Detection of Mycobacterium tuberculosis Complex Using the Xpert MTB/RIF Ultra Assay on the Stool of Pediatric Patients in Dushanbe, Tajikistan.

We report the findings of a prospective laboratory diagnostic accuracy study to evaluate the sensitivity, specificity, and predictive values of the Xpert MTB/RIF Ultra assay for Mycobacterium tuberculosis detection in fresh stool specimens from children under 15 years of age with confirmed tuberculosis (TB) disease from Dushanbe, Tajikistan. Six hundred eighty-eight (688) participants were enrolled from April 2019 to October 2021. We identified 16 participants (2.3%) with confirmed TB disease, defined as ≥1 TB sign/symptom plus microbiologic confirmation. With the Xpert MTB/RIF Ultra assay for stool, we found a sensitivity of 68.8% (95% CI, 46.0 to 91.5) and a specificity of 98.7% (95% CI, 97.8 to 99.5) in confirmed TB disease. Our results are comparable to other published studies; however, our cohort was larger and our confirmed TB disease rate lower than most. We also demonstrated that this assay was feasible to implement in a centralized hospital laboratory in a low-middle-income Central Asian country. However, we encountered obstacles such as lack of staffing, material ruptures, outdated government protocols, and decreased case presentation due to COVID-19. We found eight patients whose only positive test was an Xpert Ultra stool assay. None needed treatment during the study; however, three were treated later, suggesting such cases require close observation. Our report is the first from Central Asia and one of a few from a low-middle-income country. We believe our study demonstrates the generalizability of the Xpert MTB/RIF Ultra assay on fresh stool specimens from children and provides further evidence supporting WHO's approval of this diagnostic strategy. IMPORTANCE The importance of this report is that it provides further support for WHO's recent recommendation that fresh stool is an acceptable sample for GeneXpert TB testing in children, especially small children who often cannot produce an adequate sputum sample. Diagnosing TB in this age group is difficult, and many cases are missed, leading to unacceptable rates of TB illness and death. In our large cohort of children from Dushanbe, Tajikistan, the GeneXpert stool test was positive in 69% of proven cases of TB, and there were very few false-positive tests. We also showed that this diagnostic strategy was feasible to implement in a low-middle-income country with an inefficient health care delivery system. We hope that many more programs will adopt this form of diagnosing TB in children.

A double-edged sword: does highly active antiretroviral therapy contribute to syphilis incidence by impairing immunity to Treponema pallidum?

BACKGROUND AND HYPOTHESIS: Recently, the world has experienced a rapidly escalating outbreak of infectious syphilis primarily affecting men who have sex with men (MSM); many are taking highly active antiretroviral therapy (HAART) for HIV-1 infection. The prevailing hypothesis is that HAART availability and effectiveness have led to the perception among both individuals who are HIV-1 infected and those who are uninfected that HIV-1 transmission has become much less likely, and the effects of HIV-1 infection less deadly. This is expected to result in increased sexual risk-taking, especially unprotected anal intercourse, leading to more non-HIV-1 STDs, including gonorrhoea, chlamydia and syphilis. However, syphilis incidence has increased more rapidly than other STDs. We hypothesise that HAART downregulates the innate and acquired immune responses to Treponema pallidum and that this biological explanation plays an important role in the syphilis epidemic. METHODS: We performed a literature search and developed a mathematical model of HIV-1 and T. pallidum confection in a population with two risk groups with assortative mixing to explore the consequence on syphilis prevalence of HAART-induced changes in behaviour versus HAART-induced biological effects. CONCLUSIONS AND IMPLICATIONS: Since rising syphilis incidence appears to have outpaced gonorrhoea and chlamydia, predominantly affecting HIV-1 positive MSM, behavioural factors alone may be insufficient to explain the unique, sharp increase in syphilis incidence. HAART agents have the potential to alter the innate and acquired immune responses in ways that may enhance susceptibility to T. pallidum. This raises the possibility that therapeutic and preventative HAART may inadvertently increase the incidence of syphilis, a situation that would have significant and global public health implications. We propose that additional studies investigating the interplay between HAART and enhanced T. pallidum susceptibility are needed. If our hypothesis is correct, HAART should be combined with enhanced patient management including frequent monitoring for pathogens such as T. pallidum.

A brief tool to assess capacity to consent for medical care among homeless individuals with problematic substance use: study protocol.

BACKGROUND: Public health care increasingly uses outreach models to engage individuals who are marginalized, many of whom misuse substances. Problematic substance use, together with marginalization from the health care system, among homeless adults makes it difficult to assess their capacity to consent to medical care. Tools have been developed to assess capacity to consent; however, these tools are lengthy and unsuitable for outreach settings. The primary objective of this study is to develop, validate, and pilot a brief but sensitive screening instrument which can be used to guide clinicians in assessing capacity to consent in outreach settings. The goal of this paper is to outline the protocol for the development of such a tool. METHODS/DESIGN: A brief assessment tool will be developed and compared to the MacArthur Competency Assessment Tool for Treatment (MacCAT-T). As list of 36 possible questions will be created by using qualitative data from clinician interviews, as well as concepts from the literature. This list will be rated by content experts according to the extent that it corresponds to the test objectives. The instrument will be validated with 300 homeless adult volunteers who self-report problematic substance use. Participants will be assessed for capacity using the MacCAT-T and the new instrument. A combination of Classical Test Theory and advanced psychometric methods will be used for the psychometric analysis. Corrected Item-Total correlation will be examined to identify items that discriminate poorly. Guided exploratory factor analysis will be conducted on the final selection of items to confirm the assumptions for a unidimensional polytomous Rasch model. If unidimensionality is confirmed, an unstandardized Cronbach Alpha will be calculated. If multi-dimensionality is detected, a multidimensional Rasch analysis will be conducted. Results from the new instrument will be compared to the total score from the MacCAT-T by using Pearson's correlation test. The new instrument will then be piloted in real-time by street outreach clinicians to determine the acceptability and usefulness of the new instrument. DISCUSSION: This research will build on the existing knowledge about assessing capacity to consent and will contribute new knowledge about assessing individuals whose judgment is impaired by substance use.

Chlamydia public health programs and the epidemiology of pelvic inflammatory disease and ectopic pregnancy.

BACKGROUND: Many countries have witnessed a disturbing increase in cases of Chlamydia trachomatis infection despite enhanced control programs. Since the goal of Chlamydia control is to prevent reproductive complications such as pelvic inflammatory disease and ectopic pregnancy, an understanding of recent trends in these conditions is needed to fully evaluate the effect of control efforts. METHODS: We analyzed 2 provincial, comprehensive health services administrative databases (encompassing hospitalizations and all physician-delivered services) for pelvic inflammatory disease and ectopic pregnancy trends from 1992 through 2009 in women of reproductive age in British Columbia, Canada. Trends were compared to provincial Chlamydia surveillance data by time-series analysis, using the cross-correlation function method and Granger causality testing. RESULTS: Chlamydia cases substantially increased from 1992 through 2009. Inpatient, outpatient, and total diagnoses of pelvic inflammatory disease and ectopic pregnancy declined from 1992 through 2003. After 2003, pelvic inflammatory disease rates continued to fall, while ectopic pregnancy rates significantly increased. The male Chlamydia urethritis rate increased from 39.4 to 173.6 cases/100,000 from 1996 to 2009. CONCLUSIONS: In the context of increasing Chlamydia infection rates, the reproductive complications of Chlamydia infection in women are declining overall. A recent increase in rates of ectopic pregnancies is cause for concern.

Towards targeted screening for acute HIV infections in British Columbia.

BACKGROUND: Our objective was to describe the characteristics of acute and established HIV infections diagnosed in the Canadian province of British Columbia. Province-wide HIV testing and surveillance data were analyzed to inform recommendations for targeted use of screening algorithms to detect acute HIV infections. METHODS: Acute HIV infection was defined as a confirmed reactive HIV p24 antigen test (or HIV nucleic acid test), a non-reactive or reactive HIV EIA screening test and a non-reactive or indeterminate Western Blot. Characteristics of unique individuals were identified from the British Columbia HIV/AIDS Surveillance System. Primary drug resistance and HIV subtypes were identified by analyzing HIV pol sequences from residual sera from newly infected individuals. RESULTS: From February 2006 to October 2008, 61 individuals met the acute HIV infection case definition, representing 6.2% of the 987 newly diagnosed HIV infections during the analysis period. Acute HIV infection cases were more likely to be men who have sex with men (crude OR 1.71; 95% CI 1.01-2.89], to have had a documented previous negative HIV test result (crude OR 2.89; 95% CI 1.52-5.51), and to have reported a reason for testing due to suspected seroconversion symptoms (crude OR 5.16; 95% CI 2.88-9.23). HIV subtypes and rates of transmitted drug resistance across all classes of drugs were similar in persons with both acute and established HIV infections. CONCLUSIONS: Targeted screening to detect acute HIV infection is a logical public health response to the HIV epidemic. Our findings suggest that acute HIV infection screening strategies, in our setting, are helpful for early diagnosis in men who have sex with men, in persons with seroconversion symptoms and in previously negative repeat testers.

Using centralized laboratory data to monitor trends in herpes simplex virus type 1 and 2 infection in British Columbia and the changing etiology of genital herpes.

OBJECTIVES: Understanding the regional epidemiology of genital Herpes Simplex Virus (HSV) infections is important for clinical and public health practice, due to the increasing availability of type-specific serologic testing in Canada and the contribution of genital HSV-2 infection to ongoing HIV transmission. We used centralized laboratory data to describe trends in viral identifications of genital HSV in BC and assess the utility of these data for ongoing population surveillance. METHODS: Records of viral identifications (1997-2005) were extracted from the Provincial Public Health Microbiology & Reference Laboratory database. Classification as genital or other site was based on documented specimen site. We conducted a descriptive analysis of trends over time, and calculated odds of HSV-1 infection among individuals with genital herpes. RESULTS: Of 48,183 viral identifications, 56.8% were genital, 10.0% were peri-oral and 9.1% cutaneous; site was unknown for 22.9%. Among genital identifications, HSV-1 infection was more likely in females, younger age groups, and later time periods. The proportion of genital herpes due to HSV-1 increased over time from 31.4% to 42.8% in BC. CONCLUSIONS: Our analysis of population-level laboratory data demonstrates that the proportion of genital herpes due to HSV-1 is increasing over time in BC, particularly among women and younger age groups; this has implications for clinical practice including the interpretation of type-specific serology. Provincial viral identification data are useful for monitoring the distribution of genital HSV-1 and HSV-2 infections over time. Improving clinical documentation of specimen site would improve the utility of these data.

Protective immunity to Chlamydia trachomatis genital infection: evidence from human studies.

Background. Some screening and treatment programs implemented to control Chlamydia trachomatis genital infections and their complications have shown initial reductions in infection prevalence, followed by increases to preprogram levels or higher. One hypothesis is that treatment shortens duration of infection, attenuates development of protective immunity, and thereby, increases risk of reinfection. Methods. A literature review was undertaken to assess evidence supporting the concept of protective immunity,its characteristics, and its laboratory correlates in human chlamydial infection. The discussion is organized around key questions formulated in preparation for the Chlamydia Immunology and Control Expert Advisory Meeting held by the Centers for Disease Control and Prevention in April 2008. Results. Definitive human studies are not available, but cross-sectional studies show that chlamydia prevalence,organism load, and concordance rates in couples decrease with age, and organism load is lower in those with repeat infections, supporting the concept of protective immunity. The protection appears partial and can be overcome after reexposure, similar to what has been found in rodent models of genital infection. No data are available to define the duration of infection required to confer a degree of immunity or the time course of immunity after resolution of untreated infection. In longitudinal studies involving African sex workers, a group presumed to have frequent and ongoing exposure to chlamydial infection, interferon-g production by peripheral blood mononuclear cells in response to chlamydial heat-shock protein 60 was associated with low risk of incident infection.In cross-sectional studies, relevant T helper 1-type responses were found in infected persons, paralleling the studies in animal models. Conclusions. The data support the concept that some degree of protective immunity against reinfection develops after human genital infection, although it appears, at best, to be partial. It is likely that factors besides population levels of immunity contribute to trends in prevalence observed in screening and treatment programs.Future studies of protective immunity in humans will require longitudinal follow-up of individuals and populations,frequent biological and behavioral sampling, and special cohorts to help control for exposure.

A population-based study of infectious syphilis rediagnosis in British Columbia, 1995-2005.

BACKGROUND: The Canadian province of British Columbia has experienced an ongoing heterosexual infectious syphilis epidemic since July 1997. In this study, we sought to characterize individuals who received a diagnosis of syphilis more than once in a cohort of reported cases from 1995 through 2005 in British Columbia. METHODS: Data for all cases of primary, secondary, and early latent syphilis from 1 January 1995 through 31 December 2005 were extracted from the British Columbia Provincial Sexually Transmitted Disease Surveillance Database. A descriptive analysis was conducted on all variables from the cases, and the incidence density of syphilis rediagnosis was calculated. Bivariate and multivariate analyses were conducted using Cox proportional hazards regression techniques to compare those who received a syphilis diagnosis once with those who received a syphilis diagnosis more than once within the 10-year period. RESULTS: By 2006, up to 10% of new cases of syphilis in the province were attributed to individuals who had received a previous diagnosis of syphilis within the preceding 10 years. In Cox proportional hazards regression analysis, individuals with the following characteristics were associated with an increased risk of becoming reinfected with syphilis: human immunodeficiency virus seropositivity, history of ever having gonorrhea or chlamydia, aboriginal ethnicity, and being a man who had sex with men. CONCLUSIONS: In this study, an increasing proportion of syphilis cases in British Columbia were attributed to a rediagnosis during the previous decade. Individuals with syphilis rediagnosis may represent a core group of transmitters who continue to engage in risky behavior and sustain the epidemic. Policies for prevention need to better consider the role of interventions to decrease rates of repeat diagnoses of sexually transmitted infections.

Considerations on Chlamydia trachomatis disease expression.

Chlamydia disease expression is the result of complex molecular and cellular interactions between the host and a pathogen which appears to have been sculpted by evolutionary forces. Recent genomic, immunologic, and epidemiologic findings are reviewed. A synthesis is offered which suggests that Chlamydia disease expression results from persistent infection and host immune responses.

Seeking sexual partners on the internet: a marker for risky sexual behaviour in men who have sex with men.

OBJECTIVE: In order to generate a generalizable estimate regarding risk for STI and HIV acquisition in men who have sex with men (MSM) who seek partners on the internet, we examined the sexual practices of MSM who seek partners on the internet compared to MSM who do not, using a community-based sample of MSM from British Columbia. METHODS: 'Sex Now', a questionnaire that was developed to examine trends in sexual behaviour in gay men, was offered to men attending Gay Pride events throughout the province of British Columbia, Canada between May and August 2004. Logistic regression analysis was used to model the association between seeking sexual partners online and other variables of interest, using odds ratio as the measure of association. RESULTS: Of the 2,312 MSM who completed the survey, 766 (33.1%) had used the internet to find a partner in the past year. In logistic regression analyses, MSM who found partners on the internet were more likely to have had more than 10 sexual partners in the past year (overall, insertive and receptive), and to engage in sexual activities in public venues. They were also more likely to agree with the statement "I think most guys in relationships have condom-free sex." MSM who sought partners on the net were more likely to be from specific geographic regions, including non-urban regions. Demographic characteristics, HIV status, and use of drugs were not significantly different between men who found partners on the internet and those who did not in multivariable modeling. DISCUSSION: MSM who sought to meet partners online had significantly more sexual partners, were more likely to be from specific geographic regions of the province and to have participated in seeking sexual partners in venues known to be associated with HIV and STI acquisition. This study confirms from a community-based sample of MSM that programming for prevention and treatment of HIV and STI need to be available and offered in the cyber setting, to ensure effective messaging and interventions reach this population.

A population-based approach to determine the prevalence of transmitted drug-resistant HIV among recent versus established HIV infections: results from the Canadian HIV strain and drug resistance surveillance program.

OBJECTIVES: Published results on primary or transmitted HIV drug resistance may be biased because they have been largely derived from specific cohort studies or higher risk individuals who present symptomatically. Here, we present results from a representative population-based study of newly diagnosed cases of HIV in Canada and compare the prevalence of transmitted drug resistance between recent and established infections. METHODS: Available archived sera taken for the purpose of diagnostic HIV testing from all treatment-naive HIV-positive individuals who were newly diagnosed between 2000 and 2001 were tested for recency of infection, HIV-1 subtype, and mutations conferring reduced susceptibility to reverse transcriptase inhibitors and protease inhibitors (PIs). Recent infections were identified using the Organon Teknika Vironostika HIV-1-LS assay. After full-length sequencing of the pol gene, drug resistance mutations were identified using the 2004 International AIDS Society-USA mutations panel. Differences in drug resistance profiles between recent and prevalent infections were examined using the chi test and the Fisher exact test. The variables examined included gender, age at diagnosis, year of diagnosis, exposure category, ethnicity, and HIV-1 subtype. RESULTS: Among the study population, 8.1% had genotypic evidence of transmitted drug resistance: 4.1% against nucleoside reverse transcriptase inhibitors, 1.4% against nonnucleoside reverse transcriptase inhibitors, 1.5% against PIs, and 1% against > or =2 classes of drugs. A higher proportion of recent infections had genotypic evidence of transmitted drug resistance when compared with established infections (12.2% vs. 6.1%, respectively; P = 0.005). Transmitted drug resistance was identified mainly among recently infected Caucasian men who have sex with men but it was not limited to this group. Compared with the year 2000, a higher proportion of recently infected individuals with resistance-conferring mutations were diagnosed during the year 2001 (66.7% vs. 46.6%). CONCLUSIONS: In Canada, transmitted drug resistance is occurring within all 3 drug classes and across different population groups. The results suggest that the prevalence rates may be higher among recent versus established infections. Given the public health implications of transmitting drug-resistant HIV, it is important to continue population-based drug resistance surveillance to guide optimum prevention and treatment of HIV infection.

Sex-work harm reduction.

Sex work is an extremely dangerous profession. The use of harm-reduction principles can help to safeguard sex workers' lives in the same way that drug users have benefited from drug-use harm reduction. Sex workers are exposed to serious harms: drug use, disease, violence, discrimination, debt, criminalisation, and exploitation (child prostitution, trafficking for sex work, and exploitation of migrants). Successful and promising harm-reduction strategies are available: education, empowerment, prevention, care, occupational health and safety, decriminalisation of sex workers, and human-rights-based approaches. Successful interventions include peer education, training in condom-negotiating skills, safety tips for street-based sex workers, male and female condoms, the prevention-care synergy, occupational health and safety guidelines for brothels, self-help organisations, and community-based child protection networks. Straightforward and achievable steps are available to improve the day-to-day lives of sex workers while they continue to work. Conceptualising and debating sex-work harm reduction as a new paradigm can hasten this process.

The unexpected impact of a Chlamydia trachomatis infection control program on susceptibility to reinfection.

BACKGROUND: After the introduction of a program to control Chlamydia trachomatis infection in British Columbia, Canada, case rates fell from 216 cases/100,000 population in 1991 to 104 cases/100,000 population in 1997. Since 1998, rates have increased, and case counts now exceed those recorded before the intervention. METHODS: We used Cox proportional-hazards survival analysis and developed a compartmental mathematical model to investigate the cause of resurgence in chlamydia cases. RESULTS: Cox proportional-hazards survival analysis showed that the relative risk of C. trachomatis reinfection has increased 4.6% per year since 1989, with the increased risk greatest among the young and greater among women than men. A compartmental mathematical model of C. trachomatis transmission showed that a control strategy based on shortening the average duration of infection results in an early reduction in prevalence followed by a rebound in prevalence, reproducing the observed trends. CONCLUSIONS: We speculate that a C. trachomatis infection control program based on early case identification and treatment interferes with the effects of immunity on population susceptibility to infection and that, in the absence of strategies to alter sexual networks, a vaccine will be needed to halt the spread of infection at the population level.

Prenatal and congenital syphilis in British Columbia.

OBJECTIVE: To describe the incidence of maternal syphilis and the corresponding rate of infection in exposed neonates in British Columbia before and after a serious outbreak of infectious syphilis in the heterosexual population. METHODS: We conducted a retrospective chart review of pregnant women with positive syphilis serology and reported cases of congenital syphilis in British Columbia from 1994 to 2003. Clinical charts were reviewed for demographic information, staging of maternal syphilis, and stage of pregnancy when treatment was received. The primary outcome measure was the number of cases of congenital syphilis. We conducted a 2-sided z-test and Fisher's exact test to determine differences in the proportion of infectious syphilis in mothers and the number of cases of congenital syphilis before and during the major outbreak. RESULTS: In 389 478 live births in British Columbia between 1994 and 2003, 77% of mothers had prenatal syphilis serology. A diagnosis of syphilis was made in 183 mothers, resulting in 5 cases of congenital syphilis. Four of these were in infants whose mothers did not undergo prenatal syphilis testing. The proportion of pregnant women with infectious syphilis was significantly higher after the onset of a major outbreak of syphilis in the community than it was before (P = 0.001), but there was no significant difference in the number of cases of congenital syphilis (3 before and 2 after the outbreak, P = 0.36). CONCLUSION: Although syphilis rates in British Columbia during the study period rose steadily, the prevalence of congenital syphilis remained low. Our findings suggest that, in the context of a major outbreak, universal screening and prenatal syphilis testing may contribute to controlling rates of congenital syphilis.

The impact of syphilis mass treatment one year later: self-reported behaviour change among participants.

In 2000, syphilis mass treatment using oral azithromycin was delivered to at-risk British Columbians during a sex trade-related outbreak. The initiative included education, counselling and referral. This cross-sectional, observational study examines knowledge, attitudes and self-reported behaviour after one year among mass treatment participants compared with eligible non-participants. Participants self-reported positive changes: reduction in sexual partners overall (P=0.001) and for sex workers (P<0.01), decrease in unprotected oral sex (P=0.03), knowledge of asymptomatic syphilis (P=0.02), positive attitudes to mass treatment (P=0.02) and to the street nurses (P=0.01). Increased awareness was associated with increased condom use for vaginal sex overall (P=0.02) and for sex workers (P=0.03) and increased condom use for oral sex (P=0.05). There was no difference in syphilis incidence. Syphilis outbreak interventions that include education, support and referral can result in long-term positive behaviour changes.