Cost of Tuberculosis Therapy Directly Observed on Video for Health Departments and Patients in New York City; San Francisco, California; and Rhode Island (2017-2018).

Objectives. To assess costs of video and traditional in-person directly observed therapy (DOT) for tuberculosis (TB) treatment to health departments and patients in New York City, Rhode Island, and San Francisco, California.Methods. We collected health department costs for video DOT (VDOT; live and recorded), and in-person DOT (field- and clinic-based). Time-motion surveys estimated provider time and cost. A separate survey collected patient costs. We used a regression model to estimate cost by DOT type.Results. Between August 2017 and June 2018, 343 DOT sessions were captured from 225 patients; 87 completed a survey. Patient costs were lowest for VDOT live ($1.01) and highest for clinic DOT ($34.53). The societal (health department + patient) costs of VDOT live and recorded ($6.65 and $12.64, respectively) were less than field and clinic DOT ($21.40 and $46.11, respectively). VDOT recorded health department cost was not statistically different from field DOT cost in Rhode Island.Conclusions. Among the 4 different modalities, both types of VDOT were associated with lower societal costs when compared with traditional forms of DOT.Public Health Implications. VDOT was associated with lower costs from the societal perspective and may reduce public health costs when TB incidence is high.

Using Video Technology to Increase Treatment Completion for Patients With Latent Tuberculosis Infection on 3-Month Isoniazid and Rifapentine: An Implementation Study.

BACKGROUND: Since January 2013, the New York City (NYC) Health Department Tuberculosis (TB) Program has offered persons diagnosed with latent TB infection (LTBI) the 3-month, once-weekly isoniazid and rifapentine (3HP) treatment regimen. Patients on this treatment are monitored in-person under directly observed therapy (DOT). To address patient and provider barriers to in-person DOT, we piloted the use of a videoconferencing software app to remotely conduct synchronous DOT (video directly observed therapy; VDOT) for patients on 3HP. OBJECTIVE: The objective of our study was to evaluate the implementation of VDOT for patients on 3HP and to assess whether treatment completion for these patients increased when they were monitored using VDOT compared with that using the standard in-person DOT. METHODS: Between February and October 2015, patients diagnosed with LTBI at any of the four NYC Health Department TB clinics who met eligibility criteria for treatment with 3HP under VDOT (V3HP) were followed until 16 weeks after treatment initiation, with treatment completion defined as ingestion of 11 doses within 16 weeks. Treatment completion of patients on V3HP was compared with that of patients on 3HP under clinic-based, in-person DOT who were part of a prior study in 2013. Furthermore, outcomes of video sessions with V3HP patients were collected and analyzed. RESULTS: During the study period, 70% (50/71) of eligible patients were placed on V3HP. Treatment completion among V3HP patients was 88% (44/50) compared with 64.9% (196/302) among 3HP patients on clinic DOT (P<.001). A total of 360 video sessions were conducted for V3HP patients with a median of 8 (range: 1-11) sessions per patient and a median time of 4 (range: 1-59) minutes per session. Adherence issues (eg, >15 minutes late) during video sessions occurred 104 times. No major side effects were reported by V3HP patients. CONCLUSIONS: The NYC TB program observed higher treatment completion with VDOT than that previously seen with clinic DOT among patients on 3HP. Expanding the use of VDOT may improve treatment completion and corresponding outcomes for patients with LTBI.

Treatment for Tuberculosis Infection With 3 Months of Isoniazid and Rifapentine in New York City Health Department Clinics.

BACKGROUND: Completion of treatment for tuberculosis infection (TBI) with 9 months of self-administered daily isoniazid (9H) has historically been low (<50%) among New York City (NYC) Health Department tuberculosis clinic patients. Treatment of TBI with 3 months of once-weekly isoniazid and rifapentine (3HP) administered under directly observed therapy (DOT) might increase treatment acceptance and completion. METHODS: The study population included patients diagnosed with TBI at 2 NYC Health Department tuberculosis clinics from January 2013 through November 2013. Treatment acceptance and completion with 3HP were compared with historical estimates. Treatment outcomes, side effects, and reasons for refusing 3HP were described. RESULTS: Among 631 patients eligible for TBI treatment, 503 (80%) were offered 3HP; 302 (60%) accepted, 92 (18%) chose other treatment, and 109 (22%) refused treatment. The most common reason for refusing 3HP was the clinic-based DOT requirement. Forty (13%) patients treated with 3HP experienced side effects--9 were restarted on 3HP, 18 switched treatment regimens, and 13 discontinued. Although treatment acceptance did not differ from historical estimates (78% vs 79%, P = .75), treatment completion increased significantly (65% vs 34%, P < .01). CONCLUSIONS: Implementation of 3HP in 2 NYC Health Department tuberculosis clinics increased TBI treatment completion by 31 percentage points compared with historical estimates. More flexible DOT options may improve acceptance of 3HP. Wider use of 3HP may substantially improve TBI treatment completion in NYC and advance progress toward tuberculosis elimination.

Rifampin Mono-Resistant Tuberculosis in New York City, 2010-2021: A Retrospective Case Series.

Background: Although relatively rare, rifampin mono-resistant tuberculosis (RMR TB) poses important challenges to effective TB treatment and control. Information on the burden of RMR TB and treatment outcomes is needed to inform diagnosis and management. Methods: Standardized variables were collected from the New York City (NYC) tuberculosis surveillance system for patients treated for RMR TB in NYC during 2010-2021. Results: Of 7097 TB cases reported in 2010-2021, 31 (<1%) were treated clinically as RMR TB. Five (16%) of these patients had HIV. Seventeen patients (55%) had TB that was rifampin-resistant by both molecular and phenotypic drug susceptibility testing; 2 (6%) had rifampin resistance by phenotypic tests, and molecular tests were not done; and 12 (39%) were identified based only on molecular tests. Among these 12, 7 were rifampin-sensitive by phenotypic tests, and phenotypic testing could not be done for the other 5. Ten of the 31 (32%) were diagnosed in 2010-2015; the other 21 (including 10/12 diagnosed by molecular tests alone) were diagnosed in 2016-2021. Of the 31 patients, 21 (68%) completed treatment (median treatment duration of 18 months). Although the interval between tuberculosis treatment initiation and change to a non-rifamycin-containing regimen decreased significantly during the study period, the overall duration of treatment did not decrease significantly between 2010 and 2021. Conclusions: Molecular drug susceptibility tests identified cases of RMR TB that were not detected by phenotypic testing and helped enable timely adjustment of tuberculosis treatment regimens. Short-course regimens are needed to reduce duration of treatment for RMR TB.

Cohort study of the mortality among patients in New York City with tuberculosis and COVID-19, March 2020 to June 2022.

Both tuberculosis (TB) and COVID-19 can affect the respiratory system, and early findings suggest co-occurrence of these infectious diseases can result in elevated mortality. A retrospective cohort of patients who were diagnosed with TB and COVID-19 concurrently (within 120 days) between March 2020 and June 2022 in New York City (NYC) was identified. This cohort was compared with a cohort of patients diagnosed with TB-alone during the same period in terms of demographic information, clinical characteristics, and mortality. Cox proportional hazards regression was used to compare mortality between patient cohorts. One hundred and six patients with concurrent TB/COVID-19 were identified and compared with 902 patients with TB-alone. These two cohorts of patients were largely demographically and clinically similar. However, mortality was higher among patients with concurrent TB/COVID-19 in comparison to patients with TB-alone, even after controlling for age and sex (hazard ratio 2.62, 95% Confidence Interval 1.66-4.13). Nearly one in three (22/70, 31%) patients with concurrent TB/COVID-19 aged 45 and above died during the study period. These results suggest that TB patients with concurrent COVID-19 were at high risk for mortality. It is important that, as a high-risk group, patients with TB are prioritized for resources to quickly diagnose and treat COVID-19, and provided with tools and information to protect themselves from COVID-19.

In-Person vs Electronic Directly Observed Therapy for Tuberculosis Treatment Adherence: A Randomized Noninferiority Trial.

Importance: Electronic directly observed therapy (DOT) is used increasingly as an alternative to in-person DOT for monitoring tuberculosis treatment. Evidence supporting its efficacy is limited. Objective: To determine whether electronic DOT can attain a level of treatment observation as favorable as in-person DOT. Design, Setting, and Participants: This was a 2-period crossover, noninferiority trial with initial randomization to electronic or in-person DOT at the time outpatient tuberculosis treatment began. The trial enrolled 216 participants with physician-suspected or bacteriologically confirmed tuberculosis from July 2017 to October 2019 in 4 clinics operated by the New York City Health Department. Data analysis was conducted between March 2020 and April 2021. Interventions: Participants were asked to complete 20 medication doses using 1 DOT method, then switched methods for another 20 doses. With in-person therapy, participants chose clinic or community-based DOT; with electronic DOT, participants chose live video-conferencing or recorded videos. Main Outcomes and Measures: Difference between the percentage of medication doses participants were observed to completely ingest with in-person DOT and with electronic DOT. Noninferiority was demonstrated if the upper 95% confidence limit of the difference was 10% or less. We estimated the percentage of completed doses using a logistic mixed effects model, run in 4 modes: modified intention-to-treat, per-protocol, per-protocol with 85% or more of doses conforming to the randomization assignment, and empirical. Confidence intervals were estimated by bootstrapping (with 1000 replicates). Results: There were 173 participants in each crossover period (median age, 40 years [range, 16-86 years]; 140 [66%] men; 80 [37%] Asian and Pacific Islander, 43 [20%] Black, and 71 [33%] Hispanic individuals) evaluated with the model in the modified intention-to-treat analytic mode. The percentage of completed doses with in-person DOT was 87.2% (95% CI, 84.6%-89.9%) vs 89.8% (95% CI, 87.5%-92.1%) with electronic DOT. The percentage difference was -2.6% (95% CI, -4.8% to -0.3%), consistent with a conclusion of noninferiority. The 3 other analytic modes yielded equivalent conclusions, with percentage differences ranging from -4.9% to -1.9%. Conclusions and Relevance: In this trial, the percentage of completed doses under electronic DOT was noninferior to that under in-person DOT. This trial provides evidence supporting the efficacy of this digital adherence technology, and for the inclusion of electronic DOT in the standard of care. Trial Registration: ClinicalTrials.gov Identifier: NCT03266003.

Process monitoring of polysaccharide deketalization for vaccine bioconjugation development using in situ analytical methodology.

Pneumococcal conjugate vaccines (PCVs) are formed by bioconjugation of a carrier protein to the purified capsular polysaccharide (Ps) from multiple serological strains of Streptococcus pneumoniae. The associated bioconjugation chemistry relies on initial selective modifications to the Ps backbone structure. Among these modifications, removal of a ketal functional group, termed deketalization, is one that is important for pharmaceutical PCV production. Herein, we report a process monitoring investigation into the deketalization of a polysaccharide relevant to PCV process development. We have applied process analytical technology (PAT) for in situ process monitoring to study the deketalization reaction in real time. We find that in situ FTIR spectroscopy elucidates multiple classes of reaction kinetics, one of which correlates strongly with the deketalization reaction of interest. This PAT approach to real time reaction monitoring offers the possibility of improved process monitoring in the pharmaceutical production of PCVs. To our knowledge, this report represents the first PAT investigation into Ps deketalization. Our findings suggest that broader application of PAT to the chemical modifications associated with PCV bioconjugation, as well as other pharmaceutically relevant bioconjugation processes, carries the power to enhance process understanding, control, and efficiency through real time process monitoring.

Infectious Disease Hospitalizations, New York City, 2001-2014.

OBJECTIVE: Hospital discharge data are a means of monitoring infectious diseases in a population. We investigated rates of infectious disease hospitalizations in New York City. METHODS: We analyzed data for residents discharged from New York State hospitals with a principal diagnosis of an infectious disease during 2001-2014 by using the Statewide Planning and Research Cooperative System. We calculated annual age-adjusted hospitalization rates and the percentage of hospitalizations in which in-hospital death occurred. We examined diagnoses by site of infection or sepsis and by pathogen type. RESULTS: During 2001-2014, the mean annual age-adjusted rate of infectious disease hospitalizations in New York City was 1661.6 (95% CI, 1659.2-1663.9) per 100 000 population; the mean annual age-adjusted hospitalization rate decreased from 2001-2003 to 2012-2014 (rate ratio = 0.9; 95% CI, 0.9-0.9). The percentage of in-hospital death during 2001-2014 was 5.9%. The diagnoses with the highest mean annual age-adjusted hospitalization rates among all sites of infection and sepsis diagnoses were the lower respiratory tract, followed by sepsis. From 2001-2003 to 2012-2014, the mean annual age-adjusted hospitalization rate per 100 000 population for HIV decreased from 123.1 (95% CI, 121.7-124.5) to 40.0 (95% CI, 39.2-40.7) and for tuberculosis decreased from 10.2 (95% CI, 9.8-10.6) to 4.6 (95% CI, 4.4-4.9). CONCLUSIONS: Although hospital discharge data are subject to limitations, particularly for tracking sepsis, lower respiratory tract infections and sepsis are important causes of infectious disease hospitalizations in New York City. Hospitalizations for HIV infection and tuberculosis appear to be declining.

Quantifying lung ultrasound comets with a convolutional neural network: Initial clinical results.

Lung ultrasound comets are "comet-tail" artifacts appearing in lung ultrasound images. They are particularly useful in detecting several lung pathologies and may indicate the amount of extravascular lung water. However, the comets are not always well defined and large variations in the counting results exist between observers. This study uses a convolutional neural network to quantify these lung ultrasound comets on a 4864-image clinical lung ultrasound dataset labeled by the authors. The neural network counted the number of comets correctly on 43.4% of the images and has an intraclass correlation (ICC) of 0.791 with respect to human counting on the test set. The ICC level indicates a higher correlation level than previously reported ICC between human observers. The neural network was then deployed and applied to a clinical 6272-image dataset. The correlation between the automated comet counts and the clinical parameters was examined. The comet counts correlate positively with the diastolic blood pressure (p = 0.047, r = 0.448), negatively with ejection fraction (p = 0.061, r = -0.513), and negatively with BMI (p = 0.009, r = -0.566). The neural network can be alternatively formulated as a diagnostic test for comet-positive images with 80.8% accuracy. The results could potentially be improved with a larger dataset and a refined approach to the neural networks used.

Use of an interferon-gamma release assay to diagnose latent tuberculosis infection in foreign-born patients.

BACKGROUND: The tuberculin skin test (TST) has a low specificity in the setting of bacille Calmette-Guérin (BCG) vaccination. Interferon-gamma release assays (IGRAs) appear to be more specific but have not been validated in this population under routine clinical conditions. We sought to validate the routine clinical use of the T-SPOT.TB test (Oxford Immunotec; Oxford, UK), an IGRA, in a predominantly foreign-born population with a high rate of BCG vaccination. METHODS: We compared the TST and the T-SPOT.TB test in 96 subjects at a New York City Department of Health tuberculosis clinic. We aimed to determine which test better predicted being a close contact of a case of active tuberculosis, a surrogate for latent tuberculosis infection. RESULTS: A positive T-SPOT.TB test result was strongly associated with being a close contact of a case of active tuberculosis after adjustment for potential confounders (adjusted odds ratio, 2.9; 95% confidence interval, 1.1 to 7.3; p = 0.03). A positive TST result was associated with being a contact only in subjects without BCG vaccination (p = 0.02). The T-SPOT.TB test was more specific for being a close contact than the TST (p < 0.001). Specificity in BCG-vaccinated subjects was 3% for the TST compared with 70% for the T-SPOT.TB test (p < 0.001). CONCLUSIONS: The T-SPOT.TB test is superior in routine clinical use to the TST for identifying high-risk individuals among foreign-born populations with high rates of BCG vaccination.

Management of pediatric multidrug-resistant tuberculosis and latent tuberculosis infections in New York City from 1995 to 2003.

BACKGROUND: Few studies have assessed the management and outcomes of multidrug-resistant tuberculosis (MDR-TB) in the pediatric population. Treatment of children with second-line TB drugs is complicated by potential toxicities of these agents. METHODS: We performed a retrospective study of children <15 years of age treated for MDR-TB or MDR-latent TB infection (LTBI) from 1995 to 2003. We reviewed the New York City Department of Health and Mental Hygiene (DOHMH) computerized TB registry to characterize demographic characteristics, clinical presentations, treatment, and outcomes of the study subjects. RESULTS: Twenty subjects with MDR-TB (mean age 2.7 years) and 51 with MDR-LTBI (mean age 9.8 years) were studied. The most commonly used second-line TB drugs were cycloserine, quinolone agents, and ethionamide, which were used in 70%, 69%, and 54% of subjects, respectively. Sixteen (80%) of 20 MDR-TB and 38 (75%) of 51 MDR-LTBI cases completed treatment. A greater proportion of subjects receiving care at a DOH clinic completed treatment for LTBI (36/41, 88%), when compared with subjects treated at non-DOH sites [(2/9, 22%) P < 0.001]. Review of the TB registry indicated that no subjects had recurrent disease or progression of LTBI to active disease during the study period and for 2 years thereafter. CONCLUSIONS: Children with MDR-TB and LTBI were best cared for in public health settings. A multicenter registry for pediatric MDR-TB and MDR-LTBI would be desirable to obtain accurate rates of toxicity and cure.

The epidemiology of tuberculosis in the United States.

Effective control of tuberculosis (TB) requires an understanding of the changing epidemiology of the disease. An understanding of the epidemiology is needed for public health departments to respond with appropriate program-planning decisions. Following a marked decline in the incidence of tuberculosis in the United States over several decades, the incidence escalated dramatically and peaked in 1992. The resurgence of TB reflected several factors, including deteriorating social conditions, dismantling of the public health infrastructure, dwindling support for tuberculosis clinics and services, the new epidemic of HIV/AIDS with highly susceptible individuals at risk, and immigration of individuals from countries with high rates of TB. Since 1992, there has been a substantial decline in new cases. The success in reducing the tuberculosis burden reflects several factors, including improved public health efforts, physician and patient education, infection control measures, and the use of directly observed therapy (DOT). By 2006, cases of TB in the United States had reached historic lows. Currently, a majority of cases of TB occur in foreign-born individuals, reflecting immigration from countries with high endemic rates of TB. Future efforts to curtail the incidence of TB will require vigilant public health efforts, improving education of patients and health care personnel, identifying mechanisms and routes of transmission, and assuring adequate treatment and prophylactic regimens among infected individuals.

Changes in the transmission of tuberculosis in New York City from 1990 to 1999.

BACKGROUND: Over the past decade, there has been a reduction in the incidence of tuberculosis in New York City and in the United States. However, the reduction has been confined mainly to U.S.-born persons. Understanding the reasons for the lack of reduction among non-U.S.-born persons may lead to new strategies for tuberculosis control. METHODS: We performed DNA fingerprinting with the IS6110 insertion sequence of the organisms isolated from patients with culture-positive tuberculosis in northern Manhattan from 1990 to 1999. The goal was to identify the strains responsible for multiple infections, presumably through recent transmission (clusters of cases), as well as the strains found in only one patient, presumably representing reactivation of latent infection. RESULTS: Of 546 available isolates of Mycobacterium tuberculosis, 261 (48 percent) belonged to a cluster and 285 (52 percent) did not. In multivariate analysis, significant predictors of noncluster status included birth outside the United States (odds ratio for a strain causing a cluster among non-Hispanic foreign-born patients, 0.31; 95 percent confidence interval, 0.14 to 0.66; odds ratio among Hispanic foreign-born patients, 0.51; 95 percent confidence interval, 0.30 to 0.88), age greater than 60 years (odds ratio, 0.37), and diagnosis after 1993 (odds ratio, 0.50). All these characteristics appeared to be associated with reactivation disease rather than with tuberculosis due to recent transmission. Homelessness was associated with clustering (odds ratio, 1.78; 95 percent confidence interval, 0.99 to 3.20) and therefore with recent transmission. CONCLUSIONS: These findings from northern Manhattan suggest that among foreign-born persons, tuberculosis is largely caused by reactivation of latent infection, whereas among U.S.-born persons, many cases result from recent transmission. Strategies for the control and elimination of tuberculosis among foreign-born persons at high risk should be directed toward the treatment of latent tuberculosis infection.

Analytical and biological characterization of supercoiled plasmids purified by various chromatographic techniques.

Supercoiled plasmids are an important component of gene-based delivery vehicles. A number of production methods for clinical applications have been developed, each resulting in very high-quality product with low levels of residual contaminants. There is, however, no consensus on the optimal methods to characterize plasmid quality, and further, to determine if these methods are predictive of either product stability or biological activity. We have produced two plasmids using four production purification methodologies based on PolyFlo and hydrophobic interaction chromatography (HIC), either alone or in tandem processes. In each case, the product was analyzed using standard molecular biological methods. We also performed a number of biophysical analyses such as dynamic light scattering (DLS), circular dichroism (CD), Fourier transform infrared spectroscopy (FTIR), and differential scanning calorimetry (DSC). Minimal differences were detected among the preparations based on the more standard molecular biological methods. Some small differences were detected, however, using biophysical techniques, particularly FTIR and DSC, which may reflect small variations in plasmid tertiary structure and thermal stability. Stability after heat exposure at 60 degrees C, exposure to fetal bovine serum and long-term storage at 4 degrees C varied between plasmids. One plasmid showed no difference in stability depending on the production process, but the other showed significant differences. Evaluation in vivo in models for gene immunization and gene therapy showed significant differences in the response depending on the method of purification. Preparations using a tandem process of PolyFlo used in two separation modes provided higher biological activity compared to a tandem HIC/PolyFlo process or either resin used alone in a single column process. These data indicate that the process by which supercoiled plasmids are made can influence plasmid stability and biological activity and emphasize the need for more rigorous methods to evaluate supercoiled plasmids as gene-delivery vehicles.