Diabetes Management Based on the Phenotype and Stage of the Disease: An Expert Proposal from the AGORA Diabetes Collaborative Group.

Diabetes is a complex and rapidly growing disease with heterogeneous clinical presentations. Recent advances in molecular and genetic technologies have led to the identification of various subtypes of diabetes. These advancements offer the potential for a more precise, individualized approach to treatment, known as precision medicine. Recognizing high-risk phenotypes and intervening early and intensively is crucial. A staging system for type 1 diabetes has been proposed and accepted globally. In this article, we will explore the different methods for categorizing and classifying type 2 diabetes (T2D) based on clinical characteristics, progression patterns, risk of complications, and the use of molecular techniques for patient grouping. We, as a team of experts, will also present an easy-to-follow treatment plan and guidance for non-specialists, particularly primary care physicians, that integrates the classification and staging of diabetes. This will help ensure that the most suitable therapy is applied to the different types of T2D at each stage of the disease's progression.

Early Mediterranean-Based Nutritional Intervention Reduces the Rate of Gestational Diabetes in Overweight and Obese Pregnant Women: A Post-Hoc Analysis of the San Carlos Gestational Prevention Study.

Obesity is a risk factor for the development of gestational diabetes mellitus (GDM). However, the most optimal type of nutritional intervention to prevent GDM in high-risk women is not clearly defined. This study investigates if nutritional treatment based on the Mediterranean diet (MedDiet) before the 12th gestational week (GW) in women at high risk due to a body mass index (BMI) ≥ 25 kg/m2 reduces the rate of GDM and metabolic syndrome (MetS) at 3 years postpartum. We performed a post-hoc analysis of the San Carlos Gestational Prevention Study. A total of 735 women with BMI ≥ 25 kg/m2 were evaluated between 2015 and 2018, with 246 in the standard diet control group (CG) and 489 in the MedDiet intervention group (IG). The rate of GDM was significantly lower in IG compared to CG (25.1% vs. 31.7%), relative risk (95% confidence interval), and 0.89 (0.78-0.99); p = 0.037. Postnatal follow-up was completed by 141 women in CG (57%) and 312 women in IG (64%). At 3 years postpartum, we observed a reduction in the rates of impaired fasting glucose (IFG) (0.51 (0.28-0.92); p = 0.019), obesity (0.51 (0.28-0.92); p = 0.041), waist circumference (WC) ≥ 89.5 cm (0.54 (0.31-0.94); p = 0.022), and MetS (0.56 (0.33-0.94); p = 0.003). MedDiet reduces the rate of GDM and postpartum MetS in women with BMI) ≥ 25 kg/m2, suggesting that its implementation should be routinely recommended from the first GWs.

Genetics of inborn errors of immunity: Diagnostic strategies and new approaches to CNV detection.

BACKGROUND: Genetic diagnosis of inborn errors of immunity (IEI) is complex due to the large number of genes involved and their molecular features. Missense variants have been reported as the most common cause of IEI. However, the frequency of copy number variants (CNVs) may be underestimated since their detection requires specific quantitative techniques. At this point, the use of Next Generation Sequencing (NGS) is acquiring relevance. METHODS: In this article, we present our experience in the genetic diagnosis of IEI based on three diagnostic algorithms that allowed the detection of single nucleotide variants (SNVs) and CNVs. Following this approximation, 703 index cases were evaluated between 2014 and 2021. Sanger sequencing, MLPA, CGH array, breakpoint spanning PCR or a customized NGS-based multigene-targeted panel were performed. RESULTS: A genetic diagnosis was reached in 142 of the 703 index cases (20%), 19 of them presented deletions as causal variants. Deletions were also detected in 5 affected relatives and 16 healthy carriers during the family studies. Additionally, we compile, characterize and present all the CNVs detected by our diagnostic algorithms, representing the largest cohort of deletions related to IEI to date. Furthermore, three bioinformatic tools (LACONv, XHMM, VarSeq™) based on NGS data were evaluated. VarSeq™ was the most sensitive and specific bioinformatic tool; detecting 21/23 (91%) deletions located in captured regions. CONCLUSION: Based on our results, we propose a strategy to guide the molecular diagnosis that can be followed by expert and non-expert centres in the field of IEI.

Real-World Evidence of Off-Label Use of Commercially Automated Insulin Delivery Systems Compared to Multiple Daily Insulin Injections in Pregnancies Complicated by Type 1 Diabetes.

Aims: To compare glycemic control and maternal-fetal outcomes of women with type 1 diabetes (T1D) using hybrid closed loop (HCL) versus multiple daily insulin injections (MDI) plus continuous glucose monitoring. Methods: Multicenter prospective cohort study of pregnant women with T1D in Spain. We evaluated HbA1c and time spent within (TIR), below (TBR), and above (TAR) the pregnancy-specific glucose range of 3.5-7.8 mmol/L. Adjusted models were performed for adverse pregnancy outcomes, including baseline maternal characteristics and center. Results: One hundred twelve women were included (HCL n = 59). Women in the HCL group had a longer duration of diabetes and higher rates of prepregnancy care. There was no between-group difference in HbA1c in any trimester. However, in the second trimester, MDI users had a greater decrease in HbA1c (-6.12 ± 9.06 vs. -2.16 ± 7.42 mmol/mol, P = 0.031). No difference in TIR (3.5-7.8 mmol/L) and TAR was observed between HCL and MDI users, but with a higher total insulin dose in the second trimester [+0.13 IU/kg·day)]. HCL therapy was associated with increased maternal weight gain during pregnancy (ßadjusted = 3.20 kg, 95% confidence interval [CI] 0.90-5.50). Regarding neonatal outcomes, newborns of HCL users were more likely to have higher birthweight (ßadjusted = 279.0 g, 95% CI 39.5-518.5) and macrosomia (ORadjusted = 3.18, 95% CI 1.05-9.67) compared to MDI users. These associations disappeared when maternal weight gain or third trimester HbA1c was included in the models. Conclusions: In a real-world setting, HCL users gained more weight during pregnancy and had larger newborns than MDI users, while achieving similar glycemic control in terms of HbA1c and TIR.

Modifiable Risk Factors and Trends in Changes in Glucose Regulation during the First Three Years Postdelivery: The St Carlos Gestational Diabetes Mellitus Prevention Cohort.

OBJECTIVE: Evaluation of the influence of potential risk factors (RFs) on glycemic changes at 3 years postpartum. METHODS: The glycemic status of 1400 women, in absence of a new pregnancy, was evaluated at 3 months (3 m) and 3 years (3 y) postpartum, after participation in the St. Carlos Gestational Study (2228 normoglycemic pregnant women followed from before gestational week 12 to delivery, from 2015-2017). Abnormal glucose regulation (AGR) was defined as fasting serum glucose ≥ 100 mg/dL and/or HbA1c ≥ 5.7% and/or 2 h 75 g OGTT glucose ≥ 140 mg/dL. In total, 12 modifiable and 3 unmodifiable RFs were analyzed. RESULTS: 3 m postpartum, 110/1400 (7.9%) women had AGR; 3 y postpartum, 137 (9.8%) women exhibited AGR (110 with 3 m normal glucose tolerance [NGT]); 1263 (90.2%) had NGT (83 with 3 m AGR). More women with gestational diabetes mellitus (GDM) progressed to AGR at 3 y (OR: 1.60 [1.33-1.92]) than women without GDM. Yet, most women with 3 m and/or 3 y AGR had no GDM history. Having ≥2 unmodifiable RFs was associated with increased risk for progression to AGR (OR: 1.90 [1.28-2.83]) at 3 y postpartum. Having >5/12 modifiable RFs was associated with increased progression from NGT to AGR (OR: 1.40 [1.00-2.09]) and AGR persistence (OR: 2.57 [1.05-6.31]). Pregestational BMI ≥ 25 kg/m2 (OR: 0.59 [0.41-0.85]), postdelivery weight gain (OR: 0.53 [0.29-0.94]), and waist circumference > 89.5 cm (OR: 0.54 [0.36-0.79]) reduced the likelihood of NGT persisting at 3 y. CONCLUSIONS: 3-month and/or 3-year postpartum AGR can be detected if sought in women with no prior GDM. Modifiable and unmodifiable RF predictors of AGR at 3 y postpartum were identified. Universal screening for glycemic alterations should be considered in all women following delivery, regardless of prior GDM. These findings could be useful to design personalized strategies in women with risk factors for 3 y AGR.

The modulation of platelet function by growth hormone in growth hormone deficient Hypopituitary patients.

BACKGROUND: Growth hormone deficiency (GHD) has been implicated in increased cardiovascular and cerebrovascular disease risk seen in hypopituitarism, however the mechanism remains speculative. We hypothesise that platelet abnormalities may play a contributory role. Herein we examined platelet behaviour in GHD hypopituitary patients, pre- and post-growth hormone (GH) replacement. METHODS: This study utilizes a physiological flow-based assay to quantify platelet function in whole blood from patient cohorts under arterial shear. Thirteen GH Naïve hypopituitary adults with GHD and thirteen healthy matched controls were studied. Patients were assessed before and after GH treatment. All other pituitary replacements were optimised before the study. In addition to a full endocrine profile, whole blood was labelled and perfused over immobilised von Willibrand factor (vWF). Seven parameters of dynamic platelet-vWF interactions were recorded using digital image microscopy and analysed by customised platelet tracking software. RESULTS: We found a significantly altered profile of platelet-vWF interactions in GHD individuals compared to healthy controls. Specifically, we observed a marked increase in platelets shown to form associations such as tethering, rolling and adherence to immobilized vWF, which were reduced post GH treatment. Speed and distance platelets travelled across vWF was similar between controls and pre-therapy GHD patients, however, this was considerably increased post treatment. This may indicate reduced platelet signaling resulting in less stable adhesion of platelets post GH treatment. CONCLUSIONS: Taken together observed differences in platelet behaviour may contribute to an increased risk of thrombosis in GHD which can in part be reversed by GH therapy.

An Early Mediterranean-Based Nutritional Intervention during Pregnancy Reduces Metabolic Syndrome and Glucose Dysregulation Rates at 3 Years Postpartum.

A Mediterranean diet (MedDiet)-based intervention reduces the rate of immediate postpartum maternal metabolic disorders. Whether these effects persist long-term remains to be determined. A total of 2526 normoglycemic women were randomized before the 12th gestational week (GW). IG women followed a MedDiet with extra virgin olive oil (EVOO) (>40 mL/day) and a handful of nuts daily, whereas CG women had to restrict all kinds of dietary fat. At 3 months postpartum, a motivational lifestyle interview was held. The endpoint of the study evaluated the rate of abnormal glucose regulation (AGR) and metabolic syndrome (MetS) at 3 years postpartum in women of the San Carlos cohort. A total of 369/625 (59%) CG women and 1031/1603 (64.3%) IG women were finally analyzed. At 3 months and 3 years postdelivery, the IG women showed higher adherence to the MedDiet, which was associated with lower values of body mass index (BMI) and lipid and glycemic profiles. Body weight change and waist circumference were lower in the IG women. After applying multiple regression analysis, the ORs (95%CI) resulted in AGR (3.18 (2.48-4.08); p < 0.001)/MetS (3.79 (1.81-7.95); p = 0.001) for women with GDM and higher OR for development of MetS in CG women (3.73 (1.77-7.87); p = 0.001). A MedDiet-based intervention early in pregnancy demonstrated persistent beneficial effects on AGR and MetS rates at 3 years postpartum.

Treatment Guidelines for Hyponatremia: Stay the Course.

International guidelines designed to minimize the risk of complications that can occur when correcting severe hyponatremia have been widely accepted for a decade. On the basis of the results of a recent large retrospective study of patients hospitalized with hyponatremia, it has been suggested that hyponatremia guidelines have gone too far in limiting the rate of rise of the serum sodium concentration; the need for therapeutic caution and frequent monitoring of the serum sodium concentration has been questioned. These assertions are reminiscent of a controversy that began many years ago. After reviewing the history of that controversy, the evidence supporting the guidelines, and the validity of data challenging them, we conclude that current safeguards should not be abandoned. To do so would be akin to discarding your umbrella because you remained dry in a rainstorm. The authors of this review, who represent 20 medical centers in nine countries, have all contributed significantly to the literature on the subject. We urge clinicians to continue to treat severe hyponatremia cautiously and to wait for better evidence before adopting less stringent therapeutic limits.

The prevalence of primary and secondary hyperparathyroidism and its cardiometabolic implications in primary aldosteronism.

BACKGROUND: The aim of this study was to analyze the prevalence of primary and secondary hyperparathyroidism in patients with primary aldosteronism (PA), and its implication on cardiovascular and metabolic outcomes. METHODS: A retrospective study of patients with PA (exposed cohort, N.=44) and all hypertensive (EH) patients with adrenal lesions without PA nor other adrenal hypersecretion (non-exposed cohort, N.=41) on follow-up at our center between 2016 and 2020. RESULTS: The mean age of patients with PA and EH was 55.1±14.13 and 66.3±10.93 (P<0.001), and 50% of PA and 39.0% of EH were women (P=0.309). At diagnosis, the prevalence of primary hyperparathyroidism in PA was of 18.2%, and all were normocalcemic hyperparathyroidism cases. Globally, no differences were found in the prevalence of primary hyperparathyroidism compared to EH (18.2% vs. 29.3%, P=0.229), but hypercalcemic primary hyperparathyroidism was significantly more prevalent in EH patients than in PA (22.0% vs. 0%, P=0.001). There were 47.7% (N.=21) cases of secondary hyperparathyroidism in patients with PA (4 due to chronic kidney disease (CKD) and vitamin D deficiency, and 17 due to vitamin D deficiency alone). The cardiometabolic profile of patients with PA and hyperparathyroidism (N.=29) was similar to of those patients without hyperparathyroidism (N.=15) at diagnosis and after a median follow-up of 3.6 years (interquartile range 1.1-5.9). CONCLUSIONS: Although primary and secondary hyperparathyroidism are common in patients with PA, their prevalence was similar than the observed in EH patients. Primary hyperparathyroidism is usually mild in PA, appearing as normocalcemic forms. No negative implications of the hyperparathyroidism in the cardiometabolic profile of PA were observed.

Detection of specific RBD+ IgG+ memory B cells by flow cytometry in healthcare workers and patients with inborn errors of immunity after BNT162b2 m RNA COVID-19 vaccination.

Introduction: Inborn errors of immunity (IEI) are a heterogeneous group of diseases caused by intrinsic defects of the immune system. Estimating the immune competence of immunocompromised patients for an infection risk assessment or after SARS-CoV-2 vaccination constituted a challenge. Methods: The aim of this study was to determine the humoral responses of patients with IEI through a comprehensive analysis of specific receptor-binding domain-positive (RBD+) IgG+ memory B cells (MBCs) by flow cytometry, together with routine S-specific IgG antibodies and QuantiFERON SARS-CoV-2 (T-cell response), before the vaccine and 3 weeks after a second dose. Results and discussion: We first analyzed the percentage of specific RBD+ IgG+ MBCs in healthy healthcare workers. Within the control group, there was an increase in the percentage of specific IgG+ RBD+ MBCs 21 days after the second dose, which was consistent with S-specific IgG antibodies.Thirty-one patients with IEI were included for the pre- and post-vaccination study; IgG+ RBD+ MBCs were not evaluated in 6 patients due to an absence of B cells in peripheral blood. We detected various patterns among the patients with IEI with circulating B cells (25, 81%): an adequate humoral response was observed in 12/25, consider by the detection of positive S-specific IgG antibodies and the presence of specific IgG+ RBD+ MBCs, presenting a positive T-cell response; in 4/25, very low S-specific IgG antibody counts correlated with undetectable events in the IgG+ RBD+ MBC compartment but with positive cellular response. Despite the presence of S-specific IgG antibodies, we were unable to detect a relevant percentage of IgG+ RBD+ MBCs in 5/25; however, all presented positive T-cell response. Lastly, we observed a profound failure of B and T-cell response in 3 (10%) patients with IEI, with no assessment of S-specific IgG antibodies, IgG+ RBD+ MBCs, and negative cellular response. The identification of specific IgG+ RBD+ MBCs by flow cytometry provides information on different humoral immune response outcomes in patients with IEI and aids the assessment of immune competence status after SARS-CoV-2 mRNA vaccine (BNT162b2), together with S-specific IgG antibodies and T-cell responses.

Stress decreases spermatozoa quality and induces molecular alterations in zebrafish progeny.

BACKGROUND: Chronic stress can produce a severe negative impact on health not only in the exposed individuals but also in their offspring. Indeed, chronic stress may be contributing to the current worldwide scenario of increasing infertility and decreasing gamete quality in human populations. Here, we evaluate the effect of chronic stress on behavior and male reproductive parameters in zebrafish. Our goal is to provide information on the impact that chronic stress has at molecular, histological, and physiological level in a vertebrate model species. RESULTS: We evaluated the effects of a 21-day chronic stress protocol covering around three full waves of spermatogenesis in Danio rerio adult males. The induction of chronic stress produced anxiety-like behavior in stressed males as assessed by a novel tank test. At a molecular level, the induction of chronic stress consistently resulted in the overexpression of two genes related to endoplasmic reticulum (ER) stress in the brain. Gene set enrichment analysis (GSEA) of testes suggested a dysregulation of the nonsense-mediated decay (NMD) pathway, which was also confirmed on qPCR analysis. Histological analysis of the testicle did not show significant differences in terms of the relative proportions of each germ-cell type; however, the quality of sperm from stressed males was compromised in terms of motility. RNA-seq analysis in stress-derived larval progenies revealed molecular alterations, including those predicted to affect translation initiation, DNA repair, cell cycle control, and response to stress. CONCLUSIONS: Induction of chronic stress during a few cycles of spermatogenesis in the vertebrate zebrafish model affects behavior, gonadal gene expression, final gamete quality, and progeny. The NMD surveillance pathway (a key cellular mechanism that regulates the stability of both normal and mutant transcripts) is severely affected in the testes by chronic stress and therefore the control and regulation of RNAs during spermatogenesis may be affected altering the molecular status in the progeny.

Efficacy, Safety, and Satisfaction with the Accu-Chek Insight with Diabeloop Closed-Loop System in Subjects with Type 1 Diabetes: A Multicenter Real-World Study.

Aim: To evaluate the efficacy, safety and satisfaction of the closed-loop system Accu-Chek® Insight with Diabeloop™ (DBLG1™) in adults with type 1 diabetes (T1D) in real-world conditions. Methods: Patients with T1D using DBLG1 for at least 3 months were included. Glucometric parameters were analyzed at baseline, 1, 2, and 3 months after starting DBLG1. HbA1c was measured before and at 3 months. Technical issues and acute complications were recorded and patients completed a satisfaction questionnaire. Results: Sixty-two patients were included (43 women; age 44.2 ± 11 years; diabetes duration 24.6 ± 12 years; 40 used flash and 22 continuous glucose monitoring (CGM); 45 were on insulin pump and 17 on multiple daily injections). A significant improvement was observed in the CGM-derived glucose metrics early in the first month: Time in range (%TIR) 70-180 mg/dL (54.86 ± 17 vs. 72.23 ± 10.11); time above range level 1 (%TAR1) 180-250 mg/dL (26.26 ± 13.3 vs. 19.48 ± 6.78), time above range level 2 (%TAR2) > 250 mg/dL (12.02 ± 13.09 vs. 6.14 ± 5.23), time below range level 1 (%TBR 1) 54-70 mg/dL (5.73 ± 11.5 vs. 1.67 ± 1.3), time below range level 2 (%TBR2) < 54 mg/dL (1.18 ± 1.97 vs.0.44 ± 0.49), %CV (38.66 ± 7.53 vs. 29.63 ± 3.74), median glucose (168.57 ± 36 mg/dL vs. 154.63 ± 17.55 mg/dL), and %GMI (7.37 ± 0.91 vs. 7.02 ± 0.42). Also, HbA1c decreased significantly (7.45% ± 1.05% vs. 6.95% ± 0.7%). No acute complications or serious adverse events occurred. Similar improvement was observed regardless of prior therapy or the glucose monitoring system used. Three patients discontinued DBLG1 and 21 experienced technical issues. Overall, patient satisfaction was high. Adjustments of the settings were modified in general in the direction of greater aggressiveness. Conclusions: A significant improvement in glycemic control without serious adverse events and a high degree of patient satisfaction were observed in this first real-world study evaluating the closed-loop system, Accu-Chek Insight with Diabeloop.

Changes in Serum Creatinine Levels Can Help Distinguish Hypovolemic from Euvolemic Hyponatremia.

Background and Objectives: Differentiating between hypovolemic (HH) and euvolemic hyponatremia (EH) is crucial for correct diagnosis and therapy, but can be a challenge. We aim to ascertain whether changes in serum creatinine (SC) can be helpful in distinguishing HH from EH. Materials and Methods: Retrospective analysis of patients followed in a monographic hyponatremia outpatient clinic of a tertiary hospital during 1 January 2014−30 November 2019. SC changes during HH and EH from eunatremia were studied. The diagnostic accuracy of the SC change from eunatremia to hyponatremia (∆SC) was analyzed. Results: A total of 122 hyponatremic patients, median age 79 years (70−85), 46.7% women. In total, 70/122 patients had EH, 52/122 HH. During hyponatremia, median SC levels increased in the HH group: +0.18 mg/dL [0.09−0.39, p < 0.001], but decreased in the EH group: −0.07 mg/dL (−0.15−0.02, p < 0.001), as compared to SC in eunatremia. HH subjects presented a higher rate of a positive ∆SC than EH (90.4% vs. 25.7%, p < 0.001). EH subjects presented a higher rate of a negative/null ∆SC than HH (74.3% vs. 9.6%, p < 0.001). ROC curve analysis found an AUC of 0.908 (95%CI: 0.853 to 0.962, p < 0.001) for ∆SC%. A ∆SC% ≥ 10% had an OR of 29.0 (95%CI: 10.3 to 81.7, p < 0.001) for HH. A ∆SC% ≤ 3% had an OR of 68.3 (95%CI: 13.0 to 262.2, p < 0.001) for EH. Conclusions: The assessment of SC changes from eunatremia to hyponatremia can be useful in distinguishing between HH and EH.

Easy approach to detect cell immunity to COVID vaccines in common variable immunodeficiency patients.

BACKGROUND: Patients with primary antibody deficiencies, such as Common Variable Immunodeficiency (CVID), have some problems to assess immune response after coronavirus disease (COVID) vaccination. Cutaneous delayed-type hypersensitivity (DTH) has the potential to be used as a useful, simple, and cheaper tool to assess T-cell (T lymphocyte) function. METHODS: Seventeen patients with CVID, a rare disease, received two doses of the mRNA-based Pfizer-BioNTech COVID-19 vaccine. Humoral Immune Response (HIR) was determined by measuring specific immunoglobulin G (IgG) antibodies, and Cellular Immune Response (CIR) was evaluated using an ex vivo interferon-gamma release assay (IGRA) and in vivo by DTH skin test. RESULTS: Two weeks after the second dose of the vaccine, 12 out of 17 CVID patients have high optical density (OD) ratios of specific anti-spike protein (S) IgG whereas five patients were negative or low. Ex vivo CIR was considered positive in 14 out of 17 S1-stimulated patients. Unspecific stimulation was positive in all 17 patients showing no T-cell defect. A positive DTH skin test was observed in 16 CVID patients. The only patient with negative DTH also had negative ex vivo CIR. CONCLUSIONS: The use of DTH to evaluate CIR was validated with an optimal correlation with the ex vivo CIR. The CIR after vaccination in patients with antibody deficiencies seems to have high precision and more sensitivity to antibodies-based methods in CVID. CLINICAL IMPLICATIONS: There is a remarkable correlation between cutaneous DTH and ex vivo IGRA after COVID vaccination. A COVID-specific skin DTH test could be implemented in large populations. CAPSULE SUMMARY: Cutaneous delayed-type hypersensitivity has the potential to be used as a useful, simple, and cheaper tool to assess T-cell functioning.

Easy approach to detect cell immunity to COVID vaccines in common variable immunodeficiency patients

Background Patients with primary antibody deficiencies, such as Common Variable Immunodeficiency (CVID), have some problems to assess immune response after coronavirus disease (COVID) vaccination. Cutaneous delayed-type hypersensitivity (DTH) has the potential to be used as a useful, simple, and cheaper tool to assess T-cell (T lymphocyte) function.Methods Seventeen patients with CVID, a rare disease, received two doses of the mRNA-based Pfizer-BioNTech COVID-19 vaccine. Humoral Immune Response (HIR) was determined by measuring specific immunoglobulin G (IgG) antibodies, and Cellular Immune Response (CIR) was evaluated using an ex vivo interferon-gamma release assay (IGRA) and in vivo by DTH skin test.Results Two weeks after the second dose of the vaccine, 12 out of 17 CVID patients have high optical density (OD) ratios of specific anti-spike protein (S) IgG whereas five patients were negative or low. Ex vivo CIR was considered positive in 14 out of 17 S1-stimulated patients. Unspecific stimulation was positive in all 17 patients showing no T-cell defect. A positive DTH skin test was observed in 16 CVID patients. The only patient with negative DTH also had negative ex vivo CIR.Conclusions The use of DTH to evaluate CIR was validated with an optimal correlation with the ex vivo CIR. The CIR after vaccination in patients with antibody deficiencies seems to have high precision and more sensitivity to antibodies-based methods in CVID.Clinical Implications There is a remarkable correlation between cutaneous DTH and ex vivo IGRA after COVID vaccination. A COVID-specific skin DTH test could be implemented in large populations.Capsule Summary Cutaneous delayed-type hypersensitivity has the potential to be used as a useful, simple, and cheaper tool to assess T-cell functioning (AU)