Background
Improved tests to diagnose latent TB infection (LTBI) are needed. We sought to evaluate the performance of two commercially available interferon-gamma release assays (IGRAs) compared to the tuberculin skin test (TST) for the diagnosis of LTBI and to identify risk factors for LTBI among HIV-infected individuals in Georgia, a country with high rates of TB.
Methods
HIV-patients were enrolled from the National AIDS Center in Tbilisi, Georgia. After providing informed consent, each participant completed a questionnaire, had blood drawn for QuantiFERON-TB Gold in-Tube (QFT-GIT) and T-SPOT.TB testing and had a TST placed. The TST was read at 48–72 hrs with ≥ 5 mm induration considered positive.
Results
Between 2009–2011, 240 HIV-infected persons (66% male) with a median age of 38 years and a median CD4 count of 255 cells/μl (IQR: 124–412) had diagnostic testing for LTBI performed. 94% had visible evidence of a BCG scar. The TST was positive in 41 (17%) patients; QFT-GIT in 70 (29%); and T-SPOT.TB in 56 (24%). At least one diagnostic test was positive in 109 (45%) patients and only among 13 (5%) patients were all three tests positive. Three (1%) QFT-GIT and 19 (8%) T-SPOT.TB test results were indeterminate. The agreement among all pairs of tests was poor: QFT-GIT vs. T-SPOT.TB (κ = 0.18, 95% CI .07-.30), QFT-GIT vs. TST (κ = 0.29, 95% CI .16-.42), and TST vs. T-SPOT.TB (κ = 0.22, 95% CI .07-.29). Risk factors for LTBI varied by diagnostic test and none showed associations between positive test results and well-known risk factors for TB, such as imprisonment, drug abuse and immunological status.
Conclusions
A high proportion of HIV patients had at least one positive diagnostic test for LTBI; however, there was very poor agreement among all tests. This lack of agreement makes it difficult to know which test is superior and most appropriate for LTBI testing among HIV-infected patients. While further follow-up studies will help determine the predictive ability of different LTBI tests, improved modalities are needed for accurate detection of LTBI and assessment of risk of developing active TB among HIV-infected patients.
Introduction
The Centers for Disease Control and Prevention has recommended using a nucleic acid amplification test (NAAT) for diagnosing pulmonary tuberculosis (TB) but there is a lack of data on NAAT cost-effectiveness.
Methods
We conducted a prospective cohort study that included all patients with an AFB smear-positive respiratory specimen at Grady Memorial Hospital in Atlanta, GA, USA between January 2002 and June 2008. We determined the sensitivity, specificity, and positive and negative predictive value of a commercially available and FDA-approved NAAT (amplified MTD, Gen-Probe) compared to the gold standard of culture. A cost analysis was performed and included costs related to laboratory tests, hospital charges, anti-TB medications, and contact investigations. Average cost per patient was calculated under two conditions: (1) using a NAAT on all AFB smear-postive respiratory specimens and (2) not using a NAAT. One-way sensitivity analyses were conducted to determine sensitivity of cost difference to reasonable ranges of model inputs.
Results
During a 6 1/2 year study period, there were 1,009 patients with an AFB smear-positive respiratory specimen at our public urban hospital. We found the NAAT to be highly sensitive (99.6%) and specific (99.1%) on AFB smear-positive specimens compared to culture. Overall, the positive predictive value (PPV) of an AFB smear-positive respiratory specimen for culture-confirmed TB was 27%. The PPV of an AFB smear-positive respiratory specimen for culture-confirmed TB was significantly higher for HIV-uninfected persons compared to those who were HIV-seropositive (152/271 [56%] vs. 85/445 [19%]; RR = 2.94, 95% CI 2.36–3.65, p<0.001). The cost savings of using the NAAT was $2,003 per AFB smear-positive case.
Conclusions
Routine use of the NAAT on AFB smear-positive respiratory specimens was highly cost-saving in our setting at a U.S. urban public hospital with a high prevalence of TB and HIV because of the low PPV of an AFB smear for culture-confirmed TB.
Objectives: To determine risk factors for poor outcomes among patients with pulmonary multidrug- or extensively drug-resistant (M/XDR) tuberculosis (TB) in Georgia. Methods: This was a prospective, population-based observational cohort study. Results: Among 380M/XDR-TB patients (mean age 38 years), 179 (47%) had a poor outcome: 59 (16%) died, 37 (10%) failed, and 83 (22%) defaulted. Newly diagnosed M/XDR-TB cases were significantly more likely to have a favorable outcome than retreatment cases (odds ratio (OR) 4.26, 95% confidence interval (CI) 1.99-9.10, p<0.001). In the multivariable analysis, independent risk factors for a poor treatment outcome included previous treatment history (OR 2.92, 95% CI 1.29-6.58), bilateral disease (OR 1.90, 95% CI 1.20-3.01), body mass index (BMI, kg/m2) ≤18.5 (OR 1.91, 95% CI 1.11-3.29), and XDR-TB (OR 2.28, 95% CI 1.11-4.71). Patients who underwent surgical resection (OR 0.27, 95% CI 0.11-0.64) and had sputum culture conversion by 4 months (OR 0.33, 95% CI 0.21-0.52) were significantly less likely to have poor treatment outcomes. Conclusions: Adjunctive surgery appeared to be beneficial in treating patients with M/XDR-TB. Retreatment cases, XDR-TB, bilateral disease, and low BMI were associated with a poor outcome. Additional studies are needed to further define the apparent beneficial role of surgery in the treatment of M/XDR-TB.
Background
The country of Georgia has a high prevalence of tuberculosis (TB) and hepatitis C virus (HCV) infection.
Purpose
To determine whether HCV co-infection increases the risk of incident drug-induced hepatitis among patients on first-line anti-TB drug therapy.
Methods
Prospective cohort study; HCV serology was obtained on all study subjects at the time of TB diagnosis; hepatic enzyme tests (serum alanine aminotransferase [ALT] activity) were obtained at baseline and monthly during treatment.
Results
Among 326 study patients with culture-confirmed TB, 68 (21%) were HCV co-infected, 14 (4.3%) had chronic hepatitis B virus (HBV) infection (hepatitis B virus surface antigen positive [HBsAg+]), and 6 (1.8%) were HIV co-infected. Overall, 19% of TB patients developed mild to moderate incident hepatotoxicity. In multi-variable analysis, HCV co-infection (adjusted Hazards Ratio [aHR]=3.2, 95% CI=1.6-6.5) was found to be an independent risk factor for incident anti-TB drug-induced hepatotoxicity. Survival analysis showed that HCV co-infected patients developed hepatitis more quickly compared to HCV seronegative patients with TB.
Conclusion
A high prevalence of HCV co-infection was found among patients with TB in Georgia. Drug-induced hepatotoxicity was significantly associated with HCV co-infection but severe drug-induced hepatotoxicity (WHO grade III or IV) was rare.
Background
Multidisciplinary antimicrobial utilization teams (AUT) have been proposed as a mechanism for improving antimicrobial use, but data on their efficacy remain limited.
Objective
To determine the impact of an AUT on antimicrobial use at a teaching hospital.
Design
Randomized controlled intervention trial.
Setting
A 953-bed public university-affiliated urban teaching hospital.
Patients
Patients who were prescribed selected antimicrobial agents (piperacillin-tazobactam, levofloxacin, or vancomycin) by internal medicine ward teams.
Intervention
Twelve internal medicine teams were randomized monthly: 6 teams to intervention group (academic detailing by the AUT), and 6 teams to a control group given indication-based guidelines for prescription of broad spectrum antimicrobials (standard of care) during a 10-month study period.
Measurements
Proportion of appropriate empiric, definitive (therapeutic), and end antimicrobial (overall) usage.
Results
A total of 784 new prescriptions of piperacillin-tazobactam, levofloxacin, and vancomycin were reviewed. The proportion of appropriate antimicrobial prescriptions written by the intervention teams was significantly higher than prescribed by the control teams: 82% vs. 73% for empiric (RR=1.14, 95% CI 1.04–1.24), 82% vs. 43% for definitive (RR=1.89, 95% CI 1.53–2.33), and 94% vs. 70% for end antimicrobial usage (RR=1.34, 95% CI 1.25–1.43). In a multivariate analysis, teams that received feedback from the AUT alone (aRR=1.37, 95% CI 1.27–1.48) or from both the AUT and the ID consult service (aRR=2.28, 95% CI 1.64–3.19) were significantly more likely to prescribe end antimicrobial usage appropriately compared to control teams.
Conclusions
A multidisciplinary AUT which provides feedback to prescribing physicians was an effective method in improving antimicrobial use.
Tuberculosis (TB) is a major global health problem. Patients with TB have a high rate of vitamin D deficiency, both at diagnosis and during the course of treatment with anti-tuberculosis drugs. Although data on the efficacy of vitamin D supplementation on Mycobacterium tuberculosis (Mtb) clearance are uncertain from randomized controlled trials (RCTs), vitamin D enhances the expression of the anti-microbial peptide human cathelicidin (hCAP18) in cultured macrophages in vitro. One possible explanation for the mixed (primarily negative) results of RCTs examining vitamin D treatment in TB infection is that anti-TB drugs given to enrolled subjects may impact actions of vitamin D to enhance cathelicidin in macrophages. To address this hypothesis, human macrophage-like monocytic (THP-1) cells were treated with varying doses of first-line anti-tuberculosis drugs in the presence of the active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). The expression of hCAP18 was determined by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). 1,25(OH)2D3 strongly induced expression of hCAP18 mRNA in THP-1 cells (fold-change from control). The combination of the standard 4-drug TB therapy (isoniazid, rifampicin, pyrazinamide and ethambutol) in the cultured THP-1 cells demonstrated a significant decrease in hCAP18 mRNA at the dosage of 10 µg/mL. In 31 subjects with newly diagnosed drug-sensitive TB randomized to either high-dose vitamin D3 (1.2 million IU over 8 weeks, n = 13) versus placebo (n = 18), there was no change from baseline to week 8 in hCAP18 mRNA levels in peripheral blood mononuclear cells or in plasma concentrations of LL-37, the protein product of hCAP18. These data suggest that first-line anti-TB drugs may alter the vitamin D-dependent increase in hCAP18 and LL-37 human macrophages.
Background: The WHO has recommended the implementation of rapid diagnostic tests to detect and help combat M/XDR tuberculosis (TB). There are limited data on the performance and impact of these tests in field settings. Methods: The performance of the commercially available Genotype MTBDRplus molecular assay was compared to conventional methods including AFB smear, culture and drug susceptibility testing (DST) using both an absolute concentration method on Löwenstein-Jensen media and broth-based method using the MGIT 960 system. Sputum specimens were obtained from TB suspects in the country of Georgia who received care through the National TB Program. Results: Among 500 AFB smear-positive sputum specimens, 458 (91.6%) had both a positive sputum culture for Mycobacterium tuberculosis and a valid MTBDRplus assay result. The MTBDRplus assay detected isoniazid (INH) resistance directly from the sputum specimen in 159 (89.8%) of 177 specimens and MDR-TB in 109 (95.6%) of 114 specimens compared to conventional methods. There was high agreement between the MTBDRplus assay and conventional DST results in detecting MDR-TB (kappa = 0.95, p < 0.01). The most prevalent INH resistance mutation was S315T (78%) in the katG codon and the most common rifampicin resistance mutation was S531L (68%) in the rpoB codon. Among 13 specimens from TB suspects with negative sputum cultures, 7 had a positive MTBDRplus assay (3 with MDR-TB). The time to detection of MDR-TB was significantly less using the MTBDRplus assay (4.2 days) compared to the use of standard phenotypic tests (67.3 days with solid media and 21.6 days with broth-based media). Conclusions: Compared to conventional methods, the MTBDRplus assay had high accuracy and significantly reduced time to detection of MDR-TB in an area with high MDR-TB prevalence. The use of rapid molecular diagnostic tests for TB and drug resistance should increase the proportion of patients promptly placed on appropriate therapy.
Background
Limited data are available on the incidence and risk factors for infection among patients requiring home parenteral nutrition (HPN).
Methods
Retrospective study of 101 consecutive adults (63 female, 38 male) discharged on HPN from Emory University Hospital, Atlanta, GA. New bloodstream infections (BSI) requiring re-hospitalization and other infections were evaluated.
Results
Most infections (75%) developed during the initial 6 months after hospital discharge; rates of BSI were particularly high during the first four months. A total of 56 patients (55.4%) developed a total of 102 BSIs (11.5 BSI/1000 catheter-days). Most BSIs were attributed to Gram positive organisms (46%) including coagulase-negative staphylococcus, staphylococcus aureus, enterococcus species, and others, followed by Candida species (20%) and Gram negative organisms (13%). Twenty-one percent of BSIs were polymicrobial. The BSI incidence rate ratio (IRR) was significantly increased for patients with mean pre-hospital discharge blood glucose (BG) concentrations in the highest quartile versus the lowest quartile; IRR 2.4; P = 0.017). Patients with a peripherally inserted central catheter (PICC) versus non-PICC central venous catheters had significantly higher rates of BSI (p = 0.018). Thirty-nine (38.6%) patients developed 81 non-BSI infections, including pneumonia, urinary tract infections, and surgical site infections. Post-discharge PN dextrose, lipid, and total calorie doses were unrelated to BSI but variably related to the rate of non-BSI.
Conclusions
Adult HPN patients exhibit a very high incidence of post-hospital infections. Higher mean BG levels during pre-discharge hospitalization and use of PICCs at discharge are associated with an increased risk of BSI in the post-discharge home setting.
Background
A new generation of diagnostic tests, the interferon-γ release assays (IGRAs), have been developed for the detection of latent tuberculosis infection (LTBI). Limited data are available on their use in HIV-infected persons.
Methods
A cross-sectional study was carried out at 2 HIV clinics in Atlanta to assess the utility of two IGRA tests (T-SPOT.TB [TSPOT] and QuantiFERON-TB Gold in Tube [QFT-3G]) compared to the tuberculin skin test (TST).
Results
336 HIV-infected persons were enrolled. Median CD4 count was 335 cells/μl and median HIV viral load was 400 copies/ml. Overall, 27 patients (8.0%) had at least 1 positive diagnostic test for LTBI: 7 (2.1%) had a positive TST; 9 (2.7%) a positive QFT-3G; and 14 (4.2%) a positive TSPOT. Agreement between the 3 diagnostic tests was poor: TST and TSPOT, [κ = 0.16, 95% CI (-0.06, 0.39)], TST and QFT-3G [κ = 0.23, 95% CI (-0.05, 0.51)], QFT-3G and TSPOT [κ = 0.06, 95% CI (-0.1, 0.2)]. An indeterminate test result occurred among 6 (1.8%) of QFT-3G and 47 (14%) of TSPOT tests. In multivariate analysis, patients with a CD4 ≤ 200 cells/μl were significantly more likely to have an indeterminate result [OR = 3.6, 95% CI (1.9, 6.8)].
Conclusion
We found a low prevalence of LTBI and poor concordance between all 3 diagnostic tests. Indeterminate test results were more likely at CD4 counts ≤ 200 cells/μl. Additional studies among HIV-infected populations with a high prevalence of TB are needed to further assess the utility of IGRAs in this patient population.