Can Primary Care Drive Tuberculosis Elimination? Increasing Latent Tuberculosis Infection Testing and Treatment Initiation at a Community Health Center with a Large Non-U.S.-born Population.

Community health centers (CHC) play a key role in latent tuberculosis infection (LTBI) testing and treatment. We performed a retrospective analysis of LTBI testing and treatment among pediatric and adult patients at a CHC with a large non-U.S.-born (USB) population during a series of quality improvement (QI) interventions from 2010 to 2019. Among 124,695 patients with primary care visits, 40% of patients were tested for tuberculosis (TB) infection and among those tested, 20% tested positive, including 39% of adults aged 50-79 years. Compared to adults aged 18-49 years, children aged 6-17 had increased odds of LTBI testing and treatment initiation [odds ratio and 95% confidence interval 3.23 (3.10, 3.36) and 1.41 (1.12, 1.79), respectively], while age ≥ 65 was associated with lower odds of both testing and treatment initiation. Over the analysis period, coinciding with unfunded QI interventions intended to reduce barriers to LTBI care, there was a significant increase in the proportion of patients receiving LTBI testing for both adults (6% to 47%, p < 0.001) and children (23% to 80%, p < 0.001). During the analysis period, there was also a significant increase in the proportion of patients receiving prescriptions for LTBI treatment, as well as provider use of evidence-based strategies including rifamycin-based treatment. Our study suggests that primary care interventions can reduce barriers to LTBI treatment and drive TB elimination.

Solid organ transplant recipients with tuberculosis disease in California, 2010 to 2020.

Using California Tuberculosis (TB) Registry data from 2010-2020, we compared the presentation and outcomes of patients with TB aged >15 years with and without solid organ transplantation (SOT). We matched to the United Network for Organ Sharing registry for 1987-2020 and the estimated time from transplantation to the diagnosis of TB, the incidence of posttransplant TB, and the probability of death and graft failure in SOT recipients with TB, compared to those without TB. From 2010-2020, there were 148 posttransplant TB cases. Patients with posttransplant TB were more likely to have extrapulmonary disease and more than twice as likely to die as TB patients without SOT (relative risk [RR], 2.2; 95% confidence interval [CI], 1.6-2.9). The median time from transplantation to TB diagnosis was 1.2 years, with the shortest time among lung transplant recipients. The incidence of TB disease among Californians with SOT was 56.0 per 100 000 person-years. The risk of death was higher among SOT recipients with posttransplant TB than those without (adjusted hazard ratio, 2.8; 95% CI, 2.0-4.1); the risk of graft failure was higher among kidney transplant recipients with posttransplant TB than those without (adjusted hazard ratio, 3.4; 95% CI, 1.7-6.9). An increased risk of death and graft failure in SOT recipients with posttransplant TB highlights the need for enhanced pretransplant TB prevention.

Association of Tumor Necrosis Factor α Inhibitor Use with Diagnostic Features and Mortality of Tuberculosis in the United States, 2010-2017.

BACKGROUND: An elevated risk of tuberculosis (TB) disease in persons who have received tumor necrosis factor alpha inhibitor medications (TNF-α inhibitors) has been reported for nearly two decades, but clinical diagnostic features and outcomes of TB in this population remain poorly described. METHODS: We analyzed national surveillance data for TB cases among persons aged 15 years and older reported in the United States during 2010-2017 and associated mortality data reported through 2019 to describe the clinical characteristics of those receiving TNF-α inhibitors. RESULTS: Of 70 129 TB cases analyzed, 504 (0.7%) of the patients had TNF-α inhibitor use reported at TB diagnosis. Patients with TNF-α inhibitor use at TB diagnosis were more likely than TB patients not receiving TNF-α inhibitors to have TB diagnosed in extrapulmonary sites in conjunction with pulmonary sites (28.8% vs 10.0%, P < .001). Patients receiving TNF-α inhibitors were less likely to have acid-fast bacilli noted on sputum smear microscopy (25.6% vs 39.1%, P = .04), and more likely to have drug-resistant disease (13.5% vs 10.0%, P < .001). TB-attributed deaths did not significantly differ between patients receiving and not receiving TNF-α inhibitors (adjusted odds ratio, 1.46 [95% confidence interval, .95-2.26]). CONCLUSIONS: Clinicians evaluating TNF-α inhibitor-treated patients should have a high index of suspicion for TB and be aware that extrapulmonary or sputum smear-negative TB disease is more common in these patients. No significantly diminished survival of TB patients treated with TNF-α inhibitor therapy before TB diagnosis was noted.

Latent Tuberculosis Infection Testing and Treatment at a Federally Qualified Health Center in Southern California: A Quality Improvement Project.

BACKGROUND: A key strategy to eliminate tuberculosis (TB) in the United States is to increase latent tuberculosis infection (LTBI) screening, testing, and treatment among non-US-born Asian populations. PURPOSE: The purpose was to increase LTBI screening, testing, and treatment at a community clinic. METHODS: Retrospective baseline LTBI data were retrieved through electronic medical record review. Interventions included adoption of standardized TB risk assessment, training providers to use shorter LTBI treatment regimens, and use of a care coordinator. Chart abstraction to examine outcomes was conducted postintervention at 4 months. RESULTS: In 2017, only 3 patients (7%) with LTBI were started on treatment. At 4 months postintervention, 28 (72%) patients with LTBI were started on treatment, of which 27 (96%) were placed on 3- to 4-month regimens. CONCLUSIONS: Training for providers and changes to clinic workflow, including use of a care coordinator, can help increase LTBI screening, testing, and treatment in community clinics.

Bedaquiline for multidrug-resistant tuberculosis and QTc prolongation in California.

BACKGROUND: Bedaquiline (BDQ) is recommended for the treatment of multidrug-resistant tuberculosis (MDR TB), however, it has the potential to prolong QTc interval. We assessed the frequency and severity of QTc prolongation in patients receiving BDQ in California. METHODS: Based on chart review for patients receiving BDQ as part of MDR TB therapy from January 2013-May 2019, we analyzed QTc values at six pre-specified time points during BDQ therapy (baseline, 2, 4, 8, 12, and 24 weeks), as well as peak QTc, time to peak QTc, and the clinical characteristics of patients who had QTc elevation >500 milliseconds (ms) during therapy. RESULTS: A total of 37 patients were treated with BDQ during the analysis period, with a total of 449 QTc measurements available for analysis. Most patients (89%) received at least one QTc-prolonging drug in addition to BDQ. Median QTc values at all pre-specified time points were <450 ms. Median peak QTc was 455 ms (interquartile range [IQR]: 437-486) and median time to peak was 57 days (IQR: 19-156). Four patients (11%) had a non-transient elevation in QTc to >500 ms, including one patient with profound hypokalemia and one receiving concurrent chemotherapy, but none had cardiac arrhythmia. Less than 10% of patient in our cohort had ECGs performed at all six pre-specified time points. DISCUSSION: BDQ was generally well-tolerated in a cohort of patients treated for MDR TB in California, with 11% of patients experiencing a non-transient QTc elevation >500 ms, and no episodes of arrhythmia. Frequent ECG monitoring during BDQ therapy presents a challenge for TB clinicians, even in well-resourced countries.

Persistent Parasitemia Despite Dramatic Reduction in Malaria Incidence After 3 Rounds of Indoor Residual Spraying in Tororo, Uganda.

BACKGROUND: Indoor residual spraying of insecticide (IRS) has been associated with reductions in the incidence of malaria, but its impact on malaria parasitemia is unclear. METHODS: We followed 469 participants from August 2011 to May 2016 in Tororo, Uganda, a historically high malaria transmission setting. Three rounds of IRS with bendiocarb were implemented from December 2014 to December 2015. Symptomatic malaria episodes were identified by passive surveillance. Parasitemia was identified by active surveillance every 1-3 months using microscopy and Plasmodium falciparum-specific loop-mediated isothermal amplification. RESULTS: IRS was associated with a significant decline in the incidence of symptomatic malaria irrespective of age (episodes per person per year declined from 3.98 to 0.13 in children aged <5 years, 2.30 to 0.15 in children aged 5-10 years, and 0.41 to 0 in adults; P < .001 for all). IRS significantly reduced the prevalence of parasitemia, but the prevalence remained high (pre-IRS to post-third round: 58.5% to 11.3% in children aged <5 years, 73.3% to 23.7% in children aged 5-10 years, and 52.2% to 15.4% in adults; P < .001 for all). CONCLUSIONS: Although IRS was associated with significant reductions in the incidence of malaria and prevalence of parasitemia, a proportion of the population remained parasitemic, providing a potential reservoir for malaria transmission.

Latent Tuberculosis and Current Health Disparities in California: Making the Invisible Visible.

Tuberculosis (TB) continues to have devastating consequences for patients both globally and locally, with disease risk concentrated in specific subgroups defined by race, ethnicity, and nativity. We highlight TB disparities in California in 2016, and describe opportunities to reduce disparities by scaling up screening and treatment of latent TB infection (LTBI) in primary care settings. Primary impediments to mainstreaming LTBI screening and treatment and reducing TB disparities include poor understanding of patient-level barriers, knowledge gaps on the part of health care providers, and insufficient promotion of effective testing and treatment strategies. To overcome these barriers, efforts should focus on finding and engaging high-risk patients and the providers who serve them, as well as enabling health care systems to adopt recommended strategies for testing and treatment through improved dissemination of policy, tracking and measuring LTBI outcomes, and reducing financial barriers to LTBI treatment.

Clinical consequences of submicroscopic malaria parasitaemia in Uganda.

BACKGROUND: Submicroscopic malaria parasitaemia is common in both high- and low-endemicity settings, but its clinical consequences are unclear. METHODS: A cohort of 364 children (0.5-10 years of age) and 106 adults was followed from 2011 to 2016 in Tororo District, Uganda using passive surveillance for malaria episodes and active surveillance for parasitaemia. Participants presented every 90 days for routine visits (n = 9075); a subset was followed every 30 days. Participants who presented with fever and a positive blood smear were treated for malaria. At all routine visits microscopy was performed and samples from subjects with a negative blood smear underwent loop-mediated isothermal amplification for detection of plasmodial DNA. RESULTS: Submicroscopic parasitaemia was common; the proportion of visits with submicroscopic parasitemia was 25.8% in children and 39.2% in adults. For children 0.5-10 years of age, but not adults, having microscopic and submicroscopic parasitaemia at routine visits was significantly associated with both fever (adjusted risk ratios [95% CI], 2.64 [2.16-3.22], 1.67 [1.37-2.03]) and non-febrile illness (aRR [CI], 1.52 [1.30-1.78], 1.26 [1.09-1.47]), compared to not having parasitaemia. After stratifying by age, significant associations were seen between submicroscopic parasitaemia and fever in children aged 2-< 5 and 5-10 years (aRR [CI], 1.42 [1.03-1.98], 2.01 [1.49-2.71]), and submicroscopic parasitaemia and non-febrile illness in children aged 5-10 years (aRR [CI], 1.44 [1.17-1.78]). These associations were maintained after excluding individuals with a malaria episode within the preceding 14 or following 7 days, and after adjusting for household wealth. CONCLUSIONS: Submicroscopic malaria infections were associated with fever and non-febrile illness in Ugandan children. These findings support malaria control strategies that target low-density infections.

Performance of Loop-Mediated Isothermal Amplification for the Identification of Submicroscopic Plasmodium falciparum Infection in Uganda.

Accurately identifying and targeting the human reservoir of malaria parasitemia is critical for malaria control, and requires a reliable and sensitive diagnostic method. Loop-mediated isothermal amplification (LAMP) is increasingly used to diagnose submicroscopic parasitemia. Although most published studies report the sensitivity of LAMP compared with nested polymerase chain reaction (PCR) as ≥ 80%, they have failed to use a consistent, sensitive diagnostic as a comparator. We used cross-sectional samples from children and adults in Tororo, Uganda, a region with high but declining transmission due to indoor residual spraying, to characterize the sensitivity and specificity of pan-Plasmodium LAMP for detecting submicroscopic infections. We compared LAMP results targeting a mitochondrial DNA sequence conserved in all Plasmodium species, performed on DNA extracted from dried blood spots, to those of a gold standard quantitative PCR assay targeting the var gene acidic terminal sequence of Plasmodium falciparum (varATS qPCR), performed on DNA extracted from 200 µL of whole blood. Using LAMP and varATS qPCR increased the detection of parasitemia 2- to 5-fold, compared with microscopy. Among microscopy-negative samples, the sensitivity of LAMP was 81.5% for detecting infection ≥ 1 parasites/µL. However, low density infections were common, and LAMP failed to identify more than half of all infections diagnosed by varATS qPCR, performing with an overall sensitivity of 44.7% for detecting submicroscopic infections ≥ 0.01 parasites/µL. Thus, although the LAMP assay is more sensitive than microscopy, it missed a significant portion of the submicroscopic reservoir. These findings have important implications for malaria control, particularly in settings where low-density infections predominate.

Patterns of Healthcare Utilization Among Veterans Infected With Hepatitis C Virus (HCV) and Human Immunodeficiency Virus (HIV) and Coinfected With HIV/HCV: Unique Burdens of Disease.

Background. Hepatitis C virus (HCV) infection is a leading cause of cirrhosis and the primary cause of liver transplantation in the United States, and coinfection with human immunodeficiency virus (HIV) increases the risk of comorbidities. However, healthcare utilization (HCU) patterns among HIV/HCV-coinfected patients are poorly understood. This study compared the rates of HCU and reasons for hospital admission among HCV-infected, HIV-infected, and HIV/HCV-coinfected veterans. Methods. Hepatitis C virus- and HIV-infected and HIV/HCV-coinfected veterans in care with the Department of Veterans Affairs (VA) from 1998 to 2009 (n = 335 371, n = 28 179, n = 13 471, respectively) were identified by HIV- and HCV-associated International Classification of Diseases, Ninth Revision codes from the clinical case registry. We assessed rates of HCU using emergency department (ED) visits, outpatient visits, and hospitalization and primary diagnoses associated with hospitalization. Independent risk factors associated with hospitalization were also examined. Results. Rates of outpatient and ED visits increased over the 11-year study period for all groups, with inpatient admission rates remaining stable. The HCU rates were consistently higher for the coinfected than other cohorts. The primary reason for hospital admission for all groups was psychiatric disease/substance use, accounting for 44% of all admissions. Nadir CD4 <350 cells/mm3 was associated with higher rates of hospitalization versus nadir CD4 >500 cells/mm3. Conclusions. As the current population of HCV-infected, HIV-infected, and HIV/HCV-coinfected veterans age, they will continue to place a substantial and increasing demand on the US healthcare system, particularly in their utilization of ED and outpatient services. These data suggest the need for an ongoing investment in mental health and primary care within the VA healthcare system.

Characterizing microscopic and submicroscopic malaria parasitaemia at three sites with varied transmission intensity in Uganda.

BACKGROUND: Parasite prevalence is a key metric used to quantify the burden of malaria and assess the impact of control strategies. Most published estimates of parasite prevalence are based on microscopy and likely underestimate true prevalence. METHODS: Thick smear microscopy was performed in cohorts of children (aged 6 month to 10 years) and adults every 90 days over 2 years, at three sites of varying transmission intensity in Uganda. Microscopy-negative samples were tested for sub-microscopic parasitaemia using loop-mediated isothermal amplification (LAMP). Generalized estimating equation models were used to evaluate associations between age and parasitaemia, factors associated with sub-microscopic infection and associations between parasitaemia and haemoglobin. RESULTS: A total of 9260 samples were collected from 1245 participants. Parasite prevalence among children across the three sites was 7.4, 9.4 and 28.8 % by microscopy and 21.3, 31.8 and 69.0 % by microscopy plus LAMP. Parasite prevalence among adults across the three sites was 3.1, 3.0 and 5.2 % by microscopy and 18.8, 24.2 and 53.5 % by microscopy plus LAMP. Among those with parasitaemia, adults and persons recently treated with anti-malarial therapy had the highest prevalence of sub-microscopic infection. Children with sub-microscopic or microscopic parasitaemia had lower mean haemoglobin levels compared to children with no detectable parasites. CONCLUSIONS: Across a range of transmission intensities in Uganda, microscopy vastly underestimated parasite prevalence, especially among adults.

Community-wide Prevalence of Malaria Parasitemia in HIV-Infected and Uninfected Populations in a High-Transmission Setting in Uganda.

BACKGROUND: Malaria control strategies depend on identifying individuals with parasitemia, who may be asymptomatic but retain the ability to transmit disease. Population-level survey data on parasitemia are limited and traditionally exclude adults and human immunodeficiency virus (HIV)-infected individuals. METHODS: We performed a cross-sectional survey of residents aged 18 months to 94 years in Nankoma, Uganda. Blood specimens were collected using the dried blood spot technique from 9629 residents (87.6%), and samples from a subset of 4131 were tested for malaria parasites, using loop-mediated isothermal amplification. Population-level prevalence was estimated using a weighted proportion, and predictors of parasitemia were identified using a multivariate Poisson regression model. RESULTS: The community prevalence of parasitemia was 83.8% (95% confidence interval [CI], 82.9%-84.6%). Parasite prevalence was highest among children aged 5-14 years (94.7%) and lowest among adults (61.9%). In analysis that controlled for age, HIV-infected individuals with an undetectable viral load had a lower risk of parasitemia, compared with HIV-uninfected individuals (adjusted relative risk, 0.16; 95% CI, .10-.27; P < .001). CONCLUSIONS: In a rural Ugandan community, 2 years after distribution of long-lasting insecticide-treated bed nets, the prevalence of malaria parasitemia was high across all ages, peaking in school-aged children. Persons with well-controlled HIV infection had a lower risk of parasitemia, presumably reflecting access to HIV care.

Visceral leishmaniasis-associated hemophagocytic lymphohistiocytosis in a traveler returning from a pilgrimage to the Camino de Santiago.

We report the case of a 73-year-old American traveler who presented with 3 weeks of fatigue, fevers, chills, and pancytopenia. Clinical and laboratory findings were consistent with hemophagocytic lymphohystiocytosis (HLH) and bone marrow biopsy revealed amastigotes consistent with visceral leishmaniasis. The range of endemic visceral leishmaniasis transmission now extends into northern Spain and travelers to this region should use personal protective measures against sand fly exposure.

Integrated screening for tuberculosis and HIV in tuberculosis contact investigations: lessons learned in North Carolina.

Combating the syndemics of tuberculosis (TB) and HIV in the United States will require increasing efficiency as the incidence of TB declines. Fortunately, new tools such as the interferon gamma release assays can be combined with existing strategies such as opt-out HIV testing to facilitate simultaneous, integrated testing for both infections. We describe the lessons learned from our experience with integrated testing for TB and HIV in the setting of TB contact investigations in North Carolina. Integrated testing represents a unique opportunity to leverage TB and HIV program resources to enhance case detection and improve linkages to care. However, joint training in field investigations and diagnostics is critical prior to conducting contact investigations. Furthermore, integrated testing must be tightly coupled to treatment and prevention programs to reduce disease transmission and morbidity from untreated disease in communities.

Safety and tolerability of artemether-lumefantrine versus dihydroartemisinin-piperaquine for malaria in young HIV-infected and uninfected children.

BACKGROUND: Artemisinin combination therapy has become the standard of care for uncomplicated malaria in most of Africa. However, there is limited data on the safety and tolerability of these drugs, especially in young children and patients co-infected with HIV. METHODS: A longitudinal, randomized controlled trial was conducted in a cohort of HIV-infected and uninfected children aged 4-22 months in Tororo, Uganda. Participants were randomized to treatment with artemether-lumefantrine (AL) or dihydroartemisinin-piperaquine (DP) upon diagnosis of their first episode of uncomplicated malaria and received the same regimen for all subsequent episodes. Participants were actively monitored for adverse events for 28 days and then passively for up to 63 days after treatment. This study was registered in ClinicalTrials.gov (registration # NCT00527800). RESULTS: A total of 122 children were randomized to AL and 124 to DP, resulting in 412 and 425 treatments, respectively. Most adverse events were rare, with only cough, diarrhoea, vomiting, and anaemia occurring in more than 1% of treatments. There were no differences in the risk of these events between treatment groups. Younger age was associated with an increased risk of diarrhoea in both the AL and DP treatment arms. Retreatment for malaria within 17-28 days was associated with an increased risk of vomiting in the DP treatment arm (HR = 6.47, 95% CI 2.31-18.1, p < 0.001). There was no increase in the risk of diarrhoea or vomiting for children who were HIV-infected or on concomitant therapy with antiretrovirals or trimethoprim-sulphamethoxazole prophylaxis. CONCLUSION: Both AL and DP were safe and well tolerated for the treatment of uncomplicated malaria in young HIV-infected and uninfected children. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00527800; http://clinicaltrials.gov/ct2/show/NCT00527800.

Effect of a US National Institutes of Health programme of clinical trials on public health and costs.

BACKGROUND: Few attempts have been made to estimate the public return on investment in medical research. The total costs and benefits to society of a clinical trial, the final step in testing an intervention, can be estimated by evaluating the effect of trial results on medical care and health. METHODS: All phase III randomised trials funded by the US National Institute of Neurological Disorders and Stroke before Jan 1, 2000, were included. Pertinent publications on use, cost to society, and health effects for each studied intervention were identified by systematic review, supplemented with data from other public and proprietary sources. Regardless of whether a trial was positive or negative, information on use of tested therapies was integrated with published per-use data on costs and health effect (converted to 2004 US dollars) to generate 10-year projections for the US population. FINDINGS: 28 trials with a total cost of 335 million dollars were included. Six trials (21%) resulted in measurable improvements in health, and four (14%) resulted in cost savings to society. At 10 years, the programme of trials resulted in an estimated additional 470,000 quality-adjusted life years at a total cost of 3.6 billion dollars (including costs of all trials and additional health-care and other expenditures). Valuing a quality-adjusted life year at per-head gross domestic product, the projected net benefit to society at 10-years was 15.2 billion dollars. 95% CIs did not include a net loss at 10 years. IMPLICATIONS: For this institute, the public return on investment in clinical trials has been substantial. Although results led to increases in health-care expenditures, health gains were large and valuable.