Newborn Screening for Severe Combined Immunodeficiency-A History of the TREC Assay

Infants born with T cell lymphopenias, especially severe combined immunodeficiency (SCID) are at risk for serious, often fatal infections without intervention within the first year or two of life. The majority of these disorders can be detected through the use of the T cell recombination excision circle assay (TREC assay.) The TREC assay detects the presence of non-replicating, episomal DNA that is formed during T cell development. This assay initially developed to measure thymic output during aging and HIV infection, has undergone modifications for the purpose of newborn screening (NBS) for SCID. To meet the requirements for inclusion on NBS panels, the assay needed to utilize blood from dried blood spots on NBS cards, and be both sensitive and specific, avoiding the costs of false positives. Currently, the assay relies upon real time, quantitative PCR (RT-qPCR) to detect TRECs in punches taken from dried blood spots. This review seeks to highlight some of the early work leading up to the initial implementation of the TREC assay for SCID detection, and the subsequent revisions made to optimize the assay

Abstract 16912: Angioplasty vs. primary nitinol stent implantation in above knee femoropopliteal occlusive atherosclerotic disease: a meta-analysis of randomized controlled trials

Background: The efficacy and safety of contemporary self-expanding bare metal Nitinol stents (NS) compared to primary Percutaneous Transluminal Angioplasty (PTA) in the treatment of above-knee femoropopliteal atherosclerotic disease is still controversial. Objective: We sought to evaluate the immediate (procedural success) and intermediate (rate of restenosis and target lesion/vessel revascularization (TLR/TVR) at 1 year) clinical outcomes of primary NS implantation versus primary PTA with bailout stenting in the treatment of above-knee femoropopliteal disease by conducting a meta-analysis of the available randomized controlled trials (RCT). Methods: We searched Medline and Cochrane databases from 1990 to 2014. Risk ratios (RR) and 95% confidence intervals (CI) were calculated using random-effects model. Results: Six RCTs with a total of 827 patients (NS = 443, PTA = 384; average age 68.5 years, males = 562, average lesion length = 8.7cm in NS and 7.7cm in PTA) were analyzed on intention to treat basis. The immediate procedural success rate was significantly better in the NS group (96% vs 75%; RR= 1.26; 95% CI, 1.15-1.38) as well as restenosis rate at 1 year (30.8% vs 51.2%; RR=1.63; 95% CI, 1.11-2.38) compared to primary PTA. TLR/TVR rates at 1 year were lower in the NS group (15.5% vs 28.1%; RR=1.77; 95% CI, 0.90-3.49), but the difference did not reach the statistical significance. Four patients in each group had amputations during follow-up. Two studies noticed a 3% and 12% incidence of stent fractures. Conclusions: While there is immediate clinical benefit of acute procedural success associated with primary Nitinol stent implantation as compared to PTA with bailout stenting in patients with femoropopliteal atherosclerotic disease, this salutary effect may be partially offset by statistically non-significant difference in incidence of target lesion revascularization at 1 year. Such a risk-benefit assessment should be carefully considered in all patients

Video_1_Comparative effectiveness of mRNA-1273 and BNT162b2 COVID-19 vaccines in immunocompromised individuals: a systematic review and meta-analysis using the GRADE framework.mp4

IntroductionDespite representing only 3% of the US population, immunocompromised (IC) individuals account for nearly half of the COVID-19 breakthrough hospitalizations. IC individuals generate a lower immune response after vaccination in general, and the US CDC recommended a third dose of either mRNA-1273 or BNT162b2 COVID-19 vaccines as part of their primary series. Influenza vaccine trials have shown that increasing dosage could improve effectiveness in IC populations. The objective of this systematic literature review and pairwise meta-analysis was to evaluate the clinical effectiveness of mRNA-1273 (50 or 100 mcg/dose) vs BNT162b2 (30 mcg/dose) in IC populations using the GRADE framework.MethodsThe systematic literature search was conducted in the World Health Organization COVID-19 Research Database. Studies were included in the pairwise meta-analysis if they reported comparisons of mRNA-1273 and BNT162b2 in IC individuals ≥18 years of age; outcomes of interest were symptomatic, laboratory-confirmed SARS-CoV-2 infection, SARS-CoV-2 infection, severe SARS-CoV-2 infection, hospitalization due to COVID-19, and mortality due to COVID-19. Risk ratios (RR) were pooled across studies using random-effects meta-analysis models. Outcomes were also analyzed in subgroups of patients with cancer, autoimmune disease, and solid organ transplant. Risk of bias was assessed using the Newcastle-Ottawa Scale for observational studies. Evidence was evaluated using the GRADE framework.ResultsOverall, 17 studies were included in the pairwise meta-analysis. Compared with BNT162b2, mRNA-1273 was associated with significantly reduced risk of SARS-CoV-2 infection (RR, 0.85 [95% CI, 0.75–0.97]; P=0.0151; I2 = 67.7%), severe SARS-CoV-2 infection (RR, 0.85 [95% CI, 0.77–0.93]; P=0.0009; I2 = 0%), COVID-19–associated hospitalization (RR, 0.88 [95% CI, 0.79–0.97]; P2 = 0%), and COVID-19–associated mortality (RR, 0.63 [95% CI, 0.44–0.90]; P=0.0119; I2 = 0%) in IC populations. Results were consistent across subgroups. Because of sample size limitations, relative effectiveness of COVID-19 mRNA vaccines in IC populations cannot be studied in randomized trials. Based on nonrandomized studies, evidence certainty among comparisons was type 3 (low) and 4 (very low), reflecting potential biases in observational studies.ConclusionThis GRADE meta-analysis based on a large number of consistent observational studies showed that the mRNA-1273 COVID-19 vaccine is associated with improved clinical effectiveness in IC populations compared with BNT162b2.</p

Table_3_Comparative effectiveness of mRNA-1273 and BNT162b2 COVID-19 vaccines in immunocompromised individuals: a systematic review and meta-analysis using the GRADE framework.docx

IntroductionDespite representing only 3% of the US population, immunocompromised (IC) individuals account for nearly half of the COVID-19 breakthrough hospitalizations. IC individuals generate a lower immune response after vaccination in general, and the US CDC recommended a third dose of either mRNA-1273 or BNT162b2 COVID-19 vaccines as part of their primary series. Influenza vaccine trials have shown that increasing dosage could improve effectiveness in IC populations. The objective of this systematic literature review and pairwise meta-analysis was to evaluate the clinical effectiveness of mRNA-1273 (50 or 100 mcg/dose) vs BNT162b2 (30 mcg/dose) in IC populations using the GRADE framework.MethodsThe systematic literature search was conducted in the World Health Organization COVID-19 Research Database. Studies were included in the pairwise meta-analysis if they reported comparisons of mRNA-1273 and BNT162b2 in IC individuals ≥18 years of age; outcomes of interest were symptomatic, laboratory-confirmed SARS-CoV-2 infection, SARS-CoV-2 infection, severe SARS-CoV-2 infection, hospitalization due to COVID-19, and mortality due to COVID-19. Risk ratios (RR) were pooled across studies using random-effects meta-analysis models. Outcomes were also analyzed in subgroups of patients with cancer, autoimmune disease, and solid organ transplant. Risk of bias was assessed using the Newcastle-Ottawa Scale for observational studies. Evidence was evaluated using the GRADE framework.ResultsOverall, 17 studies were included in the pairwise meta-analysis. Compared with BNT162b2, mRNA-1273 was associated with significantly reduced risk of SARS-CoV-2 infection (RR, 0.85 [95% CI, 0.75–0.97]; P=0.0151; I2 = 67.7%), severe SARS-CoV-2 infection (RR, 0.85 [95% CI, 0.77–0.93]; P=0.0009; I2 = 0%), COVID-19–associated hospitalization (RR, 0.88 [95% CI, 0.79–0.97]; P2 = 0%), and COVID-19–associated mortality (RR, 0.63 [95% CI, 0.44–0.90]; P=0.0119; I2 = 0%) in IC populations. Results were consistent across subgroups. Because of sample size limitations, relative effectiveness of COVID-19 mRNA vaccines in IC populations cannot be studied in randomized trials. Based on nonrandomized studies, evidence certainty among comparisons was type 3 (low) and 4 (very low), reflecting potential biases in observational studies.ConclusionThis GRADE meta-analysis based on a large number of consistent observational studies showed that the mRNA-1273 COVID-19 vaccine is associated with improved clinical effectiveness in IC populations compared with BNT162b2.</p

Table_2_Comparative effectiveness of mRNA-1273 and BNT162b2 COVID-19 vaccines in immunocompromised individuals: a systematic review and meta-analysis using the GRADE framework.docx

IntroductionDespite representing only 3% of the US population, immunocompromised (IC) individuals account for nearly half of the COVID-19 breakthrough hospitalizations. IC individuals generate a lower immune response after vaccination in general, and the US CDC recommended a third dose of either mRNA-1273 or BNT162b2 COVID-19 vaccines as part of their primary series. Influenza vaccine trials have shown that increasing dosage could improve effectiveness in IC populations. The objective of this systematic literature review and pairwise meta-analysis was to evaluate the clinical effectiveness of mRNA-1273 (50 or 100 mcg/dose) vs BNT162b2 (30 mcg/dose) in IC populations using the GRADE framework.MethodsThe systematic literature search was conducted in the World Health Organization COVID-19 Research Database. Studies were included in the pairwise meta-analysis if they reported comparisons of mRNA-1273 and BNT162b2 in IC individuals ≥18 years of age; outcomes of interest were symptomatic, laboratory-confirmed SARS-CoV-2 infection, SARS-CoV-2 infection, severe SARS-CoV-2 infection, hospitalization due to COVID-19, and mortality due to COVID-19. Risk ratios (RR) were pooled across studies using random-effects meta-analysis models. Outcomes were also analyzed in subgroups of patients with cancer, autoimmune disease, and solid organ transplant. Risk of bias was assessed using the Newcastle-Ottawa Scale for observational studies. Evidence was evaluated using the GRADE framework.ResultsOverall, 17 studies were included in the pairwise meta-analysis. Compared with BNT162b2, mRNA-1273 was associated with significantly reduced risk of SARS-CoV-2 infection (RR, 0.85 [95% CI, 0.75–0.97]; P=0.0151; I2 = 67.7%), severe SARS-CoV-2 infection (RR, 0.85 [95% CI, 0.77–0.93]; P=0.0009; I2 = 0%), COVID-19–associated hospitalization (RR, 0.88 [95% CI, 0.79–0.97]; P2 = 0%), and COVID-19–associated mortality (RR, 0.63 [95% CI, 0.44–0.90]; P=0.0119; I2 = 0%) in IC populations. Results were consistent across subgroups. Because of sample size limitations, relative effectiveness of COVID-19 mRNA vaccines in IC populations cannot be studied in randomized trials. Based on nonrandomized studies, evidence certainty among comparisons was type 3 (low) and 4 (very low), reflecting potential biases in observational studies.ConclusionThis GRADE meta-analysis based on a large number of consistent observational studies showed that the mRNA-1273 COVID-19 vaccine is associated with improved clinical effectiveness in IC populations compared with BNT162b2.</p

Rituximab and antimetabolite treatment of granulomatous and lymphocytic interstitial lung disease in common variable immunodeficiency

BACKGROUND: Granulomatous and lymphocytic interstitial lung disease (GLILD) is a life-threatening complication in patients with common variable immunodeficiency (CVID), but the optimal treatment is unknown. OBJECTIVE: Our aim was to determine whether rituximab with azathioprine or mycophenolate mofetil improves the high-resolution computed tomography (HRCT) chest scans and/or pulmonary function test results in patients with CVID and GLILD. METHODS: A retrospective chart review of clinical and laboratory data on 39 patients with CVID and GLILD who completed immunosuppressive therapy was performed. Chest HRCT scans, performed before therapy and after the conclusion of therapy, were blinded, randomized, and scored independently by 2 radiologists. Differences between pretreatment and posttreatment HRCT scan scores, pulmonary function test results, and lymphocyte subsets were analyzed. Whole exome sequencing was performed on all patients. RESULTS: Immunosuppressive therapy improved patients\u27 HRCT scan scores (P \u3c .0001), forced vital capacity (P = .0017), FEV1 (P = .037), and total lung capacity (P = .013) but not their lung carbon monoxide diffusion capacity (P = .12). Nine patients relapsed and 6 completed retreatment, with 5 of 6 of these patients (83%) having improved HRCT scan scores (P = .063). Relapse was associated with an increased number of B cells (P = .016) and activated CD4 T cells (P = .016). Four patients (10%) had pneumonia while undergoing active treatment, and 2 patients (5%) died after completion of therapy. Eight patients (21%) had a damaging mutation in a gene known to predispose (TNFRSF13B [n = 3]) or cause a CVID-like primary immunodeficiency (CTLA4 [n = 2], KMT2D [n = 2], or BIRC4 [n = 1]). Immunosuppression improved the HRCT scan scores in patients with (P = .0078) and without (P \u3c .0001) a damaging mutation. CONCLUSIONS: Immunosuppressive therapy improved the radiographic abnormalities and pulmonary function of patients with GLILD. A majority of patients had sustained remissions

Table_1_Comparative effectiveness of mRNA-1273 and BNT162b2 COVID-19 vaccines in immunocompromised individuals: a systematic review and meta-analysis using the GRADE framework.docx

IntroductionDespite representing only 3% of the US population, immunocompromised (IC) individuals account for nearly half of the COVID-19 breakthrough hospitalizations. IC individuals generate a lower immune response after vaccination in general, and the US CDC recommended a third dose of either mRNA-1273 or BNT162b2 COVID-19 vaccines as part of their primary series. Influenza vaccine trials have shown that increasing dosage could improve effectiveness in IC populations. The objective of this systematic literature review and pairwise meta-analysis was to evaluate the clinical effectiveness of mRNA-1273 (50 or 100 mcg/dose) vs BNT162b2 (30 mcg/dose) in IC populations using the GRADE framework.MethodsThe systematic literature search was conducted in the World Health Organization COVID-19 Research Database. Studies were included in the pairwise meta-analysis if they reported comparisons of mRNA-1273 and BNT162b2 in IC individuals ≥18 years of age; outcomes of interest were symptomatic, laboratory-confirmed SARS-CoV-2 infection, SARS-CoV-2 infection, severe SARS-CoV-2 infection, hospitalization due to COVID-19, and mortality due to COVID-19. Risk ratios (RR) were pooled across studies using random-effects meta-analysis models. Outcomes were also analyzed in subgroups of patients with cancer, autoimmune disease, and solid organ transplant. Risk of bias was assessed using the Newcastle-Ottawa Scale for observational studies. Evidence was evaluated using the GRADE framework.ResultsOverall, 17 studies were included in the pairwise meta-analysis. Compared with BNT162b2, mRNA-1273 was associated with significantly reduced risk of SARS-CoV-2 infection (RR, 0.85 [95% CI, 0.75–0.97]; P=0.0151; I2 = 67.7%), severe SARS-CoV-2 infection (RR, 0.85 [95% CI, 0.77–0.93]; P=0.0009; I2 = 0%), COVID-19–associated hospitalization (RR, 0.88 [95% CI, 0.79–0.97]; P2 = 0%), and COVID-19–associated mortality (RR, 0.63 [95% CI, 0.44–0.90]; P=0.0119; I2 = 0%) in IC populations. Results were consistent across subgroups. Because of sample size limitations, relative effectiveness of COVID-19 mRNA vaccines in IC populations cannot be studied in randomized trials. Based on nonrandomized studies, evidence certainty among comparisons was type 3 (low) and 4 (very low), reflecting potential biases in observational studies.ConclusionThis GRADE meta-analysis based on a large number of consistent observational studies showed that the mRNA-1273 COVID-19 vaccine is associated with improved clinical effectiveness in IC populations compared with BNT162b2.</p