SARS-CoV-2 Vaccine Responses in Individuals with Antibody Deficiency: Findings From The COV-AD Study

Background Vaccination prevents severe morbidity and mortality from COVID-19 in the general population. The immunogenicity and efficacy of SARS-CoV-2 vaccines in patients with antibody deficiency is poorly understood. Objectives COVID in patients with antibody deficiency (COV-AD) is a multi-site United Kingdom study that aims to determine the immune response to SARS-CoV-2 infection and vaccination in patients with primary or secondary antibody deficiency, a population that suffers from severe and recurrent infection and does not respond well to vaccination. Methods Individuals on immunoglobulin replacement therapy or with an IgG less than 4g/L receiving antibiotic prophylaxis were recruited from April 2021. Serological and cellular responses were determined using ELISA, live-virus neutralisation and interferon gamma release assays. SARS-CoV-2 infection and clearance were determined by PCR from serial nasopharyngeal swabs. Results 5.6% (n=320) of the cohort reported prior SARS-CoV-2 infection, but only 0.3% remained PCR positive on study entry. Seropositivity, following two doses of SARS-CoV-2 vaccination, was 54.8% (n=168) compared with 100% of healthy controls (n=205). The magnitude of the antibody response and its neutralising capacity were both significantly reduced compared to controls. Participants vaccinated with the Pfizer/BioNTech vaccine were more likely to be seropositive (65.7% vs 48.0%, p=0.03) and have higher antibody levels compared with the AstraZeneca vaccine (IgGAM ratio 3.73 vs 2.39, p=0.0003). T cell responses post vaccination were demonstrable in 46.2% of participants, were associated with better antibody responses but there was no difference between the two vaccines. Eleven vaccine-breakthrough infections have occurred to date, 10 of them in recipients of the AstraZeneca vaccine. Conclusion SARS-CoV-2 vaccines demonstrate reduced immunogenicity in patients with antibody deficiency with evidence of vaccine breakthrough infection.

Tuberculosis Infection in Children and Adolescents: Testing and Treatment

Tuberculosis (TB) remains an important problem among children in the United States and throughout the world. There is no diagnostic reference standard for latent tuberculosis infection (also referred to as tuberculosis infection [TBI]). The tuberculin skin test (TST) has many limitations, including difficulty in administration and interpretation, the need for a return visit by the patient, and false-positive results caused by cross-reaction with Mycobacterium bovis–bacille Calmette-Guerin vaccines and many nontuberculous mycobacteria. Interferon-gamma release assays (IGRAs) are blood tests that use antigens specific for M tuberculosis; as a result, IGRAs yield fewer false-positive results than the TST. Both IGRAs and the TST have reduced sensitivity in immunocompromised children, including children with severe TB disease. Both methods have high positive predictive value when applied to children with risk factors for TBI, especially recent contact with a person who has TB disease. The advantages of using IGRAs and diminished experience with the placement and interpretation of the TST favor expanded use of IGRAs in children in the United States. There are now several effective and safe regimens for the treatment of TBI in children. For improved adherence to therapy, the 3 rifamycin-based regimens are preferred because of their short duration. Daily isoniazid can be used if there is intolerance or drug interactions with rifamycins. A TB specialist should be involved when there are questions regarding testing interpretation, selection of an appropriate treatment regimen, or management of adverse effects.

Performance of 4 methods for screening of latent tuberculosis infection in patients with chronic inflammatory arthritis under TNFα inhibitors: a 24-month prospective study

Background The reactivation rate of tuberculosis in patients with chronic inflammatory arthritis (CIA) on TNFα inhibitors (TNFi) and baseline negative screening for latent tuberculosis infection (LTBI) is higher than in the general population. Aim To compare the performance of tuberculin skin test (TST), TST-Booster, ELISPOT (T-SPOT.TB) and QuantiFERON-TB Gold in tube (QFT-IT) to detect LTBI in patients with CIA on TNFi. Patients and methods A total of 102 patients with CIA [rheumatoid arthritis (RA), n = 40; ankylosing spondylitis (AS), n = 35; psoriatic arthritis (PsA), n = 7; and juvenile idiopathic arthritis (JIA), n = 20] were prospectively followed-up for 24 months to identify incident LTBI cases. Epidemiologic data, TST, T-SPOT.TB, QFT-IT and a chest X-ray were performed at baseline and after 6 months of LTBI treatment. Results Thirty six percent (37/102) of patients had positive TST or Interferon Gamma Release Assays (IGRAs) tests. Agreement among TST and IGRAs was moderate (k = 0.475; p = 0.001), but high between T-SPOT.TB and QFT-IT (k = 0.785; p < 0.001). During the 24-Month follow-up, 15 (18.5%) incident cases of LTBI were identified. In comparison to TST, the IGRAs increased the LTBI diagnosis power in 8.5% (95% CI 3.16–17.49). TST-Booster did not add any value in patients with negative TST at baseline. After 6-Month isoniazid therapy, IGRAs results did not change significantly. Conclusions Almost 20% of CIA patients had some evidence of LTBI, suggesting higher conversion rate after exposition to TNFi. TST was effective in identifying new cases of LTBI, but IGRAs added diagnostic power in this scenario. Our findings did not support the repetition of IGRAs after 6-Month isoniazid therapy and this approach was effective to mitigate active TB in 2 years of follow-up.

646. Increasing Use of Interferon-Gamma Release Assay to Test for Pediatric Tuberculosis in a Low-Burden Setting

Background The American Academy of Pediatrics recommends tuberculin skin tests (TSTs) or interferon gamma release assays (IGRAs) to test for tuberculosis (TB) infection in children ≥2 years old, and prioritizes IGRA testing in Bacille Calmette-Guérin vaccine recipients due to cross-reactivity. TSTs require a return visit, which frequently results in loss to follow up. Growing evidence supports accuracy of IGRA testing in pediatric patients, including young children, leading to calls for preferential use of IGRA over TST. We sought to evaluate trends in IGRA use in children over time. Methods We identified all TB infection tests conducted in children 5-17 years old at 2 academic medical systems in Boston from October 2015–January 2021. TSTs were identified using medication administration records, and IGRAs were identified using laboratory records. We computed the proportion of tests per month that were IGRA and TST. We used Pearson correlation to determine the association between month of testing and proportion of tests that were IGRAs. Results 21,471 TB infection tests were obtained from 16,778 patients during our timeframe. Median age of testing was 13.4 years (IQR 9.2 – 16.2 years). During the study period, there was a significant increase in the monthly proportion of TB infection tests that were IGRAs (Pearson correlation coefficient 0.92, P &lt; 0.001). The total number of tests performed per month also increased, with seasonal increases in testing in late summer and early fall and a substantial decline in testing early in the COVID-19 pandemic. Tuberculosis infection tests and proportion IGRA. Total number of tuberculosis infection tests per month and proportion of tests that were interferon gamma release assays, from October 2015 - January 2021. Conclusion Use of IGRAs among patients age 5-17 years of age increased significantly overall and compared to TST in two large Boston healthcare systems over a 5-year period. These results suggest a shift towards blood-based TB infection testing in a low-burden setting, which may improve completion of the pediatric TB infection care cascade. Future research is needed to determine reasons for changing testing modalities, and similar patterns in other settings. Disclosures Gabriella S. Lamb, MD, MPH, Nothing to disclose

Practical Review of Diagnosis and Management of Cutaneous Tuberculosis in Indonesia

Tuberculosis is a life-threatening infectious disease that remains a high incidence worldwide. The classification of tuberculosis can be divided into two forms, i.e., pulmonary and extrapulmonary. The pathogenesis of tuberculosis depends on the cell-mediated immunity of the host. One of the variants of extrapulmonary tuberculosis is cutaneous tuberculosis, that commonly found in Indonesia. Based on the bacterial load, cutaneous tuberculosis is divided into two types, multibacillary and paucibacillary tuberculosis. Diagnosis of cutaneous tuberculosis often requires specific investigations, such as histopathology, Ziehl-Neelsen staining, Interferon-Gamma Release Assays, enzyme-linked immunosorbent assay serology, and Polymerase Chain Reaction. The treatment principle for cutaneous tuberculosis is the same as the treatment for pulmonary tuberculosis, which consists of an intensive and maintenance phase.

Elevated Rates of Indeterminate Results on QuantiFERON®-TB Gold Plus in COVID-19 Patients

Interferon-gamma release assays are used to screen various patient populations for latent tuberculosis infection. In this issue of the Journal of Clinical Microbiology, Ward et al. (J Clin Microbiol 59:e00811-21, 2021, https://doi.org/10.1128/JCM.00811-21 ) investigated an increased indeterminate rate in the QuantiFERON-TB Gold Plus assay among COVID-19 patients that was independent of immunosuppressive agents and lymphopenia. In their study, COVID-19 patients with indeterminate QuantiFERON-TB Gold Plus results trended toward decreased survival as well as increased serum IL-6 and IL-10 levels, though the differences were not statistically significant. They suggest that this pattern of cytokine expression supports an impairment of Th1, and specifically interferon-γ production, in critically ill COVID-19 patients, as indicated by indeterminate QuantiFERON-TB Gold Plus results. Clinicians should be aware of the increased rate of indeterminate QuantiFERON-TB Gold Plus results in critically ill COVID-19 patients.

Interferon Gamma Release Assays for Latent Mycobacterium tuberculosis Detection in Elderly Hispanics

SUMMARY Background. Aging is a tuberculosis comorbidity. Interferon Gamma Release Assays (IGRAs) are used to detect latent Mycobacterium tuberculosis (M.tb) infection (LTBI) in adults, but their performance in the elderly is not well established. We aim to evaluate the performance of IGRAs for LTBI detection in healthy elderly Hispanics with recent, remote or no history of M.tb exposure. Study Design and Methods. Cross sectional study in Hispanic elderly (60+y) and adult (18-50y) recent TB contacts (ReC) or community controls (CoC). LTBI was based on a positive T-SPOT.TB and/or QuantiFERON-Gold in-tube or Plus assay. Results. We enrolled 193 CoC (119 adults/74 elderly) and 459 ReC (361 adults/98 elderly). LTBI positivity increased with age in CoC (range 19-59%; trend p <0.001), but was similar in ReC (range 59-69%; trend p=0.329). The elderly had lower concordance between IGRAs (kappa 0.465 vs. 0.688 in adults) and more inconclusive results (indeterminate/borderline; 11.6% vs. 5.8% in adults; p=0.012). Exclusion of inconclusive results improved concordance between assays, notably in elderly ReC, who have the highest TB risk (from kappa 0.532 to 0.800). When both IGRAs were done simultaneously, inconclusive results were resolved in all cases as positive or negative with the other IGRA. The magnitude of the response to M.tb peptides used in the assays was similar between age groups, but responsiveness to mitogens was lower in the elderly. Conclusions. IGRAs are suitable for LTBI detection in the elderly. Discordant and inconclusive findings are more prevalent in the elderly, but results were resolved when performing different IGRAs simultaneously in the same participant.

Latent tuberculosis screening before kidney transplantation in the South of Brazil

Background: Tuberculosis (TB) is a prevalent infection after kidney transplantation (KT) in high-burden countries. Latent tuberculosis infection (LTBI) screening includes previous TB history, chest radiograph findings, and tuberculin test (TST) and/or interferon-gamma release assays (IGRAs) results. We aimed to compare our routine LTBI screening of KT candidates and living donors (LD) with their IGRA results, and evaluate if this would improve isoniazid (INH) treatment referral. Methods: We evaluated adult KT candidates and LD with complete routine LTBI screening and QuantiFERON-TB® Gold In-Tube (QFT) testing. Blood samples were collected from April 4th, 2014 to October 31st, 2018, with follow-up until October 31st, 2019. Results: There were 116 KT recipients, with 30% QFT-positive results. Positive QFT was associated with past TB history (p=0.007), positive TST (p<0.0001), residual radiographic lesions (p=0.003), and diabetes (p=0.035). There were 25 LD, 40% had positive QFT. Positive QFT was associated with a positive TST (p=0.002). Positive QFT results increased INH referral in 80%. Post-transplant TB incidence was 2.6% in a median follow-up of 2 (1-33) months. No variables were associated with post-transplant TB. TB patients had inferior, although non-significant, 5-year graft survival (66.7% vs. 76.5%) (p = 0.402). Conclusion: In the present study, the association of QFT to our routine LTBI screening incremented INH treatment referral, but there was still a high incidence of post-transplant TB, possibly related to other forms of infection, such as new exposure and donor transmission.