Interferon-gamma Release Assay Research Articles

Status of HIV and comorbidities in refugees with HIV from Ukraine.

To describe the clinical characteristics of refugees with HIV from Ukraine that seek continuation of medical care in Germany. Fourty-six refugees with HIV that had left Ukraine between 24 February and 30 December 2022 were examined. Information on patients' history was obtained using a standardized questionnaire for clinical care. Interviews were conducted in Russian during their first clinical presentation. Fourty-six persons (41 females and 5 males) were included and their mean age was 39.6 (±8.4) years. The mean time since HIV diagnosis was 8.0 (median, IQR 7.15) years and 70.3% of participants currently received tenfofovir-DF, lamividine and dolutegravir. Most refugees had an undetectable HIV viral load and their current mean CD4 T cell count was 702 (SD ± 289) per μL. Serology revealed previous hepatitis B infection in 50.4% without evidence for replication, with undetectable anti-hepatitis B surface antigen in the remaining refugees. Antibodies against hepatitis C were present in 23 refugees (50%), but only 10 patients had been diagnosed with hepatitis C previously. Five refugees had undergone successful antiviral treatment for hepatitis C. Detectable HCV-RNA was evident in nine patients (19.6%). Sixteen (38.6%) refugees had a positive tuberculosis (TB) interferon gamma release assay, and four were on TB treatment for previously diagnosed infection. One had been diagnosed with multidrug-resistant (MDR) TB, two with pre-extensively drug-resistant (pre-XDR) TB and two with XDR TB and were treated with combinations of second-line and novel agents according to WHO guidelines. Based on this preliminary analysis of a not fully representative cohort, refugees with HIV from Ukraine were young, mostly healthy females highly adherent to antiretroviral therapy. The rate of transmittable co-infections urges early diagnostic evaluation and treatment.

Utility of interferon-gamma releasing assay for the diagnosis of active tuberculosis in children: A systematic review and meta-analysis

IntroductionThe accurate diagnosis of tuberculosis (TB) in children is essential for its effective management and control. Reliable diagnostic tools that are currently available for identifying TB infection include the in vivo tuberculosis skin test (TST) and ex vivo interferon-gamma release assays (IGRAs). This systematic review and meta-analysis aimed to evaluate the diagnostic accuracy of IGRAs in children. MethodsOf the 768 screened studies, 47 met the eligibility criteria. Data from 9065 patients, including 1086 (12.0 %) with confirmed TB, were included in the analysis. The overall quality of the included studies, assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 tool, was unclear. ResultsThe calculated pooled sensitivity and specificity of IGRAs in children were 0.85 (95 % confidence interval [CI]: 0.79–0.89) and 0.94 (95 % CI: 0.88–0.97), respectively. Subpopulation analysis revealed that the sensitivities and specificities were as follows: QuantiFERON tests: 0.83 (95 % CI: 0.74–0.89) and 0.93 (95 % CI: 0.87–0.96), T-SPOT: 0.87 (95 % CI: 0.79–0.91) and 0.99 (95 % CI: 0.85–1.00), IGRAs in children under 15 years: 0.77 (95 % CI: 0.43–0.94) and 0.96 (95 % CI: 0.84–0.97), and IGRAs in children under 5 years: 0.85 (95 % CI: 0.52–0.97) and 0.94 (95 % CI: 0.90–0.99), respectively. ConclusionsThis study demonstrated that the sensitivity and specificity of the IGRAs in children were moderate and high, respectively. Therefore, the IGRAs may be useful for detecting TB infection in children. Clinical trial registrationThe review protocol was prospectively registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN000046737).

Analysis of Risk Factors for Developing Tuberculosis in Patients Who Received Prophylactic Latent Tuberculosis Infection Treatment with Experience of Biologic Medications.

Biologic medications have dramatically improved the treatment outcomes of immunological inflammatory diseases, but their immunosuppressive effects put patients at risk for tuberculosis (TB). We investigated the risk factors for developing TB in patients treated for latent tuberculosis infection (LTBI) who also had experience of using biologic medications. At Keio University Hospital, we retrospectively investigated patients treated with anti-mycobacterial drugs before or concurrently with biologic medications from January 2012 to August 2020. Patients in the 'follow-on cases group' who had a positive TB screening test after initiating biologic medications and subsequently started LTBI treatment were excluded. We researched and compared the patient characteristics for TB and non-TB patient groups. Of the 146 eligible patients, 5 (3.4%) developed TB. The incidence rate was 600/100000 person-years. There were no significant differences between TB and non-TB patient groups in the history of TB, interferon-gamma release assay (IGRA), duration of biologic medication therapy, LTBI treatment periods, concomitant use of calcineurin inhibitors or anti-rheumatic drugs. The percentage of patients who received prednisolone at a dose of ≥15 mg for more than 1 month was higher in those who developed TB than in those who did not (40.0 vs. 7.1%, p = 0.054); however, this difference was not statistically significant. Regular monitoring of TB is necessary for long-term concomitant use of high prednisolone doses during and after the administration of biologic medications.

Prevalence of indeterminate tuberculosis interferon-gamma release assays in COVID-19 patients: Systematic review and meta-analysis.

The reliability of interferon-gamma-release-assays (IGRAs) for tuberculosis (TB) testing in coronavirus disease 2019(COVID-19) patients is unknown. This study aimed to systematically review the prevalence of indeterminate TB-IGRA following SARS-CoV-2 infection or vaccination and to review associated factors. This systematic literature review was guided according to the PRISMA guidelines by searching PubMed, Scopus, Web of Science, Clinicalkey, and Cochrane Library. Studies reporting results of TB-IGRA tests (QuantiFERON [QFT]-TB, T-SPOT.TB) in COVID-19 patients or vaccines were included. The random effects model was used to assess the prevalence of indeterminate IGRA results. Heterogeneity was evaluated using the Τ 2 and 95% predictive interval. Of the 273 citations screened, 12 articles were included in the final analysis including a total of 2107 patients. The overall pooled effect size proportion of indeterminate QFT-TB results, estimated in eightstudies using the QFT-TB Plus assay, was 0.26 (95%CI: 0.205-0.324, Τ 2 = 0.158). The mean true effect size was 0.26 (95% predictive interval: [0.110-0.500]). A subgroup analysis was not undertaken due to the small number of studies. Indeterminate QFT-TB rates were associated with COVID-19 severity, steroid treatment, inflammation-related parameters, neutrophilia, and lymphopenia. Indeterminate QFT-TB results in COVID-19 patients occur in almost one-quarter of tests performed. Further studies are needed to assess associated factors.

Tubercolosi vertebrale atipica: un caso clinico e revisione della letteratura

Background - Rates of Extrapulmonary Tuberculosis (TB) are higher in paediatric patients, especially in those from endemic areas. Bone TB is mostly located in the spine and in children may cause rapid bone destruction with severe deformity and neurological deficits. Case report - The paper reports the case of a 14-year-old male patient from Pakistan presenting with neurological symptoms and neuroradiological features suspicious for malignant tumour. After surgical removal of the mass, PCR test showed spinal TB. Tuberculin skin test (TST) and Interferon-Gamma Release Assays (IGRA) resulted negative. Discussion - False negative IGRA and TST test results can occur due to several factors, including immunodeficiency disorders. Some cases of spinal TB do not have typical radiological features, causing diagnostic delays or mistakes. Non-typical spinal TB features include: (1) involvement of the posterior elements of the spinal column; (2) skip lesions; (3) non-osseous TB involving spinal cord, cauda equina, and/or meninges. Conclusion - The differential diagnosis between spinal TB and malignancy might be challenging. Consequently, considering TB in children with neurological symptoms and/or vertebral neoformation, especially in patients coming from endemic areas, is recommended. TB diagnosis should not be excluded in case of non-typical radiological features, negative TST and IGRA or history of anti-TB vaccination. This approach should facilitate a timely diagnosis for appropriate treatment, avoiding neurological sequalae and delayed deformities.

Latent tuberculosis infection (LTBI) in health-care workers: a cross-sectional study at a northern Peruvian hospital

BackgroundHealthcare workers (HCWs) have a higher risk of latent tuberculosis infection (LTBI) and active tuberculosis than the general population. In HCWs, the risk of tuberculosis infection depends on the local tuberculosis prevalence, HCWs’ characteristics, the healthcare facility, and prevention and control measures. We aimed to estimate the prevalence and risk factors for LTBI in HCWs at a northern Peruvian hospital.MethodsThis study had two phases: (1) a cross-sectional phase involving recruitment, history taking, and sampling for the Interferon-Gamma Release Assays (IGRA test), and (2) a prospective follow-up of IGRA-positive participants. We enrolled direct and non-direct patient caregivers among HCWs. We defined an LTBI case if the IGRA test was positive and clinical, laboratory, and radiological evaluations for active tuberculosis were negative.ResultsWe recruited 308 participants between November 2022 and May 2023. The mean age was 38.6 ± 8.3 years. Over 75% of the participants were female. The most common job category was technicians (30.5%), physicians (22.7%), nurses (20.5%), and other HCWs groups (17.5%). Most participants worked in hospital wards (28.2%), diagnostics departments (16.9%), and critical care departments (15.6%). The LTBI prevalence among HCWs was 17.86% (95% CI 13.84–22.70). In multivariate analysis, after adjusting for age, time working in our hospital, and family history of tuberculosis, males had a higher risk of LTBI (aPR 1.69, 95% CI 1.01–2.77) than females. Working for more than 10 years increased the risk of LBTI (aPR 2.4, 95% CI 1.44–3.97) compared to working for ≤10 years. Even further, participants who had worked for more than 20 years had an aPR of 4.31 (95% CI 1.09–13.65) compared to those with ≤10 years. Similarly, occupational exposure increased the risk of LTBI (aPR 2.21, 95% CI 1.27–4.08) compared to those HCWs not occupationally exposed.ConclusionThe LTBI prevalence in HCWs at a northern Peruvian hospital was lower compared to other Peruvian cities. Males, more experienced, and occupational exposed HCWs are at higher risk of LTBI. LTBI prevalence in Peruvian HCWs is still high. More studies are needed to address some aspects this study has not examined.

1882. Contact Investigation of Congenital Tuberculosis in a Neonatal Intensive Care Unit in South Korea

Abstract Background Congenital tuberculosis (TB) is uncommon and difficult to detect in neonates due to its nonspecific symptoms. We conducted a contact investigation of infants and healthcare workers (HCWs) exposed to a neonate with congenital TB in a neonatal ICU (NICU) in Korea. Methods A premature infant born was admitted to NICU on September 16, 2022. On October 24, the infant's mother was diagnosed with miliary TB, and infant’s sputum AFB stain showed 4 positive results. All NICU infants and HCWs during the same period were screened for active pulmonary TB using chest radiography (CXR) immediately. Exposed infants were evaluated with a TST and CXR three months after exposure. Interferon-Gamma Release Assay (IGRA) testing was performed on those with a positive TST or abnormal CXR finding. Prophylactic rifampin was provided to the exposed infants for 3 months, as index had isoniazid-resistant M. tuberculosis infection. Exposed HCWs underwent IGRA testing immediately after exposure (1st IGRA) and at 8 to 10 weeks post-exposure (2nd IGRA), and CXR was performed 6 months after exposure. Results Five out of 82 exposed infants had positive TST (≥ 10 mm) results, while all 31 infants who underwent IGRA testing had negative results. All five with positive TST had received BCG vaccination a median 105 days before. Of the 119 exposed HCWs, three had a conversion; two had negative results (on annual IGRA testing performed according to the national TB prevention Act) before exposure and positive at 1st IGRA test, and one had negative 1st IGRA test then positive 2nd IGRA test. None had active TB during 6-month follow-up. Conclusion We found that 6% of exposed infants had positive TST results and 0% had positive IGRA, while 2.5% of exposed HCWs had conversion. Considering the possibility of false positive TST results due to prior BCG vaccination, the chance of transmission to the infants would be 0%; otherwise, it would be 6.1%. Disclosures All Authors: No reported disclosures

2511. Screening for Hepatitis B Virus (HBV) and Tuberculosis (TB) Infection among Non-U.S.-Born Adults from High HBV and TB Burden Countries

Abstract Background Hepatitis B virus (HBV) infection and tuberculosis (TB) infection both disproportionately affect non-U.S.–born persons from countries with hepatitis B surface antigen (HBsAg) seroprevalence ≥2% or TB incidence rates ≥20/100,000 population. Early identification and treatment of chronic HBV and TB infection are critical to reduce morbidity and mortality, but little is known about HBV and TB screening among non-U.S.–born persons in the United States. Methods In a cross-sectional study using electronic health record data, we assessed HBV and TB infection screening practices among Kaiser Permanente Northern California eligible members aged ≥18 years born in countries with intermediate to high burdens of both HBV and TB infection. HBV screening was defined as testing for HBV surface antigen and HBV core antibody. TB infection screening was defined as testing with interferon gamma release assay or tuberculin skin test. We calculated the proportion of individuals from intermediate and high HBV-TB burden countries who had HBV or TB infection screening and the proportion of patients positive for HBV or TB infection. Results Of 498,339 non-U.S.–born adults, 275,708 (55.3%) were born in intermediate or high HBV-TB burden countries. Most patients were aged ≥50 years (65.3%) and 23.5% had diabetes. Among persons born in intermediate or high HBV-TB burden countries, 67.1% were screened for HBV infection, 29.4% were screened for TB infection, and only 23.7% were screened for both HBV and TB infection. Among all persons born in intermediate or high HBV-TB burden countries (both screened and unscreened), 3.7% had HBV infection and 10.1% had TB infection. Among 231,431 persons born in intermediate or high HBV-TB burden countries without current or prior HBV infection, 72.9% had received at least one HBV vaccine dose. Conclusion Among non-U.S.–born adults from intermediate or high HBV-TB burden countries, we found low screening proportions, intermediate prevalence of chronic HBV infection and high prevalence of TB infection. Given the large population of persons from intermediate or high HBV-TB burden countries in Kaiser Permanente Northern California, screening for both infections at the same time could improve early diagnosis and treatment for both conditions. Disclosures Jacek Skarbinski, MD, Genentech: Grant/Research Support|Gilead Sciences: Grant/Research Support Robert J. Wong, MD, MS, Gilead Sciences: Grant/Research Support

Clinical Features, Diagnosis, and Treatment of Congenital and Neonatal Tuberculosis: A Retrospective Study

Introduction: Limited studies have explored the clinical features, treatment, and prognosis of neonatal tuberculosis (TB). Here, we attempted to delineate the clinical characteristics of neonatal TB, which may help clinicians further understand this disease. Methods: A retrospective analysis of neonates diagnosed with congenital and/or neonatal TB disease from January 2010 to December 2020 was performed. Information on the demographic and epidemiological features, clinical symptoms, laboratory and imaging examinations, therapeutic regimens, and outcomes was collected. Kaplan-Meier analysis was used to present the time to disease onset, time to diagnosis, etc. Results: Forty-eight cases of neonatal TB were classified into congenital (n = 33) and postnatal (n = 15). The median time to disease onset in postnatal group was significantly longer than that in congenital group. Positive results for gastric fluid acid-fast bacilli, TB culture, Xpert MTB/RIF, interferon-γ release assay (IGRA), and tuberculin skin test were detected in 26/48 (54.2%), 14/34 (41.2%), 11/18 (61.1%), 19/29 (65.5%), and 8/24 (33.3%) patients, respectively. For lymphadenopathy, computed tomography (CT) scans showed a higher detection rate than did X-ray (80.0% vs. 0). Of the 48 infants, 44/48 (91.7%) received anti-TB therapy, and 33/44 (75%) were clinically improved or cured after 22.1 months (interquartile range: 12.4–27.7) of follow-up. Drug-induced liver injury occurred in 14/44 (31.8%) patients. Discussion/Conclusion: IGRA and Xpert MTB/RIF showed good positive rate in neonatal TB infection/disease. In cases where TB is presumed but etiological evidence is lacking, low-dose CT could be considered. Prompt treatment under careful surveillance is important for preventing mortality and avoiding severe adverse effects.

1538. Is there value in performing yearly screening for latent tuberculosis infection by interferon-gamma release assay among patients living with HIV in non-endemic settings?

Abstract Background People with HIV (PWH) are at increased risk of reactivation of tuberculosis (TB) from latent tuberculosis infection (LTBI). Current guidelines recommend all PWH be initially screened for LTBI with either interferon-gamma release assays (IGRA) or tuberculin skin testing (TST). Also, repeat screening is recommended in either PWH with CD4 count < 200 cells/mm3 after initial negative screen or any PWH with new TB exposure risk. Despite such guideline, there are centers that continue to screen LTBI in all PWH with annual IGRA testing. Our study evaluated the utility of universal yearly LTBI screening by IGRA among PWH in non-endemic settings. Methods A retrospective chart review of PWH in care from 2017-2021 at two urban academic medical centers. Demographics and annual IGRA results were collected. Patients were further stratified into three groups based on IGRA seroconversion: those with negative to positive (Group A), indeterminate to positive (Group B), and negative to indeterminate (Group C). Data for 3 groups, included risk factors for TB, chest imaging results, HIV data, and treatment. Descriptive statistics, chi-square, and Welch’s ANOVA were performed. Results A total of 2694 PWH were in care, comprised of 66% male, 50% Black, and 23% LatinX. Of the 2694, 2255 (84%) had a negative baseline IGRA. Seventy-two patients (2.7%) had IGRA seroconversion: 39 in Group A, 1 in Group B, and 32 in Group C (Table 1). Group A had lower CD4 counts (p=0.04) and higher HIV viral loads (p=0.03) than Group C. Only 12 PWH (0.5%) with negative baseline IGRA developed new LTBI, with an incidence 1.1 cases/1000 patient-years. Of these, 8 PWH (67%) had ≥ 1 TB risk factor and none had CD4< 200. Travel to endemic region (33%) was most common risk factor. Among those with new LTBI, N=6/7 had confirmation of LTBI with repeat positive IGRA after initial seroconversion. Nine (75%) patients completed LTBI treatment and none developed tuberculosis. Features of patients with conversion to a positive or indeterminate QuantiFERON Conclusion In two large diverse clinics in non-TB endemic settings, the true incidence of developing LTBI in PWH was rare among those with negative baseline IGRA. Due to low yield of cases with universal annual screening, our findings support the targeted approach recommended by current guidelines. Disclosures Michael Virata, MD, Gilead Sciences: Advisor/Consultant|Janssen: Advisor/Consultant|ViiV Healthcare: Advisor/Consultant

Screening Practices and Risk Factors for Co-Infection with Latent Tuberculosis and Hepatitis B Virus in an Integrated Healthcare System — California, 2008-2019

BackgroundHepatitis B virus (HBV) and latent tuberculosis infection are associated with a significant global burden, but both are underdiagnosed and undertreated. We described the screening patterns and risk factors for co-infection with latent tuberculosis and HBV within a large healthcare system. MethodsUsing data from Kaiser Permanente Southern California during 2008-2019, we described HBV infections, defined as a positive HBV surface antigen, e-antigen, or DNA test, and latent tuberculosis, defined as a positive Mantoux tuberculin skin test or interferon-gamma release assay test. We estimated adjusted odds ratios (aOR) for co-infection among screened adults with either infection. ResultsAmong 1997 HBV patients screened for latent tuberculosis, 23.1% were co-infected, and among 35,820 patients with latent tuberculosis screened for HBV, 1.3% were co-infected. Among HBV patients, co-infection risk was highest among Asians compared with White race/ethnicity (29.4% vs 5.7%, aOR 4.78; 95% confidence interval [CI], 2.75-8.31), and persons born in a high-incidence country compared with low-incidence countries (31.0% vs 6.6%; aOR 4.19; 95% CI, 2.61-6.73). For patients with latent tuberculosis, risk of co-infection was higher among Asian (aOR 9.99; 95% CI, 5.79-17.20), or Black race/ethnicity (aOR 3.33; 95% CI, 1.78-6.23) compared with White race/ethnicity. Persons born in high-incidence countries had elevated risk of co-infection compared with persons born in low-incidence countries (aOR 2.23; 95% CI, 1.42-3.50). However, Asians or persons born in high-incidence countries were screened at similar rates to other ethnicities or persons born in low-incidence countries. ConclusionsLatent tuberculosis risk is elevated among HBV patients, and vice versa. Risk of co-infection was highest among persons born in high-incidence countries and Asians. These findings support recent guidelines to increase HBV and tuberculosis screening, particularly among persons with either infection.

Maternal HIV Status and Risk of Infant Mycobacterium tuberculosis Infection as Measured by Tuberculin Skin Test.

The effect of maternal HIV on infant Mycobacterium tuberculosis (Mtb) infection risk is not well-characterized. Pregnant women with/without HIV and their infants were enrolled in a longitudinal cohort in Kenya. Mothers had interferon gamma-release assays (QFT-Plus) and tuberculin skin tests (TST) at enrollment in pregnancy; children underwent TST at 12 and 24 months of age. We estimated the incidence and correlates of infant TST-positivity using Cox proportional hazards regression. Among 322 infants, 170 (53%) were HIV-exposed and 152 (47%) were HIV-unexposed. Median enrollment age was 6.6 weeks [interquartile range (IQR): 6.1-10.0]; most received Bacillus Calmette-Guerin (320, 99%). Thirty-nine (12%) mothers were TST-positive; 102 (32%) were QFT-Plus-positive. Among HIV-exposed infants, 154 (95%) received antiretrovirals for HIV prevention and 141 (83%) of their mothers ever received isoniazid preventive therapy (IPT). Cumulative 24-month infant Mtb infection incidence was 3.6/100 person-years (PY) [95% confidence interval (CI): 2.4-5.5/100 PY]; 5.4/100 PY in HIV-exposed infants (10%, 17/170) versus 1.7/100 PY in HIV-unexposed infants (3.3%, 5/152) [hazard ratio (HR): 3.1 (95% CI: 1.2-8.5)]. More TST conversions occurred in the first versus second year of life [5.8 vs. 2.0/100 PY; HR: 2.9 (95% CI: 1.0-10.1)]. Infant TST-positivity was associated with maternal TST-positivity [HR: 2.9 (95% CI: 1.1-7.4)], but not QFT-Plus-positivity. Among HIV-exposed children, Mtb infection incidence was similar regardless of maternal IPT. Mtb infection incidence (by TST) by 24 months of age was ~3-fold higher among HIV-exposed children, despite high maternal IPT uptake. Overall, more TST conversions occurred in the first 12 months compared to 12-24 months of age, similar in both HIV-exposed and HIV-unexposed children.

Latent tuberculosis infection in Korean patients with multiple sclerosis and neuromyelitis optica spectrum disorder

BackgroundLatent tuberculosis infection (LTBI) is defined as an immune response to Mycobacterium tuberculosis infection that does not manifest clinically as active tuberculosis (TB). Since some immunotherapies can alter cellular immunity, LTBI screening has been recommended for patients with multiple sclerosis (pwMS) before initiation of long-term immunotherapies. In this study, we investigated the frequency of LTBI in Korean pwMS and patients with neuromyelitis optica spectrum disorder (pwNMOSD) and reported the long-term observation of untreated LTBI under various immunotherapies. MethodsWe enrolled pwMS or pwNMOSD who visited the Neurology department of the National Cancer Center between 2017 and 2021. LTBI was determined based on positive results of interferon-gamma release assay (IGRA) using QuantiFERON Gold Plus test and no evidence of active TB. Annual chest X-ray and careful monitoring for TB symptoms were performed until April 2023 or the time of follow-up loss. ResultsAmong 531 patients who underwent the IGRA test, 25 pwMS (10.5%) and 42 pwNMOSD (14.3%) were diagnosed with LTBI. Of the 67 patients with LTBI, 59 patients (24 pwMS and 35 pwNMOSD) declined to receive preventive anti-TB drugs. None of the 59 with untreated LTBI demonstrated TB reactivation during 74.8 person-years in pwMS and 166.1 person-years in pwNMOSD. In addition, eight patients who completed the treatment for LTBI experienced no TB reactivation for a median of 5.5 years. ConclusionThe LTBI prevalence in Korean pw MS and pwNMOSD was 10.5% and 14.3%, respectively, which was much higher than that in pwMS from Western countries. Notably, none of the 59 patients with untreated LTBI showed TB reactivation over 240 person-years even under long-term immunotherapies, indicating the need for additional research to stratify the risk of LTBI-reactivation.

Humoral and cellular immunity against different SARS-CoV-2 variants in patients with chronic kidney disease

Chronic kidney disease (CKD) patients are at higher risk of severe COVID-19. Humoral and cellular immunity from prior infection or vaccination are important for protection, but the neutralizing antibody (nAb) response against SARS-CoV-2 variants is impaired. We investigated the variant-specific nAb and T cell immunity among CKD patients. Adult CKD patients were recruited between August and October 2022. nAb against the SARS-CoV-2 (ancestral strains and four Omicron sublineages) and T cell response were measured using the live virus neutralization assay and interferon-gamma release assay (IGRA). The correlation between nAb/T-cell response and subsequent infection after recruitment were also determined. Among the 88 recruited patients, 95.5% had prior infection or had completed the primary vaccine series. However, only 77.3% had detectable nAb against at least one SARS-CoV-2 strains, 59.1% tested positive in IGRA, and 52.3% had detectable nAb and tested positive in the IGRA. The nAb geometic mean titers (GMTs) against XBB.1, BA.5 and BA.2.3.20 were significantly lower than those against BA.2 and ancestral strain. Prior SARS-CoV-2 infection was associated with elevated nAb and T cell response. More kidney transplant recipients (KTRs) showed absent nAb and T cell response (36.8% vs. 10.1%), despite a higher prevalence of vaccine booster in this population (94.7% vs. 50.7%). Lower levels of nAb titer and T cell response were significantly associated with subsequent infection. A considerable proportion of CKD patients, especially KTRs, showed absence of humoral and cellular protective immunity against SARS-CoV-2. Strategies to improve immunogenicity in this population are urgently needed.

Latent tuberculosis infection in myasthenia gravis patients on immunosuppressive therapy: high incidence yet moderate reactivation rate

Background Immunosuppressive therapies (ISTs) are mainstays for management of myasthenia gravis (MG). Meanwhile, latent tuberculosis infection (LTBI) is common in the setting of high-burden countries. However, the prevalence of LTBI among MG patients and whether receiving ISTs for MG would aggravate LTBI reactivation remain unknown. Methods We retrospectively analyzed the frequency of LTBI via interferon-gamma release assay (IGRA) positivity among hospitalized MG patients from both rural and urban areas in a tertiary hospital, and those receiving ISTs were followed up to investigate the reactivation risk of LTBI. Results A total of 300 MG patients with determinate IGRA results were enrolled, where the frequency of LTBI was 35.0%. Male (OR = 1.910, 95% CI: 1.181–3.089, p = .008) and elderly (OR = 1.044, 95% CI: 1.027–1.061, p < .001) patients were prone to LTBI. Of those with LTBI, 78 individuals on ISTs were successfully followed up for a median duration of 18.3 (8.5–24.0) months, of which 25 (32.1%) received anti-tuberculosis (TB) treatments. The rate of various degrees of adverse events was 82.1% over the course of the follow-up, but was not different between individuals with and without therapies against TB (χ 2 < 0.001, p > .999). Only 1 patient eventually reported lymph node and intestinal TB, with the incidence rate of LTBI reactivation preliminarily estimated to be 0.81 per 100 person years. Conclusion The frequency of LTBI is high in our MG cohort, especially among those with advanced age and males. However, receiving immunosuppressives seems not to increase the risk of LTBI reactivation. LTBI screening is strongly recommended for all MG patients ready to receive ISTs, while preventive anti-TB chemotherapy should be prescribed after weighing potential benefits against the risk of side effects in those with LTBI. In-depth investigation is still entailed to further verify these findings due to the limitation of the retrospective single-center design of our study.

Sars-Cov-2 Antibody and T-Cell Responses in Patients with Paroxysmal Nocturnal Hemoglobinuria and Aplastic Anemia after Four COVID-19 Vaccinations

Introduction: There is limited data on SARS-CoV-2 vaccination responses in the rare hematological disorders paroxysmal nocturnal hemoglobinuria (PNH) and aplastic anemia (AA). These patients were expected to have more severe COVID-19 infection and reduced vaccination responses due to their underlying disease and immunosuppressive treatment. We previously reported limited anti-spike IgA/G/M responses after first COVID-19 vaccination which improved following second vaccination (Pike et al, Lancet Haematology 2022). Here we report spike-specific IgG, in vitro viral neutralization and T-cell responses in 244 patients with PNH and/or AA and in 49 healthy volunteers, following the first four vaccinations. Methods: In 2021, the United Kingdom National PNH service centre based in Leeds initiated a prospective observational non-interventional study evaluating immune responses to COVID-19 vaccinations in patients with PNH and/or AA. All patients were consented to the Leeds PNH Research Tissue Bank. At baseline, the patient cohort comprised 94 patients with classic PNH, 75 with AA-PNH overlap and 75 with AA with asymptomatic PNH clones &amp;lt;50%. Serological humoral responses were evaluated in blood samples using a quantitative spike-specific IgG SARS-CoV-2 ELISA (EuroImmun). Samples were further analyzed using a high-throughput live-virus neutralization assay performed at the Francis Crick Institute, London, against wild-type SARS-CoV-2 and against omicron B.1.1.529 and delta B.1.617.2 variants. Adaptive T-cell immune responses were assessed by incubating cryopreserved peripheral blood mononuclear cells with SARS-CoV-2 spike and nucleocapsid peptides in an ELISpot interferon-gamma release assay (Oxford Immunotec). Results: Prior to vaccination (baseline) in-vitro anti-spike IgG response was not significantly different between patients and healthy volunteers (p&amp;gt;0.99). After first vaccination, 2/40 (5%) healthy volunteers and 66/155 (42.6%) PNH and AA patients failed to mount a detectible spike-specific IgG. The antibody titre was also significantly reduced (median spike-specific IgG titre in patients 37.9 BAU/ml [IQR 11.56-120.7] versus 289.4 BAU/ml in healthy volunteers [IQR 177.7-1326], p&amp;lt;0.0001). The magnitude of IgG response improved after second vaccination but remained lower than healthy volunteers (median IgG titre in patients 408.6 BAU/ml [IQR 184.1-942.6] versus healthy volunteers 2639 BAU/ml [IQR 894.0-3706], p&amp;lt;0.001). However, responses improved sequentially following repeated vaccinations and after the third dose were equivalent to healthy volunteers (p&amp;gt;0.99). Viral neutralizing antibody activity elicited by vaccination showed similar results, with significantly reduced titres post first vaccination against wild-type SARS-CoV-2 in patients compared with healthy volunteers (p=0.0001). After second vaccination, neutralizing antibody titres in patients versus healthy volunteers remained significantly reduced against wild-type (p=0.0088) and the delta variant (p=0.0001) but not the omicron variant (p=0.078). Reassuringly, responses improved after 3 rd dose of vaccine following which there was no significant difference detected for all three strains (p&amp;gt;0.99). Of the evaluable samples, anti-spike T-cell responses were reduced at all timepoints in patients compared with healthy volunteers but improved with each vaccination. After first vaccination, a reactive result was seen in 32.1% (n=27/84) versus 40% in healthy volunteers (n=16/40) and remained low after second vaccination (35.0% (n=43/123) in patients versus 64.1% (n=24/39) in healthy volunteers). However, after third vaccination, responses had improved to 58.7% (n=44/75) in patients versus 75% (n=24/32) in healthy volunteers. After 4 th vaccination, spike-specific responses were detectable in 67.6% (n=25/37) of patients. There was limited reactivity to nucleocapsid antigens in both groups at all timepoints highlighting that the observed responses were due to vaccination rather than COVID-19 infection. To date there have been no deaths due to COVID-19 infection in patients in this study or in our wider service population since the introduction of the vaccination programme. Conclusion: This study demonstrates the importance of repeated SARS-Cov-2 vaccinations in patients with PNH and/or AA in order to improve humoral and cellular immune responses.

Abstract 27 — Prevalence and Management Approach of Latent Tuberculosis Infection in Rheumatology Patients

Prior to immunosuppression, rheumatology patients are routinely screened for latent tuberculosis infection (LTBI) using Interferon-Gamma Release Assays (IGRA). The management of latent and indeterminate IGRA results varied among institutions and long-term outcome data is lacking. We conducted a retrospective study at Tawam Hospital, United Arab Emirates, to examine the frequency and management of positive and indeterminate IGRA results and tuberculosis infection in rheumatic patients. Methods Laboratory records and hospital electronic medical system were used to obtain information about IGRA results over a 12 years period (April 2010-April 2022). Results In our hospital record over a 12-year period, we found a total of 1012 positive and 223 indeterminate IGRA test results. Within the rheumatology department, 123 positive and 39 indeterminate IGRA results were identified. In the indeterminate IGRA group, the majority were female (n=24, 61.5%), UAE nationals (n=22, 56.4%), and had a mean age of 38.6 years. Systemic lupus erythematosus (SLE) was the most prevalent rheumatologic condition (n=21, 53.8%). 33.3% (n=13) were on disease modifying anti-rheumatic drugs (DMARDs) and 66.7% (n=26) were on corticosteroid during IGRA testing. A total of 8 patients (20.5%) received anti-TB medications. In a positive IGRA group, the mean age of 55.7 years and a female-to-male ratio of 3:1. The most common rheumatologic conditions were RA (n=67, 54.4%). Approximately 52.8% (n=65) of patients were on conventional DMARDs, 66.7% (n=26) were on corticosteroids during IGRA testing, and 60% (n=74) received anti-TB medications. Two cases (1.6%) of active TB infections were detected among patients with positive IGRA tests, both of whom were receiving anti-TNFa inhibitor treatment in combination with methotrexate. No cases of active TB infection were observed in the indeterminate IGRA group. Conclusion Tuberculosis risk in positive and indeterminate IGRA results for rheumatological conditions is low. Further multicenter studies are required to analyze patient outcomes and differences in TB-endemic and non-endemic regions.

A costing framework to compare tuberculosis infection tests

ObjectiveTo develop a framework to estimate the practical costs incurred from, and programmatic impact related to, tuberculosis (TB) infection testing—tuberculin skin tests (TST) versus interferon gamma release assay (IGRA)—in a...

Prior Screening for Latent Tuberculosis Among Patients Diagnosed With Tuberculosis Disease: Missed Opportunities?

California has the largest number of tuberculosis (TB) disease cases in the United States. This study in a large California health system assessed missed opportunities for latent tuberculosis (LTBI) screening among patients with TB disease. Kaiser Permanente Southern California patients who were ≥18 years old with membership for ≥24 months during the study period from 1 January 2008 to 31 December 2019 were included. Prior LTBI test (tuberculin skin test or interferon-γ release assay) or diagnosis code prior to TB disease diagnosis was assessed among patients with observed TB disease (confirmed by polymerase chain reaction and/or culture). In the absence of current treatment practices, more patients screened for LTBI may have developed TB disease. We estimated hypothetical TB disease cases prevented by multiplying LTBI progression rates by the number of LTBI-positive patients prescribed treatment. A total of 1289 patients with observed TB disease were identified; 148 patients were LTBI positive and 84 were LTBI negative. Patients not prescreened for LTBI made up 82.0% of observed TB disease cases (1057/1289). Adding the hypothetical maximum estimate for prevented cases decreased the percentage of patients who were not prescreened for LTBI to 61.7% [1057/(1289 + 424)]. One-fifth of patients were screened for LTBI prior to their active TB diagnosis. Assuming the upper bound of cases prevented through current screening, almost 62% of TB disease patients were never screened for LTBI. Future work to elucidate gaps in LTBI screening practices and to identify opportunities to improve screening guidelines is needed.

Vaccination of calves with Bacillus Calmette-Guerin Danish strain 1331 results in a duration of immunity of at least 52 weeks

Bacillus Calmette-Guérin (BCG) Danish strain 1331 (CattleBCG) is currently the lead vaccine candidate for the control of bovine tuberculosis (TB) in cattle in GB, where prior vaccination has shown to result in a significant reduction in bovine TB pathology induced by infection with Mycobacterium bovis (M. bovis). A critical knowledge gap in our understanding of CattleBCG is the duration of immunity post vaccination at the minimum intended vaccine dose. To this end, we performed an experiment where calves were vaccinated with a targeted dose of 106 CFU and, after a period of 52 weeks, experimentally infected with M. bovis. Post mortem examination performed 13 weeks after infection revealed a statistically significant reduction in the severity of TB pathology in the CattleBCG vaccinated group compared with the unvaccinated control group. Additionally, this study allowed us to further assess the diagnostic performance of a defined antigen DIVA reagent (DST-F) developed to detect infected amongst vaccinated animals. Our results demonstrate that when used in a skin test format, DST-F showed high specificity (100 %) in BCG-vaccinated animals when tested prior to infection, whilst detecting all infected animals when re-tested after infection. Furthermore, we also present results supporting the use of the DST-F reagent in an interferon-gamma release assay. In conclusion, the results of this study demonstrate a 52-week duration of immunity following administration of a minimum dose of CattleBCG. This evidence will be a fundamental component in our efforts to apply for UK marketing authorisation to enable vaccination of cattle as a significant additional control measure in the ongoing fight against bovine TB in GB.