Laboratory-confirmed Tuberculosis Research Articles

A retrospective study of extrapulmonary tuberculosis in the Khuzestan province of southwest Iran between 2002 and 2023.

Worldwide, tuberculosis (TB) is among the most common causes of death. To our knowledge, there has been no study showing the prevalence of EPTB in Khuzestan province. Therefore, the objective of this research was to investigate the prevalence of EPTB in patients with or without pulmonary TB in different cities of Khuzestan province from 2002 to 2023. Additionally, the correlation between patient's gender, and age groups with the disease was also investigated. In this retrospective study, the existing records in Tuberculosis Regional Reference Laboratory of Khuzestan province related to patients were used. The research was carried out by investigating the archive information in 19 years (from 1st January 2002 to December 30, 2023). All confirmed cases of EPTB and simultaneous EPTB and PTB, based on laboratory results and medical examination were included in the study. Patients with incomplete information and military TB were excluded from the study. Information collected from patients includes age, gender, involved organ, place of residence, and year of disease. A total of 12,900 EPTB-related medical records were extracted from Tuberculosis Regional Reference Laboratories in southwest Iran, Ahvaz. After excluding records, 12,836 clinically diagnosed or laboratory-confirmed tuberculosis patients were included in this study, including 5991 patients with simultaneous PTB and EPTB, and 6845 patients with EPTB only. The mean age of male EPTB patients was 37.5 years (SD ± 14.6), while the mean age of male patients with simultaneous PTB and EPTB was 45.8 years (SD ± 15.3). The mean age of female patients with EPTB only, and with simultaneous PTB and EPTB was 31.2 years (SD ± 12.6), and 31.5 years respectively. tuberculosis is a systemic disease with different clinical manifestations. This study described different epidemiologic patterns of concurrent EPTB. The proportion of different types of EPTB was simultaneously determined for a group of hospitalized patients and shown to be different with gender and age. This study will likely increase clinicians' awareness of the disease and help them better address diagnostic challenges and improve treatment outcomes for patients with EPTB.

Risk Factors for Extrapulmonary Tuberculosis Among US Veterans, 1990-2022.

To determine factors that put US veterans with active tuberculosis at risk for extrapulmonary tuberculosis (EPTB) compared with pulmonary tuberculosis. We included veterans with laboratory-confirmed tuberculosis from 1990-2022 in our retrospective cohort study. Multivariable logistic regression was used to estimate the association of demographic and clinical risk factors with EPTB. Of 7493 veterans aged 20-100 years (median, 58 years) with laboratory-confirmed tuberculosis, 1397 (19%) had EPTB. The most common EPTB infection among veterans was pleural (31.4%), while meningitis carried the highest mortality risk at 90 days. Factors independently associated with EPTB among veterans were non-Hispanic black race/ethnicity, diabetes mellitus, human immunodeficiency virus infection, severe kidney disease, and all-cause mortality within 90 days after tuberculosis diagnosis. Our study demonstrated several risk factors for EPTB among US veterans. Healthcare providers should be educated regarding patient populations at risk for EPTB, especially given the challenges in diagnosing this disease and the importance of instituting early treatment to prevent severe illness and death.

Five-year tuberculosis trends analysis in eight districts of Mwanza region, Tanzania; (2017-2021).

In Tanzania like other developing countries, TB detection is hindered by totally missed, late notification, and delayed diagnosis of active cases. Apart from having TB control strategies and interventions to detect patients and put them on treatment to cut down the chain of transmission, TB remains a health concern. Limited data exist on the burden and trends of tuberculosis in Mwanza, which includes fishing communities and living conditions that are associated with high TB transmission like overcrowding. This study aimed to determine tuberculosis trends in the Mwanza region of Tanzania for five years, from 2017 to 2021. We extracted routine TB diagnostic data from 2017 to 2021 from eight districts of the Mwanza region of Tanzania from the electronic TB database. Data were captured in Microsoft Office Excel 2007 with district TB and leprosy coordinators and then imported into STATA 13 (Stata Corp LLC, College Station, TX, USA) for analysis. We estimated the TB case detection rate per 100,000 population. A total of 6,414 laboratory-confirmed tuberculosis cases were detected in eight districts of the Mwanza region in Tanzania from 2017 to 2021. The average tuberculosis detection rate in five years was 34.7 per 100,000 population. Overall, the TB detection rate was two times higher in people without HIV (30.5) compared to those infected with HIV; 13.4 per 100,000 population. Of the 15 rifampicin-resistant TB cases detected in the year 2018, 66.7% (10/15) were HIV-negative compared to 33.3% (5/15) infected with HIV. The TB case detection rate decreased in Mwanza region from 43.9 in 2017 to 21.4 per 100,000 population in 2021. Other parameters were missing in the database, which indicates remarkable gaps in the established database to monitor TB management in the region. The program may consider investigating and improving the documentation of information necessary to attain its goals.

Changes in the incidence, clinical features and outcomes of tuberculosis during COVID-19 pandemic

BackgroundCOVID-19 pandemic has disrupted tuberculosis (TB) services in many countries, but the impacts on sites of involvement, drug susceptibility, smear positivity and clinical outcomes, and clinical outcomes of co-infection with influenza and COVID-19 remain unclear. MethodsDescriptive epidemiological study using episode-based and patient unique data of tuberculosis from Hospital Authority’s territory-wide electronic medical record database, comparing baseline (January 2015-December 2019) and COVID-19 period (January 2020-December 2022), followed by univariate and multivariate analyses. Effects of co-infection with influenza and COVID-19 were investigated. ResultsThe study included 10,473 episodes of laboratory-confirmed TB, with 6818 in baseline period and 3655 during COVID-19 period. During COVID-19 period, TB patients had a lower proportion of smear positivity (49.2 % vs 54.7 %, P < 0.001), and fewer cases of extrapulmonary TB (7.0 % vs 8.0 %, P = 0.078) and multidrug resistant TB (1.0 % vs 1.6 %, P = 0.020). Mortality was higher in TB patients with COVID-19 coinfection (OR 1.7, P = 0.003) and influenza coinfection (OR 2.6, P = 0.004). During COVID-19 period, there were higher rates of treatment delay (20.5 % vs 15.5 %, P < 0.001) and episodic death (15.1 % vs 13.3 %, P = 0.006). Factors associated with higher mortality included age ≥ 70 years (OR 7.24), treatment delay (OR 2.16), extrapulmonary TB (OR 2.13). smear positivity (OR 1.71) and Charlson comorbidity index score ≥ 3 (OR 1.37). Higher mortality was observed with co-infection by influenza (OR 1.18) and COVID-19 (OR 1.7). ConclusionsThe epidemiology and outcomes of TB were changed during COVID-19 period. Mortality was higher during COVID-19 period and with co-infection by influenza and COVID-19.

Bronchial lavage tNGS in the diagnosis of pulmonary tuberculosis.

Tuberculosis (TB), primarily caused by Mycobacterium tuberculosis, remains a significant global health concern. Targeted Next-Generation Sequencing (tNGS) has emerged as a rapid and comprehensive diagnostic tool for tuberculosis, offering advantages over traditional methods and serving as an effective alternative for drug susceptibility testing and the detection of drug-resistant tuberculosis. This study aimed to retrospectively analyze the clinical characteristics of pulmonary tuberculosis patients. After explore the application value of targeted next-generation sequencing technology in this patient population, providing valuable insights for clinical diagnosis and treatment. In this retrospective study, we analyzed data from 65 patients with laboratory-confirmed tuberculosis admitted to Tianjin Baodi Hospital from November 14, 2020, to February 1, 2023. Patients underwent bronchoalveolar lavage fluid (BALF) testing, including acid-fast staining, culture, and tNGS. Biopsies and histopathological examinations were performed on some patients, along with comprehensive radiological assessments for all. Among the 65 pulmonary tuberculosis patients, targeted next-generation sequencing detected pathogens in bronchoalveolar lavage fluid with a positivity rate of 93.8%, significantly higher than traditional methods such as acid-fast staining, culture, and pathology. Compared to bronchoalveolar lavage fluid smear, targeted next-generation sequencing demonstrated significantly higher diagnostic sensitivity (98.46% vs. 26.15%) and accuracy (98.46% vs. 26.15%). Targeted next-generation sequencing, with its high sensitivity and specificity compared to traditional methods, provides unique advantages in detecting pathogens among these patients, highlighting its importance in disease management.

Second Nationwide Tuberculosis Outbreak Caused by Bone Allografts Containing Live Cells - United States, 2023.

During July 7-11, 2023, CDC received reports of two patients in different states with a tuberculosis (TB) diagnosis following spinal surgical procedures that used bone allografts containing live cells from the same deceased donor. An outbreak associated with a similar product manufactured by the same tissue establishment (i.e., manufacturer) occurred in 2021. Because of concern that these cases represented a second outbreak, CDC and the Food and Drug Administration worked with the tissue establishment to determine that this product was obtained from a donor different from the one implicated in the 2021 outbreak and learned that the bone allograft product was distributed to 13 health care facilities in seven states. Notifications to all seven states occurred on July 12. As of December 20, 2023, five of 36 surgical bone allograft recipients received laboratory-confirmed TB disease diagnoses; two patients died of TB. Whole-genome sequencing demonstrated close genetic relatedness between positive Mycobacterium tuberculosis cultures from surgical recipients and unused product. Although the bone product had tested negative by nucleic acid amplification testing before distribution, M. tuberculosis culture of unused product was not performed until after the outbreak was recognized. The public health response prevented up to 53 additional surgical procedures using allografts from that donor; additional measures to protect patients from tissue-transmitted M. tuberculosis are urgently needed.

Genomic, phenotypic and demographic characterization of Mycobacterium tuberculosis in Israel in 2021.

According to World Health Organization WHO, Tuberculosis (TB) is the second cause of death from infectious disease worldwide. During 2021, 10.6 million people were infected with TB, and 1.6 million people died. TB is caused by pathogens belonging to the Mycobacterium tuberculosis complex (MTBC), mainly by Mycobacterium tuberculosis (M.tb). Members of this complex are acid-fast bacilli, which can cause intrapulmonary and extra pulmonary TB, and can be divided into various lineages, based on genomic markers. The main public health threat comes from drug resistant M.tb strains, which are responsible for about 25% of TB death and treatment failure worldwide. Treating drug resistant TB patients significantly raises the costs of TB treatment. This study provides an overview of the demographic and drug susceptibility characteristics of newly diagnosed TB patients in Israel in 2021. The State of Israel has a very low level of TB endemicity and is at a pre-elimination phase. Notably, only 11.7% of the newly diagnosed TB patients were born in Israel. In this report, of the 154 new laboratory-confirmed TB patients, 66.7% had pulmonary TB, while 16% had extrapulmonary TB. Males accounted for 52% of the patients, with the most prevalent age group being 21-40. Most patients were citizens of Israel (53.9%), while 37.7% had no Israeli citizenship. Among non-citizens, there was a predominance of males and patients aged 21-40. The susceptibility profile showed a high resistance rate to streptomycin (18.2%) and to a lower extent to isoniazid (13.6%), pyrazinamide (8.4%), rifampicin (7.8%), and ethambutol (3.2%). Only 2 cases of XDR-TB and 10 MDR-TB strains were detected in Israel in 2021, with both XDR strains and 5 out of 10 MDR strains belonging to the Beijing lineage. Most of Beijing isolates were resistant to at least one tested drug. Genomic sequencing of 134 out of 156 strains and bioinformatics analysis using the MTBseq program and WHO mutation catalogue shows a good match with only 9 discrepancies between phenotypic and genotypic susceptibility profiles in first line drugs. The most common lineage is Delhi-Cas (23%) followed by the Beijing lineage (17%). Most patients from the Delhi-Cas lineage were born in Africa, while patients with Beijing isolates were born in different countries. Minimum spanning tree analysis identified 15 clusters. The study highlights the need for ongoing surveillance of TB using molecular and phenotypic tools to further decreasing the spreading level of the disease and develop effective treatment strategies.

Higher Abundance of Vitronectin (S-protein) in Serum-derived Exosomes of Pulmonary and Extra-Pulmonary Tuberculosis Patients as Compared to HIV-Tuberculosis Dual-infected Patients and Healthy Humans

Background: Despite the crucial involvement of vitronectin in affecting the perseverance of certain respiratory pathogens and the progression of several lung diseases, the association of vitronectin with tuberculosis (TB) has been poorly studied. The present study aimed to determine whether vitronectin levels are altered in TB patients compared to healthy humans. Methods: Twenty-four laboratory-confirmed tuberculosis patients (pulmonary TB -8, extrapulmonary- 8 and HIV-TB dual infected -8) and eight healthy individuals were included in this study. The quantitative detection of vitronectin in serum-derived exosomes of study participants was performed using a sandwich enzyme-linked immunosorbent assay. Measured concentrations of vitronectin were compared with the demographic variables of the study participants and between the study groups. The Mann–Whitney U unpaired test was used in statistical analysis, and the p-value &lt; 0.05 was considered statistically significant. Results: Vitronectin was detected in serum-derived exosomes of all study participants. The demographic characteristics (gender, age, smoking and alcohol consumption habit, history of cough, and weight loss) were not significantly correlated with the vitronectin concentrations of the study participants (p-value&gt; 0.05). The level of vitronectin was higher in patients with pulmonary TB (778.54 ng/l) and extra-pulmonary-TB patients (773.04 ng/l) while lower in HIV-pulmonary TB dual-infected patients (354.86 ng/l) as compared to healthy humans (456.20ng/l). There was a significant difference between vitronectin concentrations of patients with pulmonary TB (p-value: 0.0002) and extrapulmonary TB (p-value: 0.003) compared to healthy controls. Conclusion: The present study reported an increased concentration of vitronectin in serum-derived exosomes of pulmonary and extra-pulmonary TB patients compared to HIV-TB dual-infected patients and healthy humans. Further studies are needed to fully elucidate the diagnostic potential and functionalities of higher concentrations of vitronectin in the pathogenic processes of human TB.

Significant difference in Th1/Th2 paradigm induced by tuberculosis-specific antigens between IGRA-positive and IGRA-negative patients.

False negative interferon-γ release assay (IGRA) results constitute the major dilemma for the diagnosis of tuberculosis (TB) infections. Herein, we conducted a cohort study to compare the host immunological response to TB-specific antigens between active TB patients with positive and negative IGRA results and control groups. A total of 274 laboratory-confirmed TB patients were included in our analysis, consisting of 221 were IGRA positive and 53 were IGRA negative. Patients with the elderly were identified as an independent risk factor for negative IGRA results. In addition, the elevated level of IL-4 and the decreased levels of IFN-γ, IL-2, IL-6, IL-1β, and IL-12 in IGRA negative TB relative to IGRA positive TB group, demonstrating a significant difference in Th1/Th2 paradigm between two groups. The IFN-γ&IL-2 based assay could correctly identify 247 out of 307 MTB-infected individuals [271 TB patients and 36 individuals with latent TB infection (LTBI)], demonstrating a sensitivity of 80.5%. Then the IFN-γ and IL-4 were applied to distinguish healthy control and IGRA-negative group. When using the stepwise algorithm, the sensitivity for detecting Mycobacterium tuberculosis (MTB) infections was significantly increased from 80.5% to 89.6%. Additionally, patients with negative IGRA results had a conversion to culture-negative status longer than those with positive IGRA results. In conclusion, a stepwise algorithm outperforms IGRA assays to accurately identify MTB infections by the combination IFN-γ, IL-2, and IL-4. Further study is needed to evaluate the accuracy of our diagnostic algorithm in the LTBI population.

Impact of COVID-19 on Tuberculosis Case Detection and Treatment Outcomes in Sierra Leone

The COVID-19 pandemic has adversely affected tuberculosis (TB) care delivery in high burden countries. We therefore conducted a retrospective study to assess the impact of COVID-19 on TB case detection and treatment outcomes at the Chest Clinic at Connaught Hospital in Freetown, Sierra Leone. Overall, 2300 presumptive cases were tested during the first three quarters of 2020 (intra-COVID-19) versus 2636 in 2019 (baseline), representing a 12.7% decline. Testing declined by 25% in women, 20% in children and 81% in community-initiated referrals. Notwithstanding, laboratory-confirmed TB cases increased by 37.0% and treatment success rate was higher in 2020 (55.6% vs. 46.7%, p = 0.002). Multivariate logistic regression analysis found that age < 55 years (aOR 1.74, 95% CI (1.80, 2.56); p = 0.005), new diagnosis (aOR 1.69, 95% CI (1.16, 2.47); p = 0.007), pulmonary TB (aOR 3.17, 95% CI (1.67, 6.04); p < 0.001), HIV negative status (aOR 1.60, 95%CI (1.24, 2.06); p < 0.001) and self-administration of anti-TB drugs through monthly dispensing versus directly observed therapy (DOT) (aOR 1.56, 95% CI (1.21, 2.03); p = 0.001) independently predicted treatment success. These findings may have policy implications for DOTS in this setting and suggest that more resources are needed to reverse the negative impact of the COVID-19 pandemic on TB program activities in Sierra Leone.

The effect of empirical and laboratory-confirmed tuberculosis\xa0on treatment outcomes

The World Health Organization (WHO) criteria for diagnosing and treating Tuberculosis (TB) includes clinical signs, therefore not requiring bacteriological laboratory confirmation. In resource-limited settings, including Kenya, this empirical TB treatment is routine practice however limited data exist on patient clinical outcomes when comparing the method of diagnosis. We evaluated TB treatment outcomes comparing clinically diagnosed and bacteriologically confirmed TB, 6 months after starting treatment of TB in a rural county in Kenya. Our analysis compared patients with a clinical versus a bacteriologically confirmed TB diagnosis. In this retrospective analysis, we included all adults (≥ 18 years) starting treatment of TB and followed up for 6 months, within the County TB surveillance database from 2012 to 2018. Patients included from both public and private facilities. The TB treatment outcomes assessed included treatment success, treatment failure, death, defaulted and transferred out. We used survival regression models to assess effect of type of diagnosis on TB treatment outcome defining time at risk from date of starting treatment to experiencing one of the treatment outcomes or completing 6-months of treatment. A total of 12,856 patients; median age 37 [IQR 28 − 50] years were included. 7639 (59%) were male while 11,339 (88%) were pulmonary TB cases. Overall, 11,633 (90%) were given first-line TB treatment and 3791 (29%) were HIV infected. 6472 (50%) of the patients were clinically diagnosed of whom 4521/6472 (70%) had a negative sputum/GeneXpert test. During the study 5565 person-years (PYs) observed, treatment success was 82% and 83% amongst clinically and bacteriologically diagnosed patients (P = 0.05). There were no significant differences in defaulting (P = 0.70) or transfer out (P = 0.19) between clinically and bacteriologically diagnosed patients. Mortality was significantly higher among clinically diagnosed patients: 639 (9.9%) deaths compared to 285 (4.5%) amongst the bacteriologically diagnosed patients; aHR 5.16 (95%CI 2.17 − 12.3) P < 0.001. Our study suggests survival during empirical TB treatment is significantly lower compared to patients with laboratory evidence, irrespective of HIV status and age. To improve TB treatment outcomes amongst clinically diagnosed patients, we recommend systematic screening for comorbidities, prompt diagnosis and management of other infections.

Mycobacterium bovis in humans and M. tuberculosis in animals in Nigeria: an overview from 1975-2014.

Zoonotic transmission of mycobacteria between humans and other animal species is an important aspect of the epidemiology of tuberculosis (TB) in regions of the world where the burden of the disease in humans and other animals is high. This is particularly important in areas in which sociocultural factors increase the possibility for interspecies transmission of different mycobacteria. Carrying out a review of the published literature involving laboratory-confirmed TB cases (by culture) and/or biochemical and molecular identification, we described the presence of Mycobacterium bovis and M. tuberculosis infections in humans and animals from 1975 to 2014. Overall, 1693 isolates of M. tuberculosis complex and other mycobacteria were identified and reported, of which 1131 represented M. tuberculosis, 286 represented M. bovis, 71 represented M. africanum, and 205 represented other mycobacteria. Importantly, 1.3% (15/1131) of the M. tuberculosis isolates reported were identified in cattle, while 8.0% (23/286) of the M. bovis isolates reported were isolated from humans. We suggest that representative sampling of TB cases in both hosts, studied by molecular identification tools, will help significantly in deciphering ongoing transmission between animals and humans in both directions and will enhance TB control in Nigeria.

1882. Tuberculosis in the Department of Veterans Affairs: Missed Opportunities for Prevention

BackgroundUS and global elimination of tuberculosis (TB) is an important goal. Despite decreased incidence, CDC predicts elimination of TB in the US will not occur in the 21st century without improved detection and treatment of latent TB infection (LTBI). We describe the current burden of active TB infection and LTBI testing and treatment among patients within the Department of Veterans Affairs (VA).MethodsUsing the 2009 CDC case definition for laboratory-confirmed TB, we queried VA data sources from January 2010 to December 2018 for Mycobacterium tuberculosis detected via culture or nucleic acid amplification test (NAAT) from specimens from all body sites. For all TB patients, we extracted demographic, ICD-9 and ICD-10 risk factor, and LTBI testing and treatment data.ResultsBetween 2010 and 2018, the average annual incidence of TB was 1.7 cases per 100,000 unique users of VA care (ranging from a high of 2.8 in 2010 to low of 0.8 in 2018). For 899 identified cases, demographic factors associated with highest TB rates were age between 45 and 64, Asian race, and residence in District of Columbia (Table 1). The most frequently occurring risk factors were substance abuse, diabetes, and homelessness. Of 90 patients with susceptibility documentation, 14 (15%) had resistance to 1 or more anti-TB drug (1 with multi-drug-resistant TB). Fifteen patients (1.7%) died within 7 days of their TB diagnosis; in all but 2 cases, TB was the primary cause of death (Table 2). Figure 1 depicts screening and treatment for LTBI among patients with TB. Only 228/899 (25.4%) TB patients had LTBI screening ≥ 3 months prior to diagnosis. Of the 347 TB patients never screened for LTBI, 264 (76%) had ≥ 1 documented TB risk factor. Among 228 patients screened for LTBI >3 months prior to active disease, 69 (30%) screened positive; however, only 24 (35%) had LTBI treatment initiated.ConclusionAlthough rates of TB infection are decreasing, VHA providers would benefit from education on recognizing patients with risk factors which place them at high risk for TB who should be screened for LTBI. CDC recommends preventive treatment of patients who screen positive for LTBI, and provider collaboration with local public health departments to provide directly observed therapy in cases where adherence may be in question. Disclosures All Authors: No reported Disclosures.

Impact of ethnic disparities on the treatment outcomes of HIV-negative drug-resistant tuberculosis patients in Kuala Lumpur, Malaysia: A call for a culturally-sensitive community intervention approach.

Little is known about the treatment outcomes of HIV-negative drug-resistant tuberculosis (TB) patients in Malaysia. With respect to this issue, this study aimed to determine factors associated with unsuccessful treatment outcomes among drug-resistant TB patients at the Institute of Respiratory Medicine, Kuala Lumpur, Malaysia. This retrospective cohort study involved laboratory-confirmed drug-resistant TB patients from January 2009 to June 2013. Multiple logistic regression was used to model the outcome, which was subsequently defined according to the recent definition by the WHO. Data were analysed using IBM SPSS Statistics for Windows version 22.0. Among the 403 patients who were analysed, 66.7% of them were found to have achieved successful outcomes (cured or completed treatment) while the remaining 33.3% had unsuccessful treatment outcomes (defaulted, treatment failure or died). Multivariable analysis showed that the type of resistance [polyresistant (aOR = 3.00, 95% CI 1.14-7.91), multidrug resistant (MDR) (aOR = 5.37, 95% CI 2.65-10.88)], ethnicity [Malay (aOR = 2.86, 95% CI 1.44-5.71), Indian (aOR = 3.04, 95% CI 1.20-7.70)], and treatment non-compliance (aOR = 26.93, 95% CI 14.47-50.10) were the independent risk factors for unsuccessful treatment outcomes among this group of patients. Notably, the odds of unsuccessful treatment outcome was also amplified among Malay MDR-TB patients in this study (aOR = 13.44, 95% CI 1.99-90.58). In order to achieve better treatment outcomes for TB, effective behavioural intervention and thorough investigation on ethnic disparities in TB treatment are needed to promote good compliance.

Diagnostic value of the urine lipoarabinomannan assay in HIV-positive, ambulatory patients with CD4 below 200 cells/μl in 2 low-resource settings: A prospective observational study

BackgroundCurrent guidelines recommend the use of the lateral flow urine lipoarabinomannan assay (LAM) in HIV-positive, ambulatory patients with signs and symptoms of tuberculosis (TB) only if they are seriously ill or have CD4 count ≤ 100 cells/μl. We assessed the diagnostic yield of including LAM in TB diagnostic algorithms in HIV-positive, ambulatory patients with CD4 < 200 cells/μl, as well as the risk of mortality in LAM-positive patients who were not diagnosed using other diagnostic tools and not treated for TB.Methods and findingsWe conducted a prospective observational study including HIV-positive adult patients with signs and symptoms of TB and CD4 < 200 cells/μl attending 6 health facilities in Malawi and Mozambique. Patients were included consecutively from 18 September 2015 to 27 October 2016 in Malawi and from 3 December 2014 to 22 August 2016 in Mozambique. All patients had a clinical exam and LAM, chest X-ray, sputum microscopy, and Xpert MTB/RIF assay (Xpert) requested. Culture in sputum was done for a subset of patients. The diagnostic yield was defined as the proportion of patients with a positive assay result among those with laboratory-confirmed TB. For the 456 patients included in the study, the median age was 36 years (IQR 31–43) and the median CD4 count was 50 cells/μl (IQR 21–108). Forty-five percent (205/456) of the patients had laboratory-confirmed TB. The diagnostic yields of LAM, microscopy, and Xpert were 82.4% (169/205), 33.7% (69/205), and 40.0% (84/205), respectively. In total, 50.2% (103/205) of the patients with laboratory-confirmed TB were diagnosed only through LAM. Overall, the use of LAM in diagnostic algorithms increased the yield of algorithms with microscopy and with Xpert by 38.0% (78/205) and 34.6% (71/205), respectively, and, specifically among patients with CD4 100–199 cells/μl, by 27.5% (14/51) and 29.4% (15/51), respectively. LAM-positive patients not diagnosed through other tools and not treated for TB had a significantly higher risk of mortality than LAM-positive patients who received treatment (adjusted risk ratio 2.57, 95% CI 1.27–5.19, p = 0.009). Although the TB diagnostic conditions in the study sites were similar to those in other resource-limited settings, the added value of LAM may depend on the availability of microscopy or Xpert results.ConclusionsLAM has diagnostic value for identifying TB in HIV-positive patients with signs and symptoms of TB and advanced immunodeficiency, including those with a CD4 count of 100–199 cells/μl. In this study, the use of LAM enabled the diagnosis of TB in half of the patients with confirmed TB disease; without LAM, these patients would have been missed. The rapid identification and treatment of TB enabled by LAM may decrease overall mortality risk for these patients.

Initiation of anti-tuberculosis treatment in children following gastric aspirate testing, Botswana, 2008-2012.

Diagnosing pediatric tuberculosis (TB) is difficult; to improve diagnosis, gastric aspiration (GA) was performed in 121 Botswana health facilities. To describe treatment initiation and outcomes in children with a positive GA result and those treated empirically. Children with smear or culture-positive GA or those clinically diagnosed were referred for anti-tuberculosis treatment. Treatment initiation and outcomes were assessed from February 2008 to December 2012 using name-based matching algorithms of the GA database; treatment initiation was captured in the electronic TB registry. Analyses included descriptive statistics and regression models. GA was conducted in 1268 children. Among these, 121 (9.5%) were GA-positive; and treatment was initiated in 90 (74.3%). An additional 137 (11.9%) were treated empirically. More than a third (36.4%) had known human immunodeficiency virus status (positive or negative); this was significantly associated with TB treatment initiation (adjusted odds ratio [aOR] 1.8, 95%CI 1.3-2.5); P < 0.05). Among the 90 children with a positive GA result, nearly all either completed treatment (78.9%) or were on treatment (20.0%) at the time of data collection. We could not find documentation of treatment for more than a quarter of the children with laboratory-confirmed TB, an important gap that calls for further examination. The failure to initiate prompt treatment requires investigation and urgent action.

The Impact of Influenza and Tuberculosis Interaction on Mortality Among Individuals Aged ≥15 Years Hospitalized With Severe Respiratory Illness in South Africa, 2010-2016.

BackgroundData on the prevalence and impact of influenza–tuberculosis coinfection on clinical outcomes from high–HIV and –tuberculosis burden settings are limited. We explored the impact of influenza and tuberculosis coinfection on mortality among hospitalized adults with lower respiratory tract infection (LRTI).MethodsWe enrolled patients aged ≥15 years admitted with physician-diagnosed LRTI or suspected tuberculosis at 2 hospitals in South Africa from 2010 to 2016. Combined nasopharyngeal and oropharyngeal swabs were tested for influenza and 8 other respiratory viruses. Tuberculosis testing of sputum included smear microscopy, culture, and/or Xpert MTB/Rif.ResultsAmong 6228 enrolled individuals, 4253 (68%) were tested for both influenza and tuberculosis. Of these, the detection rate was 6% (239/4253) for influenza, 26% (1092/4253) for tuberculosis, and 77% (3113/4053) for HIV. One percent (42/4253) tested positive for both influenza and tuberculosis. On multivariable analysis, among tuberculosis-positive patients, factors independently associated with death were age group ≥65 years compared with 15–24 years (adjusted odds ratio [aOR], 3.6; 95% confidence interval [CI], 1.2–11.0) and influenza coinfection (aOR, 2.3; 95% CI, 1.02–5.2). Among influenza-positive patients, laboratory-confirmed tuberculosis was associated with an increased risk of death (aOR, 4.5; 95% CI, 1.5–13.3). Coinfection with other respiratory viruses was not associated with increased mortality in patients positive for tuberculosis (OR, 0.7; 95% CI, 0.4–1.1) or influenza (OR, 1.6; 95% CI, 0.4–5.6).ConclusionsTuberculosis coinfection is associated with increased mortality in individuals with influenza, and influenza coinfection is associated with increased mortality in individuals with tuberculosis. These data may inform prioritization of influenza vaccines or antivirals for tuberculosis patients and inform tuberculosis testing guidelines for patients with influenza.

Low expression Macrophage Migration Inhibitory Factor (MIF) alleles and tuberculosis in HIV infected South Africans

Host immunity is crucial for controlling M. tuberculosis infection. Functional polymorphisms in the cytokine macrophage migration inhibitory factor (MIF) show global population stratification, with the highest prevalence of low expression MIF alleles found in sub-Saharan Africans, which is a population with the greatest confluence of both TB and HIV infection and disease. We investigated the association between MIF alleles and tuberculosis (TB) and HIV in South Africa. We acquired clinical information and determined the frequency of two MIF promoter variants: a functional −794 CATT5-8 microsatellite and an associated −173 G/C SNP in two HIV-positive cohorts of patients with active laboratory-confirmed TB and in controls without active TB who were all HIV positive. We found a greater frequency of low expression MIF promoter variants (-794 CATT5,6) among TB disease cases compared to controls (OR = 2.03, p = 0.023), supporting a contribution of genetic low MIF expression to the high prevalence of TB in South Africa. Among those with HIV, circulating MIF levels also were associated with lower CD4 cell counts irrespective of TB status (p = 0.016), suggesting an influence of HIV immunosuppression on MIF expression.

Interferon-γ Release Assay Performance for Tuberculosis in Childhood.

Interferon-γ release assays (IGRAs) are important adjunctive tests for diagnosing tuberculosis (TB) disease in children. We analyzed California TB registry data for patients ≤18 years with laboratory-confirmed TB disease during 2010-2015 to identify case characteristics associated with test selection and performance and measure IGRA sensitivity. In total, 778 cases of TB were reported; 360 were laboratory confirmed. Indeterminate IGRAs were associated with being <1 year old (prevalence rate ratio 9.23; 95% confidence interval 2.87 to 29.8) and having central nervous system disease (prevalence rate ratio 2.69; 95% confidence interval 1.06 to 6.86) on multivariable analysis. Ninety-five children had both an IGRA and tuberculin skin test (TST) performed. Among those, the sensitivity of IGRA in 5- to 18-year-olds was 96% (66 out of 69) vs 83% (57 out of 69) for TST (P = .01); IGRA sensitivity compared with TST in children ages 2 to 4 was 91% (10 out of 11) vs 91% (10 out of 11) (P > .99), and the sensitivity compared with TST in children aged <2 years was 80% (12 out of 15) vs 87% (13 out of 15) (P > .99). This is the largest North American analysis of IGRA use and performance among children with TB disease. In children <5 years old, IGRA sensitivity is similar to TST, but sensitivity of both tests are reduced in children <2 years old. Indeterminate results are higher in children <1 year old and in central nervous system disease. In children ≥5 years old with laboratory-confirmed TB, IGRA has greater sensitivity than TST and should be considered the preferred immunodiagnostic test..

Functional Analysis of Phagocyte Activity in Whole Blood from HIV/Tuberculosis-Infected Individuals Using a Novel Flow Cytometry-Based Assay.

The accurate assessment of immune competence through ex vivo analysis is paramount to our understanding of those immune mechanisms that lead to protection or susceptibility against a broad range of human pathogens. We have developed a flow cytometry-based, whole blood phagocyte functional assay that utilizes the inflammatory inducer zymosan, coupled to OxyBURST-SE, a fluorescent reporter of phagosomal oxidase activity. The assay measures both phagocytic uptake and the superoxide burst in the phagocyte populations in whole blood. We utilized this assay to demonstrate impaired superoxide burst activity in the phagocytes of hospitalized HIV-positive patients with laboratory-confirmed tuberculosis. These data validate the use of the assay to assess the immune competence of patients in a clinical setting. The method is highly reproducible with minimal intraindividual variation and opens opportunities for the rapid assessment of cellular immune competence in peripheral blood in a disease setting.