Comparison of Tuberculin Skin Testing and Interferon-γ Release Assays in Predicting Tuberculosis Disease.

Importance: Elimination of tuberculosis (TB) disease in the US hinges on the ability of tests to detect individual risk of developing disease to inform prevention. The relative performance of 3 available TB tests-the tuberculin skin test (TST) and 2 interferon-γ release assays (IGRAs; QuantiFERON-TB Gold In-Tube [QFT-GIT] and SPOT.TB [TSPOT])-in predicting TB disease development in the US remains unknown. Objective: To compare the performance of the TST with the QFT-GIT and TSPOT IGRAs in predicting TB disease in high-risk populations. Design, Setting, and Participants: This prospective diagnostic study included participants at high risk of TB infection (TBI) or progression to TB disease at 10 US sites between 2012 and 2020. Participants of any age who had close contact with a case patient with infectious TB, were born in a country with medium or high TB incidence, had traveled recently to a high-incidence country, were living with HIV infection, or were from a population with a high local prevalence were enrolled from July 12, 2012, through May 5, 2017. Participants were assessed for 2 years after enrollment and through registry matches until the study end date (November 15, 2020). Data analysis was performed in June 2023. Exposures: At enrollment, participants were concurrently tested with 2 IGRAs (QFT-GIT from Qiagen and TSPOT from Oxford Immunotec) and the TST. Participants were classified as case patients with incident TB disease when diagnosed more than 30 days from enrollment. Main Outcomes and Measures: Estimated positive predictive value (PPV) ratios from generalized estimating equation models were used to compare test performance in predicting incident TB. Incremental changes in PPV were estimated to determine whether predictive performance significantly improved with the addition of a second test. Case patients with prevalent TB were examined in sensitivity analysis. Results: A total of 22 020 eligible participants were included in this study. Their median age was 32 (range, 0-102) years, more than half (51.2%) were male, and the median follow-up was 6.4 (range, 0.2-8.3) years. Most participants (82.0%) were born outside the US, and 9.6% were close contacts. Tuberculosis disease was identified in 129 case patients (0.6%): 42 (0.2%) had incident TB and 87 (0.4%) had prevalent TB. The TSPOT and QFT-GIT assays performed significantly better than the TST (PPV ratio, 1.65 [95% CI, 1.35-2.02] and 1.47 [95% CI, 1.22-1.77], respectively). The incremental gain in PPV, given a positive TST result, was statistically significant for positive QFT-GIT and TSPOT results (1.64 [95% CI, 1.40-1.93] and 1.94 [95% CI, 1.65-2.27], respectively). Conclusions and Relevance: In this diagnostic study assessing predictive value, IGRAs demonstrated superior performance for predicting incident TB compared with the TST. Interferon-γ release assays provided a statistically significant incremental improvement in PPV when a positive TST result was known. These findings suggest that IGRA performance may enhance decisions to treat TBI and prevent TB.

Examining Test Cutoffs to Optimize Diagnosis of Latent Tuberculosis Infection in People Born Outside the United States.

Rationale: Detection of latent tuberculosis infection (LTBI) in persons born in high tuberculosis (TB) incidence countries living in low TB incidence countries is key to TB elimination in low-incidence countries. Optimizing LTBI tests is critical to targeting treatment. Objectives: To compare the sensitivity and specificity of tuberculin skin test (TST) and two interferon-γ release assays at different cutoffs and of a single test versus dual testing. Methods: We examined a subset (N = 14,167) of a prospective cohort of people in the United States tested for LTBI. We included non-U.S.-born, human immunodeficiency virus-seronegative people ages 5 years and older with valid TST, QuantiFERON-TB Gold-in-Tube (QFT), and T-SPOT.TB (TSPOT) results. The sensitivity/specificity of different test cutoffs and test combinations, obtained from a Bayesian latent class model, were used to construct receiver operating characteristic (ROC) curves and assess the area under the curve (AUC) for each test. The sensitivity/specificity of dual testing was calculated. Results: The AUC of the TST ROC curve was 0.81 (95% credible interval (CrI), 0.78-0.86), with sensitivity/specificity at cutoffs of 5, 10, and 15 mm of 86.5%/61.6%, 81.7%/71.3%, and 55.6%/88.0%, respectively. The AUC of the QFT ROC curve was 0.89 (95% CrI, 0.86-0.93), with sensitivity/specificity at cutoffs of 0.35, 0.7, and 1.0 IU/mL of 77.7%/98.3%, 66.9%/99.1%, and 61.5%/99.4%. The AUC of the TSPOT ROC curve was 0.92 (95% CrI, 0.88-0.96) with sensitivity/specificity for five, six, seven, and eight spots of 79.2%/96.7%, 76.8%/97.7%, 74.0%/98.6%, and 71.8%/99.5%. Sensitivity/specificity of TST-QFT, TST-TSPOT, and QFT-TSPOT at standard cutoffs were 73.1%/99.4%, 64.8%/99.8%, and 65.3%/100%. Conclusion: Interferon-γ release assays have a better predictive ability than TST in people at high risk of LTBI.

Higher Completion Rates With Self-administered Once-weekly Isoniazid-rifapentine Versus Daily Rifampin in Adults With Latent Tuberculosis.

BACKGROUND: Treatment of latent tuberculosis (LTBI) is important for tuberculosis (TB) prevention, and short course rifamycin-based therapies are preferred. Once-weekly isoniazid-rifapentine by self-administered therapy (3HP-SAT) has never been compared with 4 months of daily rifampin (4R). METHODS: Retrospective cohort study of adults ≥18 years of age initiating LTBI treatment with either 3HP-SAT or 4R in a United States (US)-based TB clinic between 11 April 2016 and 31 December 2018. We evaluated treatment completion through pharmacy fills and reviewed charts for reasons of noncompletion, including adverse events (AEs). The χ 2 test and a log-binomial multivariable model were used to compare treatment completion and AEs. RESULTS: Five hundred sixty individuals (42%) initiated 3HP-SAT and 773 (58%) initiated 4R. Median age was 38, 55% were female, and 89% were born outside of the US. Among those aged 18-49 years, treatment completion with 3HP-SAT was 79% compared to 68% with 4R (adjusted risk ratio [aRR], 1.17 [95% CI, 1.17-1.27]; P < .0001). Among individuals aged ≥50 years, treatment completion with 3HP-SAT was 87% compared to 64% with 4R (aRR, 1.35 [95% CI, 1.19-1.52]; P < .0001). Compared to 4R, there was no difference in risk of AEs in the 18-49 age group (aRR, 0.93 [95% CI, .58-1.48]; P = .75). Reduced risk of AEs was noted among patients aged ≥50 years who received 3HP-SAT (aRR, 0.37 [95% CI, .16-.85]; P = .02). CONCLUSIONS: 3HP-SAT was associated with higher LTBI treatment completion and lower rates of AEs compared to 4R in individuals aged 50 and older. Expanding 3HP-SAT as an option for patients with LTBI may enhance TB prevention strategies in the US.

Optimizing the Design of Latent Tuberculosis Treatment Trials: Insights from Mathematical Modeling.

Rationale: Noninferiority trials of treatment for latent tuberculosis infection (LTBI) are challenging because of imperfect LTBI diagnostic tests.Objectives: To assess the effect on study outcomes of different enrollment strategies for a noninferiority trial of LTBI treatment.Methods: We mathematically simulated a two-arm randomized clinical trial of LTBI in which the experimental therapy was 50% efficacious and the control was 80% efficacious, with an absolute 0.75% noninferiority margin. Five enrollment strategies were assessed: 1) enroll based on no LTBI diagnostic test; 2) enroll based on a positive tuberculin skin test (TST); 3) enroll based on a positive IFN-γ release assay (IGRA); 4) enroll based on either a positive TST or IGRA; and 5) enroll regardless of test result, assuming 70% had negative TSTs, 20% positive TSTs, and 10% unknown results.Measurements and Main Results: Under most LTBI prevalence assumptions, enrolling based on a positive IGRA was least likely to result in falsely declaring noninferiority of the experimental regimen. Enrolling based on no test or regardless of test result led to falsely declaring noninferiority unless LTBI prevalence in the underlying population was higher than 45%. Enrolling based on a mix of TST and IGRA substantially reduced the likelihood of falsely declaring noninferiority over enrolling based on TST alone, even if as many as 70% of participants were enrolled based on positive TST.Conclusions: Noninferiority trials of LTBI should enroll based on the most specific diagnostic tests available (i.e., IGRAs) to avoid misclassifying inferior treatment regimens as noninferior.

Diagnostic Tests for Latent Tuberculosis Infection.

Diagnosing latent tuberculosis (TB) infection (LTBI) is important globally for TB prevention. LTBI diagnosis requires a positive test for infection and negative evaluation for active disease. Current tests measure an immunologic response and include the tuberculin skin test (TST) and interferon-gamma release assays (IGRAs), T-SPOT.TB and QuantiFERON. The IGRAs are preferred in bacille Calmette-Guérin-vaccinated populations. The TST is still used when cost or logistical advantages over the IGRAs exist. Both TST and IGRAs have low positive predictive values. Tests that differentiate the TB spectrum and better predict future TB risk are needed.

Comparing QuantiFERON-TB Gold Plus with Other Tests To Diagnose Mycobacterium tuberculosis Infection.

The fourth-generation QuantiFERON test for tuberculosis infection, QuantiFERON-TB Gold Plus (QFT-Plus) has replaced the earlier version, QuantiFERON-TB Gold In-Tube (QFT-GIT). A clinical need exists for information about agreement between QFT-Plus and other tests. We conducted this study to assess agreement of test results for QFT-Plus with those of QuantiFERON-TB Gold In-Tube (QFT-GIT), T-SPOT.TB (T-SPOT), and the tuberculin skin test (TST). Persons at high risk of latent tuberculosis infection (LTBI) and/or progression to tuberculosis (TB) disease were enrolled at the 10 sites of the Tuberculosis Epidemiologic Studies Consortium from October 2016 through May 2017; each participant received all four tests. Cohen's kappa (κ) and Wilcoxon signed-rank test compared qualitative and quantitative results of QFT-Plus with the other tests. Test results for 506 participants showed 94% agreement between QFT-Plus and QFT-GIT, with 19% positive and 75% negative results. When the tests disagreed, it was most often in the direction of QFT-GIT negative/QFT-Plus positive. QFT-Plus had similar concordance as QFT-GIT with TST (77% and 77%, respectively) and T-SPOT (92% and 91%, respectively). The study showed high agreement between QFT-GIT and QFT-Plus in a direct comparison. Both tests had similar agreement with TST and T-SPOT.

Current Medical Management of Pulmonary Tuberculosis.

Tuberculosis (TB) remains a common cause of infection and disease in much of the world. The majority of disease occurs from reactivation months or years after initial infection and most often involves the lungs. Sputum smears for acid-fast bacilli remain the initial diagnostic test but have limited sensitivity and specificity. Nucleic acid amplification tests are more sensitive and specific and can detect some mutations that cause drug resistance. Treatment of TB resistant to rifamycins alone or in combination with isoniazid and other drugs remains difficult and should be done in consultation with an expert in treating drug-resistant disease.

Updates in the Treatment of Active and Latent Tuberculosis.

First-line therapy for active tuberculosis (TB) has remained unchanged for nearly 40 years. Isoniazid, rifampin, pyrazinamide, and ethambutol for the initial two-month phase followed by isoniazid and rifampin for 4 to 7 months is standard treatment for people at low risk for drug-resistant disease. Directly-observed therapy (DOT) remains the standard of care for pulmonary TB. Virtual treatment monitoring using digital technologies is becoming more common as a way to provide a more patient-centered approach to care. Attempts to shorten treatment duration have been unsuccessful based on recent clinical trials evaluating the role of fluoroquinolones. Treatment-shortening trials using higher doses of rifamycins are currently underway. Recently approved medications for TB treatment are recommended only for drug-resistant disease, but novel agents in varying stages of development are being evaluated. Rifamycin-based regimens for latent TB infection (LTBI) have been successful in preventing progression to TB disease. Once-weekly isoniazid and rifapentine for 12 weeks by DOT was shown to be safe and effective compared with 9 months of isoniazid. The same regimen was shown to have acceptable treatment completion when given self-administered. Newer studies are investigating even shorter LTBI treatment with durations of less than 2 months. Treatment of LTBI in people likely infected with multidrug resistant TB is very limited, but one observational study found that fluoroquinolones appear to be effective. The first randomized trials for treating LTBI in contacts to MDR-TB are currently enrolling.

Tuberculosis Mortality in the United States: Epidemiology and Prevention Opportunities.

Rationale: More information on risk factors for death from tuberculosis in the United States could help reduce the tuberculosis mortality rate, which has remained steady for more than a decade.Objective: To identify risk factors for tuberculosis-related death in adults.Methods: We performed a retrospective study of 1,304 adults with tuberculosis who died before treatment completion and 1,039 frequency-matched control subjects who completed tuberculosis treatment in 2005 to 2006 in 13 states reporting 65% of U.S. tuberculosis cases. We used in-depth record abstractions and a standard algorithm to classify deaths in persons with tuberculosis as tuberculosis-related or not. We then compared these classifications to causes of death as coded in death certificates. We used multivariable logistic regression to calculate adjusted odds ratios for predictors of tuberculosis-related death among adults compared with those who completed tuberculosis treatment.Results: Of 1,304 adult deaths, 942 (72%) were tuberculosis related, 272 (21%) were not, and 90 (7%) could not be classified. Of 847 tuberculosis-related deaths with death certificates available, 378 (45%) did not list tuberculosis as a cause of death. Adjusting for known risks, we identified new risks for tuberculosis-related death during treatment: absence of pyrazinamide in the initial regimen (adjusted odds ratio, 3.4; 95% confidence interval, 1.9-6.0); immunosuppressive medications (adjusted odds ratio, 2.5; 95% confidence interval, 1.1-5.6); incomplete tuberculosis diagnostic evaluation (adjusted odds ratio, 2.2; 95% confidence interval, 1.5-3.3), and an alternative nontuberculosis diagnosis before tuberculosis diagnosis (adjusted odds ratio, 1.6; 95% confidence interval, 1.2-2.2).Conclusions: Most persons who died with tuberculosis had a tuberculosis-related death. Intensive record review revealed tuberculosis as a cause of death more often than did death certificate diagnoses. New tools, such as a tuberculosis mortality risk score based on our study findings, may identify patients with tuberculosis for in-hospital interventions to prevent death.

Exposure to Latent Tuberculosis Treatment during Pregnancy. The PREVENT TB and the iAdhere Trials.

RATIONALE: Data are limited regarding the safety of 12-dose once-weekly isoniazid (H, 900 mg) plus rifapentine (P, 900 mg) (3HP) for latent infection treatment during pregnancy. OBJECTIVES: To assess safety and pregnancy outcomes among pregnant women who were inadvertently exposed to study medications in two latent tuberculosis infection trials (PREVENT TB or iAdhere) evaluating 3HP and 9 months of daily isoniazid (H, 300 mg) (9H). METHODS: Data from reproductive-age (15-51 yr) women who received one or more study dose of 3HP or 9H in either trial were analyzed. Drug exposure during pregnancy occurred if the estimated date of conception was on or before the last dose date. RESULTS: Of 126 pregnancies (125 participants) that occurred during treatment or follow-up, 87 were exposed to study drugs. Among these, fetal loss was reported for 4/31 (13%) and 8/56 (14%), 3HP and 9H, respectively (difference, 13% - 14% = -1%; 95% confidence interval = -17% to +18%) and congenital anomalies in 0/20 and 2/41 (5%) live births, 3HP and 9H, respectively (difference, 0% - 5% = -5%; 95% confidence interval = -18% to +16%). All fetal losses occurred in pregnancies of less than 20 weeks. Of the total 126 pregnancies, fetal loss was reported in 8/54 (15%) and 9/72 (13%), 3HP and 9H, respectively; and congenital anomalies in 1/37 (3%) and 2/56 (4%) live births, 3HP and 9H, respectively. The overall proportion of fetal loss (17/126 [13%]) and anomalies (3/93 [3%]) were similar to those estimated for the United States, 17% and 3%, respectively. CONCLUSIONS: Among reported pregnancies in these two latent tuberculosis infection trials, there was no unexpected fetal loss or congenital anomalies. These data offer some preliminary reassurance to clinicians and patients in circumstances when these drugs and regimens are the best option in pregnancy or in women of child-bearing potential. This work used the identifying trial registration numbers NCT00023452 and NCT01582711, corresponding to the primary clinical trials PREVENT TB and iAdhere (Tuberculosis Trials Consortium Study 26 and 33).

High Rates of Tuberculosis and Opportunities for Prevention among International Students in the United States.

RATIONALE: Foreign-born persons traveling on a student visa are not currently screened for tuberculosis on entry into the United States, despite residing in the United States for up to several years. OBJECTIVES: To characterize the risk of tuberculosis in international students entering the United States and to identify strategies for early diagnosis and prevention in this population. METHODS: Data were collected in 18 tuberculosis control jurisdictions in the United States. A cohort of 1,268 foreign-born patients of known visa status, diagnosed with active tuberculosis between 2004 and 2007, was used for analysis. Incidence rates were estimated on the basis of immigration data from study jurisdictions. MEASUREMENTS AND MAIN RESULTS: Tuberculosis was diagnosed in 46 student residents, providing an annual estimate of 308 cases nationally. The estimated tuberculosis case rate in student residents was 48.1 cases per 100,000 person-years (95% confidence interval, 35.6-64.8), more than twice that of the general foreign-born population. Students identified by tuberculosis screening programs were more likely to be diagnosed within 6 months of U.S. arrival (75 vs. 6%; P < 0.001), and those with pulmonary disease were less likely to have a positive sputum smear for acid-fast bacilli compared with those not screened (18 vs. 63%; P = 0.05). In unscreened students, 71% were diagnosed more than 1 year after U.S. arrival and only 6% were previously treated for latent tuberculosis infection. CONCLUSIONS: The tuberculosis case rate in foreign-born students is significantly higher than in other foreign-born individuals. Screening this group after arrival to the United States is an effective strategy for earlier diagnosis of active tuberculosis.

Prophylactic antibiotics in open fractures: a pilot randomized clinical safety study.

OBJECTIVE: To develop preliminary data on Staphylococcus aureus colonization and surgical site infections (SSIs) in patients with open fractures who received standard antibiotic prophylaxis compared with a regimen including targeted methicillin-resistant Staphylococcus aureus (MRSA) coverage. DESIGN: Randomized prospective clinical trial. PATIENTS: Adult patients who presented to the emergency department with an open fracture between April 2009 and July 2011. INTERVENTIONS: One hundred thirty patients were randomized to receive prophylaxis with either cefazolin alone (control arm) or vancomycin and cefazolin (experimental arm) from presentation to the emergency department until 24 hours after the surgical intervention. Screening for S. aureus carriage was performed with nares swabs and predebridement and postdebridement open fracture wound swabs. Patients underwent prospective assessment for the development of SSI for no less than 30 days and up to 12 months. RESULTS: Nasal colonization of methicillin-sensitive S. aureus and MRSA among the sample was 20% and 3%, respectively. No significant difference in the rates of SSI was observed between the study arms (15% vs 19%, respectively, P = 0.62). Staphylococcus aureus caused 55% of the deep incisional/organ space SSI, with 18% attributed to MRSA. A significantly higher rate of MRSA SSIs was observed among MRSA carriers compared with noncarriers (33% vs 1%, respectively, P = 0.003). CONCLUSIONS: Staphylococcus aureus nasal colonization in trauma patients with open fractures is similar to that of the general community. In this pilot study, the addition of vancomycin to standard antibiotic prophylaxis was found safe, but its efficacy should be evaluated in a larger multiinstitutional trial.

Successful limb-sparing treatment strategy for diabetic foot osteomyelitis.

BACKGROUND: Diabetic foot osteomyelitis is common and causes substantial morbidity, including major amputations, yet the optimal treatment approach is unclear. We evaluated an approach to limb salvage that combines early surgical debridement or limited amputation with antimicrobial therapy. METHODS: We conducted a retrospective cohort study of patients treated between May 1, 2005, and May 31, 2007. The primary end point was cure, defined as not requiring further treatment for osteomyelitis of the affected limb. The secondary end point was limb salvage, defined as not requiring a below-the-knee amputation or a more proximal amputation. RESULTS: Fifty patients with diabetic foot osteomyelitis met the study criteria. Initial surgical management included local amputation in 43 patients (86%) and debridement without amputation in seven (14%). Most infections (n = 30; 60%) were polymicrobial, and Staphylococcus aureus was the most common pathogen (n = 23; 46%). Parenteral antibiotics were used in 45 patients (90%). Patients who had pathologic evidence of osteomyelitis at the surgical margin received therapy for a median of 43 days (interquartile range [IQR], 36-56 days), whereas those without evidence of residual osteomyelitis received therapy for a median of 19 days (IQR, 13-40 days). Overall, 32 patients (64%) were considered cured after a median follow-up of 26 months (IQR, 12-38 months). Fifteen of 18 patients (83%) who failed initial therapy were treated again with limb-sparing surgery. Limb salvage was achieved in 47 patients (94%), with only three patients (6%) requiring below-the-knee amputation. CONCLUSIONS: In patients with diabetic foot osteomyelitis, surgical debridement or limited amputation plus antimicrobial therapy is effective at achieving clinical cure and limb salvage.

The role of prophylactic antibiotics in open fractures in an era of community-acquired methicillin-resistant Staphylococcus aureus.

Infection is a feared complication and a common cause of loss of function following open fractures. Despite the evidence supporting the administration of prophylactic antibiotics after open fractures, data demonstrating the optimal regimen is lacking. We reviewed the data supporting the current prophylaxis recommendations and the changing epidemiology of Staphylococcus aureus, the most common cause of surgical site infection in patients with open fractures. Although widespread emergence of methicillin-resistant Staphylococcus aureus (MRSA) has been described in both hospital and community settings, to date, no studies have addressed the need for prophylaxis against MRSA in patients with open fractures. Until well-designed randomized trials are conducted, we recommend that providers consider selecting antibiotics active against MRSA for open fracture prophylaxis based on the local prevalence of MRSA carriage and individualized risk factors.

Eradication of multidrug-resistant Acinetobacter baumannii in a female patient with total hip arthroplasty, with debridement and retention: a case report.

INTRODUCTION: Multidrug-resistant Acinetobacter baumannii has become a significant cause of healthcare-associated infections, but few reports have addressed Acinetobacter baumannii infections associated with orthopedic devices. The current recommended treatment for complicated infections due to orthopedic devices, including resistant gram-negative rods, consists of antimicrobial therapy with debridement and removal of implants. CASE PRESENTATION: The patient, a 47-year-old woman, had previously had a prior total hip arthroplasty at 16 years of age for a complex femoral neck fracture, and multiple subsequent revisions. This time, she underwent a fifth revision secondary to pain. Surgery was complicated by hypotension resulting in transfer to the intensive care unit and prolonged respiratory failure. She received peri-operative cefazolin but postoperatively developed surgical wound drainage requiring debridement of a hematoma. Cultures of this grew ampicillin-sensitive Enterococcus and Acinetobacter baumannii (sensitive only to amikacin and imipenem). The patient was started on imipenem. Removal of the total hip arthroplasty was not recommended because of the recent surgical complications, and the patient was eventually discharged home. She was seen weekly for laboratory tests and examinations and, after 4 months of therapy, the imipenem was discontinued. She did well clinically for 7 months before recurrent pain led to removal of the total hip arthroplasty. Intra-operative cultures grew ampicillin-sensitive Enterococcus and coagulase-negative Staphylococcus but no multidrug-resistant Acinetobacter baumannii. The patient received ampicillin for 8 weeks and had not had recurrent infection at the time of writing, 37 months after discontinuing imipenem. CONCLUSION: We describe the successful treatment of an acute infection from multidrug-resistant Acinetobacter baumannii with debridement and retention of the total hip arthroplasty, using monotherapy with imipenem. This case challenges the general assumption that all orthopedic-device infections due to multidrug-resistant gram-negative organisms will require hardware removal. Further studies are needed to determine if organisms such as multidrug-resistant Acinetobacter baumannii are amenable to treatment with hardware retention.

Clostridium butyricum sepsis in an injection drug user with an indwelling central venous catheter.

Clostridium novyi has been associated with a large outbreak of severe infections in injection drug users. A case of bacteraemia with Clostridium butyricum in an injection drug user is reported. During treatment for Staphylococcus aureus osteomyelitis, the patient used an indwelling central venous catheter to inject cocaine. He was admitted with C. butyricum sepsis that responded to broad spectrum antibiotics, including vancomycin. Local investigation for other cases was unrevealing; however, growth of an unusual pathogen in clinical specimens should be investigated as it may represent a sentinel event with public health implications.