transmission of tuberculosis among illicit drug use linkages total a cross sectional CORD-Papers-2022-06-02 (Version 1)

Title: Transmission Of Tuberculosis Among illicit drug use Linkages (TOTAL): A cross-sectional observational study protocol using respondent driven sampling
Abstract: People who use illicit drugs (PWUDs) have been identified as a key at-risk group for tuberculosis (TB). Examination of illicit drug use networks has potential to assess the risk of TB exposure and disease progression. Research also is needed to assess mechanisms for accelerated TB transmission in this population. This study aims to 1) assess the rate of TB exposure risk of disease progression and disease burden among PWUD; 2) estimate the proportion of active TB cases resulting from recent transmission within this network; and 3) evaluate whether PWUD with TB disease have physiologic characteristics associated with more efficient TB transmission. Our cross-sectional observational study aims to assess TB transmission through illicit drug use networks focusing on methamphetamine and Mandrax (methaqualone) use in a high TB burden setting and identify mechanisms underlying accelerated transmission. We will recruit and enroll 750 PWUD (living with and without HIV) through respondent driven sampling in Worcester South Africa. Drug use will be measured through self-report and biological measures with sputum specimens collected to identify TB disease by Xpert Ultra (Cepheid) and mycobacterial culture. We will co-enroll those with microbiologic evidence of TB disease in Aim 2 for molecular and social network study. Whole genome sequencing of Mycobacteria tuberculosis (Mtb) specimens and social contact surveys will be done for those diagnosed with TB. For Aim 3 aerosolized Mtb will be compared in individuals with newly diagnosed TB who do and do not smoke illicit drug. Knowledge from this study will provide the basis for a strategy to interrupt TB transmission in PWUD and provide insight into how this fuels overall community transmission. Results have potential for informing interventions to reduce TB spread applicable to high TB and HIV burden settings. Trial registration: Clinicaltrials.gov Registration Number: NCT041515602. Date of Registration: 5 November 2019.
Published: 2022-02-15
Journal: PLoS One
DOI: 10.1371/journal.pone.0262440
DOI_URL: http://doi.org/10.1371/journal.pone.0262440
Author Name: Carney Tara
Author link: https://covid19-data.nist.gov/pid/rest/local/author/carney_tara
Author Name: Rooney Jennifer A
Author link: https://covid19-data.nist.gov/pid/rest/local/author/rooney_jennifer_a
Author Name: Niemand Nandi
Author link: https://covid19-data.nist.gov/pid/rest/local/author/niemand_nandi
Author Name: Myers Bronwyn
Author link: https://covid19-data.nist.gov/pid/rest/local/author/myers_bronwyn
Author Name: Theron Danie
Author link: https://covid19-data.nist.gov/pid/rest/local/author/theron_danie
Author Name: Wood Robin
Author link: https://covid19-data.nist.gov/pid/rest/local/author/wood_robin
Author Name: White Laura F
Author link: https://covid19-data.nist.gov/pid/rest/local/author/white_laura_f
Author Name: Meade Christina S
Author link: https://covid19-data.nist.gov/pid/rest/local/author/meade_christina_s
Author Name: Chegou Novel N
Author link: https://covid19-data.nist.gov/pid/rest/local/author/chegou_novel_n
Author Name: Ragan Elizabeth
Author link: https://covid19-data.nist.gov/pid/rest/local/author/ragan_elizabeth
Author Name: Walzl Gerhard
Author link: https://covid19-data.nist.gov/pid/rest/local/author/walzl_gerhard
Author Name: Horsburgh Robert
Author link: https://covid19-data.nist.gov/pid/rest/local/author/horsburgh_robert
Author Name: Warren Robin M
Author link: https://covid19-data.nist.gov/pid/rest/local/author/warren_robin_m
Author Name: Jacobson Karen R
Author link: https://covid19-data.nist.gov/pid/rest/local/author/jacobson_karen_r
sha: 08af3110c978c7e97d17342103debdb6cf188ac3
license: cc-by
license_url: https://creativecommons.org/licenses/by/4.0/
source_x: Medline; PMC
source_x_url: https://www.medline.com/https://www.ncbi.nlm.nih.gov/pubmed/
pubmed_id: 35167586
pubmed_id_url: https://www.ncbi.nlm.nih.gov/pubmed/35167586
pmcid: PMC8846525
pmcid_url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8846525
url: https://doi.org/10.1371/journal.pone.0262440 https://www.ncbi.nlm.nih.gov/pubmed/35167586/
has_full_text: TRUE
Keywords Extracted from Text Content: sputum specimens Mandrax methaqualone People illicit methamphetamine Mtb PWUDs individuals PWUD tobacco PLHIV/TB sedatives methaqualone sputa sputum specimen People Instrument Boston Medical Center methamphetamines people participants Mtb culture N-Acetyl-L-Cysteine [1] urine CA Coriolis1μ DNA methamphetamine r-project.org individuals stimulants Arm 1 US COVID-19 Fig 2 enrollments Mandrax IQ-TREE Blood cannabis � transmitter-contacts [2] sputum HIV sputum samples seed hexadecyltrimethylammonium bromide wine PWUDs Volz-Heckathorn lockdown blood Mtb DNA WGS patients PWUD [12] Alcohol Town Mtb WGS pulmonary ADEGENET Fig 1 Province 604/2020 seeds persons � CTAB 1-4 alcohol tubes Arm 2 pulmonary TB exhaled primer-probes PLHIV Breede Valley human MEGA Mtb persons Mtb DNA amphetamines [13] . RaxML 192.24 PWUD participants
Extracted Text Content in Record: First 5000 Characters:People who use illicit drugs (PWUDs) have been identified as a key at-risk group for tuberculosis (TB). Examination of illicit drug use networks has potential to assess the risk of TB exposure and disease progression. Research also is needed to assess mechanisms for accelerated TB transmission in this population. This study aims to 1) assess the rate of TB exposure, risk of disease progression, and disease burden among PWUD; 2) estimate the proportion of active TB cases resulting from recent transmission within this network; and 3) evaluate whether PWUD with TB disease have physiologic characteristics associated with more efficient TB transmission. Our cross-sectional, observational study aims to assess TB transmission through illicit drug use networks, focusing on methamphetamine and Mandrax (methaqualone) use, in a high TB burden setting and identify mechanisms underlying accelerated transmission. We will recruit and enroll 750 PWUD (living with and without HIV) through respondent driven sampling in Worcester, South Africa. Drug use will be measured through self-report and biological measures, with sputum specimens collected to identify TB disease by Xpert Ultra (Cepheid) and mycobacterial culture. We will co-enroll those with microbiologic evidence of TB disease in Aim 2 for molecular and social network study. Whole genome sequencing of Mycobacteria tuberculosis (Mtb) specimens and social PLOS ONE | https://doi.contact surveys will be done for those diagnosed with TB. For Aim 3, aerosolized Mtb will be compared in individuals with newly diagnosed TB who do and do not smoke illicit drug. Knowledge from this study will provide the basis for a strategy to interrupt TB transmission in PWUD and provide insight into how this fuels overall community transmission. Results have potential for informing interventions to reduce TB spread applicable to high TB and HIV burden settings. Introduction Tuberculosis (TB) is one of the leading infectious diseases globally that cause death, including among people living with HIV (PLHIV) [1] . An effective method to reduce TB incidence and mortality is to interrupt transmission, which requires finding and treating individuals with subclinical and clinical TB disease early. Molecular epidemiologic studies and mathematical models have shown that household contact tracing, our primary approach to case finding, identifies less than 19% of transmissions in high TB and TB/HIV burden settings [2] . There is a clear need to identify additional risk groups and settings where TB transmission occurs. New approaches have focused on congregate settings, such as prisons and healthcare facilities, to identify additional TB transmission [3] . A major source of transmission also may exist in venues where individuals smoke illicit drugs, making these social networks potential amplifiers for the broader population epidemic and a group to target for transmission interventions. Globally, people who use drugs (PWUD) have higher TB infection prevalence and disease incidence compared to people who do not use drugs, likely reflecting a combination of withingroup transmission and clustered vulnerability [4] . In the US, nearly one third of persons � 15 years old with TB disease reported problem alcohol or drug use [5] , and the majority of USbased outbreaks between 2002 and 2015 were among PWUD. TB outbreaks among PWUD have also been reported in other countries [6] [7] [8] [9] [10] [11] . In the past 20 years, TB incidence has decreased in most high-income countries with TB disease burden concentrated in at-risk subpopulations, including PWUD [12] . Similar higher rates of TB disease among PWUD may occur in high TB burden settings as well, reflecting increased transmission within these groups, but the phenomenon may be harder to isolate given the general high population burden. South Africa is an ideal context to study the relationship between drug use and TB due to its concurrent high TB/HIV burden and high drug use prevalence [13, 14] . Nationally, an estimated 13.3% of the adult population meet criteria for a lifetime substance use disorder (SUD), with rates as high as 20.6% for the Western Cape Province [14] . Community-based data related to illicit drug use in South Africa are limited but suggest a growing problem. A 2012 population-based study of adults found the past 3-month prevalence was 4.0% for cannabis, 0.4% for sedatives, and 0.3% for amphetamines [13] . A 2017 national study estimated the prevalence of any drug use in the last 3 months increased to 8.6% of adults, largely driven by cannabis use followed by Mandrax (methaqualone) and stimulants such as methamphetamine [15] . Polysubstance use is common [16, 17] , and likely to be under-reported due to the illicit nature of substance use and concerns about stigma. In the Western Cape, methamphetamine (referred to as tik), which is generally smoked, has been a popular self-reported drug of choice among patients entering SUD treatment for a
Keywords Extracted from PMC Text: patients sputa PWUD Mtb WGS transmitter-contacts People Instrument human COVID-19 ≥15 people Blood Breede Valley PWUDs exhaled 's RaxML wine urine CA blood CO2 methamphetamines sputum samples alcohol Mtb ADEGENET hexadecyltrimethylammonium bromide persons cannabis Coriolis®μ MEGA Alcohol Province pulmonary enrollments N-Acetyl-L-Cysteine tobacco Mtb culture sputum specimen seed 192.24 seeds PLHIV/TB r-project.org lockdown PLHIV individuals Mtb DNA methamphetamine Arm 1 primer-probes Volz-Heckathorn Mtb DNA WGS CTAB participants Mandrax DNA IQ-TREE sputum tubes pulmonary TB Fig 2
Extracted PMC Text Content in Record: First 5000 Characters:The Transmission Of Tuberculosis Among illicit drug use Linkages (TOTAL) study has three aims. The first is to assess the TB exposure, risk of disease progression, and disease burden among PWUD, including people living with and without HIV. We hypothesize that TB prevalence in PWUD will be significantly higher compared to results from a community-wide survey [32] and that the prevalence of incipient TB (host RNA signature presence) will be significantly higher among PWUD compared to the general community. We also hypothesize that PWUD living with HIV will have higher rates of incipient, subclinical, and clinical TB disease compared to those PWUD who are HIV negative. Second, we aim to estimate the proportion of active TB cases that are the result of transmission within the social network of PWUD. We hypothesize that there will be a high proportion of linked isolates from Aim 1, reflecting predominance of recent transmission within this cohort. We also expect that persons with TB/HIV co-infection will more often appear as contacts with fewer links compared to persons with TB disease alone, reflecting their increased susceptibility to TB and their decreased ability to transmit TB. Third, we aim to evaluate whether PWUD with TB disease have physiologic characteristics associated with more efficient TB transmission compared to people with TB disease who do not use drugs. Among individuals with TB, we hypothesize that PWUD will produce larger amounts of aerosolized Mtb than people who do not use drugs, after adjusting for bacterial burden (tested by mycobacterial culture time to positivity and GeneXpert Ultra). We will include people with and without HIV in each arm to assess any modifying effects of HIV, and record other smoked substances (tobacco, cannabis) and alcohol use to assess their impact as well. We will recruit participants residing in the greater Worcester area. Worcester is the main town of the Breede Valley municipality in the Western Cape Province, South Africa, and is a prominent wine producing region [34] with high rates of TB and HIV. Though the prevalence of methamphetamine and Mandrax use in this community is not precisely known, both drugs are widely available as reflected in reports from local SUD treatment providers [16]. We recently found that among persons initiating TB treatment and recruited into a prospective research study in the Worcester Community Day Centre (CDC), 53% reported smoked drug use including methamphetamines, Mandrax, and cannabis [35]. Study participants will be recruited by referral chains of PWUD that start with seeds who will be ≥15 years old, reside locally, are willing and able to provide written informed consent and participate in study activities. Inclusion criteria by study arm in shown in Fig 2. For Aim 1, additional inclusion criteria will include self-reported methamphetamine or Mandrax use in the past month and a positive urine drug screen for either of these drugs at enrollment, and a coupon indicating their recruitment into the study by another participant (with the exception of seeds). For Aims 2 and 3, individuals will have microbiologic evidence of active TB disease Xpert Ultra (Cepheid, CA) or Mtb culture]. For Aim 3, participants will be excluded if they are pregnant, have taken >5 days of TB medication, or for the control group in Aim 3 Arm 2, if they self-report any past month drug use or have positive urine drug test results. Exclusion criteria for all study aims will include current alcohol or drug intoxication and inability to provide informed consent. For Aim 1, we will invite eligible participants to enroll as initial study participants (seeds). Individuals will provide written informed consent (and parental consent will be obtained for individuals <18 years) before being screened for Aim 1 eligibility. Enrollment will include the collection of biometric fingerprints. Seeds will then complete interviewer-administered biobehavioural questionnaires and provide blood for COVID-19 serology, rapid HIV testing, and host RNA sequencing, and induced sputa for Xpert Ultra and mycobacterial culture respectively. Those with a new HIV diagnosis will be referred to a clinic so that they can access HIV care services. For the latter, sputum will be liquefied and decontaminated (N-Acetyl-L-Cysteine) and neutralized in PBS. The bacilli will be collected by centrifugation, with positive MGIT cultures assessed for acid fast bacilli and Capilia TB Testing to confirm the Mtb presence. Each seed will then be given two coupons to recruit two people with whom they currently use methamphetamine and/or Mandrax. The initial recruits who are successfully enrolled into the study will be given two recruitment coupons to disperse in the same manner. This will continue until we reach 750 participants. Additional seeds will be included as needed until we reach the target sample size (n = 750). Participants will be asked to return approximately two weeks after their first visi
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