The study included 173 421 patients from 700 neighbourhoods. Higher Socio-Economic Index was associated with a lower risk of recurrence compared with average Socio-Economic Index. An increased risk was found for higher household size and TB burden, with an increase of 20% for every additional person in mean household size and 10% for every additional TB episode/100 inhabitants. No association was found with population density. CONCLUSION: Recurrent TB was associated with increased household size and TB burden at neighbourhood level. These findings could be used to target TB screening activities.

Mycobacterium tuberculosis Transmission in High-Incidence Settings-New Paradigms and Insights.

Tuberculosis has affected humankind for thousands of years, but a deeper understanding of its cause and transmission only arose after Robert Koch discovered Mycobacterium tuberculosis in 1882. Valuable insight has been gained since, but the accumulation of knowledge has been frustratingly slow and incomplete for a pathogen that remains the number one infectious disease killer on the planet. Contrast that to the rapid progress that has been made in our understanding SARS-CoV-2 (the cause of COVID-19) aerobiology and transmission. In this Review, we discuss important historical and contemporary insights into M. tuberculosis transmission. Historical insights describing the principles of aerosol transmission, as well as relevant pathogen, host and environment factors are described. Furthermore, novel insights into asymptomatic and subclinical tuberculosis, and the potential role this may play in population-level transmission is discussed. Progress towards understanding the full spectrum of M. tuberculosis transmission in high-burden settings has been hampered by sub-optimal diagnostic tools, limited basic science exploration and inadequate study designs. We propose that, as a tuberculosis field, we must learn from and capitalize on the novel insights and methods that have been developed to investigate SARS-CoV-2 transmission to limit ongoing tuberculosis transmission, which sustains the global pandemic.

Improving Estimates of Social Contact Patterns for Airborne Transmission of Respiratory Pathogens.

Data on social contact patterns are widely used to parameterize age-mixing matrices in mathematical models of infectious diseases. Most studies focus on close contacts only (i.e., persons spoken with face-to-face). This focus may be appropriate for studies of droplet and short-range aerosol transmission but neglects casual or shared air contacts, who may be at risk from airborne transmission. Using data from 2 provinces in South Africa, we estimated age mixing patterns relevant for droplet transmission, nonsaturating airborne transmission, and Mycobacterium tuberculosis transmission, an airborne infection where saturation of household contacts occurs. Estimated contact patterns by age did not vary greatly between the infection types, indicating that widespread use of close contact data may not be resulting in major inaccuracies. However, contact in persons >50 years of age was lower when we considered casual contacts, and therefore the contribution of older age groups to airborne transmission may be overestimated.

Non-volatile organic compounds in exhaled breath particles correspond to active tuberculosis.

Human breath contains trace amounts of non-volatile organic compounds (NOCs) which might provide non-invasive methods for evaluating individual health. In previous work, we demonstrated that lipids detected in exhaled breath aerosol (EBA) could be used as markers of active tuberculosis (TB). Here, we advanced our analytical platform for characterizing small metabolites and lipids in EBA samples collected from participants enrolled in clinical trials designed to identify molecular signatures of active TB. EBA samples from 26 participants with active TB and 73 healthy participants were processed using a dual-phase extraction method, and metabolites and lipids were identified via mass spectrometry database matching. In total, 13 metabolite and 9 lipid markers were identified with statistically different optimized relative standard deviation values between individuals diagnosed with active TB and the healthy controls. Importantly, EBA lipid profiles can be used to separate the two sample types, indicating the diagnostic potential of the identified molecules. A feature ranking algorithm reduced this number to 10 molecules, with the membrane glycerophospholipid, phosphatidylinositol 24:4, emerging as the top driver of segregation between the two groups. These results support the use of this approach to identify consistent NOC signatures from EBA samples in active TB cases. This suggests the potential to apply this method to other human diseases which alter respiratory NOC release.

Diagnostic accuracy of WHO screening criteria to guide lateral-flow lipoarabinomannan testing among HIV-positive inpatients: A systematic review and individual participant data meta-analysis.

BACKGROUND: WHO recommends urine lateral-flow lipoarabinomannan (LF-LAM) testing with AlereLAM in HIV-positive inpatients only if screening criteria are met. We assessed the performance of WHO screening criteria and alternative screening tests/strategies to guide LF-LAM testing and compared diagnostic accuracy of the WHO AlereLAM algorithm (WHO screening criteria followed by AlereLAM if screen positive) with AlereLAM and FujiLAM (a novel LF-LAM test) testing in all HIV-positive inpatients. METHODS: We searched MEDLINE, Embase, and Cochrane Library from Jan 1, 2011 to March 1, 2020 for studies among adult/adolescent HIV-positive inpatients regardless of tuberculosis signs and symptoms. The reference standards were (1) AlereLAM or FujiLAM for screening tests/strategies and (2) culture or Xpert for AlereLAM/FujiLAM. We determined proportion of inpatients eligible for AlereLAM using WHO screening criteria; assessed accuracy of WHO criteria and alternative screening tests/strategies to guide LF-LAM testing; compared accuracy of WHO AlereLAM algorithm with AlereLAM/FujiLAM testing in all; and determined diagnostic yield of AlereLAM, FujiLAM, and Xpert MTB/RIF (Xpert). We estimated pooled proportions with a random-effects model, assessed diagnostic accuracy using random-effects bivariate models, and assessed diagnostic yield descriptively. FINDINGS: We obtained data from all 5 identified studies (n = 3,504). The pooled proportion of inpatients eligible for AlereLAM using WHO criteria was 93% (95%CI 91, 95). Among screening tests/strategies to guide LF-LAM testing, WHO criteria, C-reactive protein (≥5 mg/L), and CD4 count (<200 cells/µL) had high sensitivities but low specificities; cough (≥2 weeks), hemoglobin (<8 g/dL), body mass index (<18.5 kg/m2), lymphadenopathy, and WHO-defined danger signs had higher specificities but suboptimal sensitivities. AlereLAM in all had the same sensitivity (62%) and specificity (88%) as WHO AlereLAM algorithm. Sensitivity of FujiLAM and AlereLAM was 69% and 48%, while specificity was 88% and 96%, respectively. In 2 studies that collected sputum and non-sputum samples for Xpert and/or culture, diagnostic yield of sputum Xpert was 40-41%, AlereLAM was 39-76%, and urine Xpert was 35-62%. In one study, FujiLAM diagnosed 80% of tuberculosis cases (vs 39% for AlereLAM), and sputum Xpert combined with AlereLAM, urine Xpert, or FujiLAM diagnosed 61%, 81%, and 92% of all cases, respectively. INTERPRETATION: WHO criteria and alternative screening tests/strategies have limited utility in guiding LF-LAM testing, suggesting that AlereLAM testing in all HIV-positive medical inpatients be implemented. Routine FujiLAM may improve tuberculosis diagnosis. FUNDING: None.

Aerosolization of Mycobacterium tuberculosis by Tidal Breathing.

Rationale: Interrupting tuberculosis (TB) transmission requires an improved understanding of how and when the causative organism, Mycobacterium tuberculosis (Mtb), is aerosolized. Although cough is commonly assumed to be the dominant source of Mtb aerosols, recent evidence of cough-independent Mtb release implies the contribution of alternative mechanisms. Objectives: To compare the aerosolization of Mtb bacilli and total particulate matter from patients with TB during three separate respiratory maneuvers: tidal breathing (TiBr), FVC, and cough. Methods: Bioaerosol sampling and Mtb enumeration by live-cell, fluorescence microscopy were combined with real-time measurement of CO2 concentration and total particle counts from 38 patients with GeneXpert-positive TB before treatment initiation. Measurements and Main Results: For all maneuvers, the proportions of particles detected across five size categories were similar, with most particles falling between 0.5-5 µm. Although total particle counts were 4.8-fold greater in cough samples than either TiBr or FVC, all three maneuvers returned similar rates of positivity for Mtb. No correlation was observed between total particle production and Mtb count. Instead, for total Mtb counts, the variability between individuals was greater than the variability between sampling maneuvers. Finally, when modelled using 24-hour breath and cough frequencies, our data indicate that TiBr might contribute more than 90% of the daily aerosolized Mtb among symptomatic patients with TB. Conclusions: Assuming the number of viable Mtb organisms released offers a reliable proxy of patient infectiousness, our observations imply that TiBr and interindividual variability in Mtb release might be significant contributors to TB transmission among active cases.

Antiretroviral Initiation at ≥800 CD4+ Cells/mm3 Associated With Lower Human Immunodeficiency Virus Reservoir Size.

BACKGROUND: Identifying factors that determine the frequency of latently infected CD4+ T cells on antiretroviral therapy (ART) may inform strategies for human immunodeficiency virus (HIV) cure. We investigated the role of CD4+ count at ART initiation for HIV persistence on ART. METHODS: Among participants of the Strategic Timing of Antiretroviral Treatment Study, we enrolled people with HIV (PWH) who initiated ART with CD4+ T-cell counts of 500-599, 600-799, or ≥ 800 cells/mm3. After 36-44 months on ART, the levels of total HIV-DNA, cell-associated unspliced HIV-RNA (CA-US HIV-RNA), and two-long terminal repeat HIV-DNA in CD4+ T cells were quantified and plasma HIV-RNA was measured by single-copy assay. We measured T-cell expression of Human Leucocyte Antigen-DR Isotype (HLA-DR), programmed death-1, and phosphorylated signal transducer and activator of transcription-5 (pSTAT5). Virological and immunological measures were compared across CD4+ strata. RESULTS: We enrolled 146 PWH, 36 in the 500-599, 60 in the 600-799, and 50 in the ≥ 800 CD4 strata. After 36-44 months of ART, total HIV-DNA, plasma HIV-RNA, and HLA-DR expression were significantly lower in PWH with CD4+ T-cell count ≥ 800 cells/mm3 at ART initiation compared with 600-799 or 500-599 cells/mm3. The median level of HIV-DNA after 36-44 months of ART was lower by 75% in participants initiating ART with ≥ 800 vs 500-599 cells/mm3 (median [interquartile range]: 16.3 [7.0-117.6] vs 68.4 [13.7-213.1] copies/million cells, respectively). Higher pSTAT5 expression significantly correlated with lower levels of HIV-DNA and CA-US HIV-RNA. Virological measures were significantly lower in females. CONCLUSIONS: Initiating ART with a CD4+ count ≥ 800 cells/mm3 compared with 600-799 or 500-599 cells/mm3 was associated with achieving a substantially smaller HIV reservoir on ART.