Correlation of the two most frequent HLA haplotypes in the Italian population to the differential regional incidence of Covid-19.

BACKGROUND: Understanding how HLA polymorphisms may affect both susceptibility, course and severity of Covid-19 infection could help both at the clinical level to identify individuals at higher risk from the disease and at the epidemiological one to explain the differences in the epidemic trend among countries or even within a specific country. Covid-19 disease in Italy showed a peculiar geographical distribution from the northern most affected regions to the southern ones only slightly touched. METHODS: In this study we analysed the regional frequencies for the most common Italian haplotypes from the Italian Bone Marrow Donor Registry (HLA-A, -B, -C and -DRB1 at four-digit level). Then we performed Pearson correlation analyses among regional haplotypes estimated frequency in the population and Covid-19 incidence and mortality. RESULTS: In this study we found that the two most frequent HLA haplotypes in the Italian population, HLA-A*:01:01g-B*08:01 g-C*07:01g-DRB1*03:01g and HLA-A*02.01g-B*18.01g-C*07.01g-DRB1*11.04g, had a regional distribution overlapping that of Covid-19 and showed respectively a positive (suggestive of susceptibility) and negative (suggestive of protection) significant correlation with both Covid-19 incidence and mortality. CONCLUSIONS: Based on these results, in order to define such HLA haplotypes as a factor effectively associated to the disease susceptibility, the creation of national networks that can collect patients' samples from all regions for HLA typing should be highly encouraged.

Unrelated donor vs HLA-haploidentical α/ß T-cell- and B-cell-depleted HSCT in children with acute leukemia.

Traditionally, hematopoietic stem cell transplantation (HSCT) from both HLA-matched related and unrelated donors (UD) has been used for treating children with acute leukemia (AL) in need of an allograft. Recently, HLA-haploidentical HSCT after αß T-cell/B-cell depletion (αßhaplo-HSCT) was shown to be effective in single-center studies. Here, we report the first multicenter retrospective analysis of 127 matched UD (MUD), 118 mismatched UD (MMUD), and 98 αßhaplo-HSCT recipients, transplanted between 2010 and 2015, in 13 Italian centers. All these AL children were transplanted in morphological remission after a myeloablative conditioning regimen. Graft failure occurred in 2% each of UD-HSCT and αßhaplo-HSCT groups. In MUD vs MMUD-HSCT recipients, the cumulative incidence of grade II to IV and grade III to IV acute graft-versus-host disease (GVHD) was 35% vs 44% and 6% vs 18%, respectively, compared with 16% and 0% in αßhaplo-HSCT recipients (P < .001). Children treated with αßhaplo-HSCT also had a significantly lower incidence of overall and extensive chronic GVHD (P < .01). Eight (6%) MUD, 32 (28%) MMUD, and 9 (9%) αßhaplo-HSCT patients died of transplant-related complications. With a median follow-up of 3.3 years, the 5-year probability of leukemia-free survival in the 3 groups was 67%, 55%, and 62%, respectively. In the 3 groups, chronic GVHD-free/relapse-free (GRFS) probability of survival was 61%, 34%, and 58%, respectively (P < .001). When compared with patients given MMUD-HSCT, αßhaplo-HSCT recipients had a lower cumulative incidence of nonrelapse mortality and a better GRFS (P < .001). These data indicate that αßhaplo-HSCT is a suitable therapeutic option for children with AL in need of transplantation, especially when an allele-matched UD is not available.

The Rome Transplant Network model compared to the Italian Bone Marrow Donor Registry activity for unrelated donor search process and transplant efficiency for hematologic malignancy.

BACKGROUND: From 2011 to 2014, a total of 71% of the 3834 patients with hematologic malignancies successfully identified a matched unrelated donor (MUD) through the Italian Bone Marrow Donor Registry (IBMDR), corresponding to a transplant efficiency of 62%. STUDY DESIGN AND METHODS: From 2006, the Rome Transplant Network (RTN) followed a hierarchical selection strategy for the alternative donor search: first MUD, second cord blood, and third haploidentical donor. Using a low-resolution HLA, a preliminary query (PQ) was performed in all cases with assignment of good or poor score if more or less than 10 MUDs were identified in Bone Marrow Donors Worldwide. Herein we assessed the utility of PQ and of high-resolution (HR) HLA from the start of the search. Moreover, we compared the donor identification and the transplant efficiency between IBMDR and RTN. RESULTS: At RTN 79% of 417 patients met a good PQ with a 50% MUD identification versus 12.5% with poor PQ. Our policy led to 78 and 74% of alternative donor identification and transplant efficiency, respectively, higher than IBMDR data equal to 71% (p = 0.007) and 62% (p < 0.0001). The timing for donor identification was significantly reduced using HR HLA at the start of the search from 88 to 66 days at IBMDR (p < 0.001) and from 61 to 41 days at RTN (p < 0.001). CONCLUSIONS: Both PQ and HR HLA at the start of the process represents a useful tool to address the search towards the best and timely donor choice. Moreover, establishing a specific donor policy significantly improves the transplant efficiency.

PLI: a web-based tool for the comparison of protein-ligand interactions observed on PDB structures.

MOTIVATION: A large fraction of the entries contained in the Protein Data Bank describe proteins in complex with low molecular weight molecules such as physiological compounds or synthetic drugs. In many cases, the same molecule is found in distinct protein-ligand complexes. There is an increasing interest in Medicinal Chemistry in comparing protein binding sites to get insight on interactions that modulate the binding specificity, as this structural information can be correlated with other experimental data of biochemical or physiological nature and may help in rational drug design. RESULTS: The web service protein-ligand interaction presented here provides a tool to analyse and compare the binding pockets of homologous proteins in complex with a selected ligand. The information is deduced from protein-ligand complexes present in the Protein Data Bank and stored in the underlying database. AVAILABILITY: Freely accessible at http://bioinformatics.istge.it/pli/.

Strong humoral response after Covid-19 vaccination correlates with the common HLA allele A*03:01 and protection from breakthrough infection.

Few data exist on the role of genetic factors involving the HLA system on response to Covid-19 vaccines. Moving from suggestions of a previous study investigating the association of some HLA alleles with humoral response to BNT162b2, we here compared the HLA allele frequencies among weak (n = 111) and strong (n = 123) responders, defined as those healthcare workers with the lowest and the highest anti-Spike antibody levels after vaccination. Individuals with clinical history of Covid-19 or positive anti-nucleocapside antibodies were excluded. We found the common HLA-A*03:01 allele as an independent predictor of strong humoral response (OR = 12.46, 95% CI: 4.41-35.21, p < 0.0001), together with younger age of vaccines (p = 0.004). Correlation between antibody levels and protection from breakthrough infection has been observed, with a 2-year cumulative incidence of 42% and 63% among strong and weak responders, respectively (p = 0.03). Due to the high frequency of HLA-A*03:01 and the need for seasonal vaccinations against SARS-CoV-2 mutants, our findings provide useful information about the inter-individual differences observed in humoral response after Covid-19 vaccine and might support further studies on the next seasonal vaccines.

Polymorphism of the HLA system and weak antibody response to BNT162b2 mRNA vaccine.

The polymorphism of the HLA system has been extensively studied in COVID-19 infection, however there are no data about the role of HLA on vaccine response. We report here the HLA-A, -B, -C, and DRB1 allelic frequencies of n = 111 individuals after BNT162b2 mRNA vaccine, selected on the basis of lower antibody levels (<5% percentile) after the second dose among a total of n = 2569 vaccinees, and compare them with the frequencies of a reference population. We found that differences in the frequencies of the alleles HLA-A*03:01, A*33:03, B*58:01 and at least one haplotype (HLA-A*24:02~C*07:01~B*18:01~DRB1*11:04) are associated with a weaker antibody response after vaccination, together with the age of vaccinees. Our results might suggest a role played by some HLA alleles or haplotypes in antibody production after the BNT162b2 mRNA vaccine, giving insights into the tracking of potentially susceptible individuals across populations. Further studies are needed to better define our exploratory findings and dissect the role of HLA polymorphism on response to anti-COVID-19 vaccines.

CKD awareness and blood pressure control in the primary care hypertensive population.

BACKGROUND: Chronic kidney disease (CKD) is associated with poor renal and cardiovascular outcomes, and early identification largely depends on general practitioners' (GPs') awareness of it. To date, no study has evaluated CKD prevalence in patients with hypertension in primary care. STUDY DESIGN: Cross-sectional evaluation of the Italian GPs' database. SETTING & PARTICIPANTS: 39,525 patients with hypertension representative of the Italian hypertensive population followed up by GPs in 2005. FACTOR: Estimated glomerular filtration rate (eGFR); eGFR <60 mL/min/1.73 m² was defined as CKD. OUTCOMES: GPs' awareness of CKD assessed using International Classification of Diseases, Ninth Revision, Clinical Modification diagnostic codes for CKD, and blood pressure (BP) control. MEASUREMENTS: Data concerning serum creatinine levels, BPs, and antihypertensive medications were obtained for each patient from the GPs' database; eGFR was calculated according to the 4-variable Modification of Diet in Renal Disease (MDRD) Study equation. RESULTS: CKD prevalence was 23%, but kidney disease was diagnosed by GPs in only 3.9% of patients. BP control was inadequate in patients with CKD and those with eGFR >60 mL/min/1.73 m², with only 44% of patients reaching a BP target <140/90 mm Hg and 11% achieving <130/80 mm Hg. Patients with eGFR <60 mL/min/1.73 m² whose GPs were aware of CKD were more likely to reach recommended BP target values (OR, 1.35; 95% CI, 1.15-1.59; P < 0.001). LIMITATIONS: The prevalence of decreased eGFR may be overestimated because of the lack of creatinine calibration. Proteinuria data were not available. CONCLUSIONS: Awareness of CKD by GPs is critical for achieving the recommended guideline BP targets. However, awareness of CKD by GPs is still far too low, highlighting the need to systematically adopt eGFR for more accurate identification of CKD in high-risk populations.

Is left ventricular hypertrophy a powerful predictor of progression to dialysis in chronic kidney disease?

BACKGROUND: The role of cardiovascular factors in predicting renal outcome has not been extensively elucidated. Herein, we report a prospective evaluation of the impact of left ventricular hypertrophy (LVH) on outcome in non-diabetic patients with chronic kidney disease (CKD). METHODS: We studied 144 patients (99 men; age 62±14 years) with stage 3-4 CKD, with baseline assessment of left ventricular mass index (LVMi) by echocardiography, estimated glomerular filtration rate (eGFR) by MDRD equation, 24-h blood pressure profile and 24-h proteinuria. Combined end point was progression to ESRD requiring dialysis, or death within 5 years. RESULTS: Forty-nine patients (34%) progressed to dialysis, 24 (17%) died, 57 (39%) were dialysis-free after 5 years and 14 were lost to follow-up. Multivariate Cox proportional hazards analysis showed that increased LVMi (HR 1.28, 95% CI 1.17-1.40 for each 10-g/m2 increase, P<0.0001) and reduced eGFR (5% risk increase for each 1-mL/min reduction, P=0.027) were the significant predictors of the combined end point in stage 3 CKD patients, whereas LVMi proved to be the only significant predictor of the combined end point in patients with stage 4 CKD (HR 1.19, 95% CI 1.09-1.31, P<0.0001). The same analysis showed that LVMi was the only significant predictor of progression to dialysis in stage 3 CKD patients (HR 1.42, 95% CI 1.23-1.64 for each 10-g/m2 increase, P<0.0001), while a 20% increase in the risk of progression to ESRD was observed for each 10-g/m2 increase in LVMi (P<0.0001), and a 10% increase for each 1-mL/min reduction in eGFR (P=0.046) in patients with stage 4 CKD. When evaluating the predictive role of LVMi on outcome using AUC-ROC curves, the overall performance of the model including LVMi (AUC 0.877, 95% CI 0.8-0.954) was superior to the model including eGFR (AUC 0.737, 95% CI 0.656-0.817) for the end point of progression to dialysis (P=0.026, Hanley test). CONCLUSIONS: LVH proved to be the strongest predictor of the risk of progression to dialysis in non-diabetic CKD, especially among patients with less advanced renal dysfunction. Regardless of whether it is a simple marker or a pathogenetic factor, LVH encompasses all factors possibly affecting renal and general outcome in CKD patients.

Soluble HLA-G molecule in patients with perennial allergic rhinitis.

BACKGROUND: Allergic rhinitis (AR) is characterized by T helper 2 polarized immune response. The soluble HLA-G (sHLA-G) molecule has an immunomodulatory activity. However, so far, no study has investigated this activity in perennial AR (PAR). OBJECTIVE: The aim of this study was to evaluate serum sHLA-G levels in PAR patients and in a group of healthy controls. METHODS: Twenty-five PAR patients were enrolled. A group of 50 healthy non-allergic subjects was considered as control. sHLA-G serum levels were determined by immunoenzymatic method. RESULTS: Allergic patients had significantly higher levels of the sHLA-G (p < 0.001) molecule than normal controls. Moreover, there was a very strong correlation between sHLA-G and symptom severity and drug use (r = 0.85 and 0.793, respectively). CONCLUSION: The present study provides first evidence that serum sHLA-G levels are significantly increased in PAR patients. Moreover, sHLA-G might be considered as a biomarker for assessing clinical severity.

Chronic kidney disease and cardiovascular risk in hypertensive type 2 diabetics: a primary care perspective.

BACKGROUND: Chronic kidney disease (CKD) is associated with poor renal and cardiovascular (CV) outcome, and early identification largely depends on the general practitioners' (GPs) awareness of it. Only a few studies have evaluated the prevalence of CKD in type 2 diabetes in primary care, and no studies are available on hypertensive diabetics. Thus, the aim of this study was to assess the prevalence of CKD and its association with CV morbidity in such a population. METHODS: On the basis of an Italian national project involving GPs and nephrologists, we retrieved demographic, laboratory and clinical data regarding 7582 hypertensive type 2 diabetics (3564 men; age 25-89 years) who were selected using the diagnostic code Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) for diabetes and hypertension. Blood pressure (BP) values, serum creatinine, ECG-diagnosed left ventricular hypertrophy (LVH) and the occurrence of previous major CV events were obtained for each patient from the GPs' Health Search Database. Estimated glomerular filtration rate (GFR) was calculated according to the four-variable MDRD equation. CKD was defined as an estimated GFR < 60 mL/min/ 1.73 m2. RESULTS: CKD prevalence was 26%, although renal disease was diagnosed by GPs in only 5.4% of cases. The prevalence of both LVH and major CV events was 8%. Adequate BP control was only achieved in 10.4% of patients. Patients whose GFR was <60 mL/min/1.73 m2 were older, prevalently female, had increased pulse pressure and higher prevalence of dyslipidaemia. Moreover, the prevalence of both LVH and major CV events was higher in patients with CKD as compared to patients with normal GFR. Multivariate logistic regression analysis showed that patients with CKD had a higher risk of LVH and/or CV events adjusted for eight covariates, and this risk increased by 23% with each 21 mL/min/1.73 m2 decrease in GFR. CONCLUSIONS: This study shows that CKD is highly prevalent in hypertensive type 2 diabetic patients, where it is a strong predictor of CV adverse outcome. However, awareness of CKD by GPs is low. Equations for calculating estimated GFR should be included in the GPs' database in order to detect the presence of CKD and to improve CV outcome of such a high-risk population.

V.A.S. in the follow-up of turbinectomy.

BACKGROUND: Nasal airflow resistance, as measured by rhinomanometry, is frequently impaired in allergic rhinitis (AR). However, rhinomanometry is not widely available. Visual analogue scales (VAS) have been proposed to assess symptom severity in AR. AIM OF THE STUDY: To verify the suitability of the use of the VAS as a surrogate for rhinomanometry in patients with persistent allergic rhinitis and treated with turbinectomy in quantifying nasal obstruction during the follow-up. METHODS: Fifty patients (27 males, mean age 23 years, SD 2.24) were studied. VAS for nasal obstruction and rhinomanometry were performed in all patients before turbinectomy and after 6 months. RESULTS: A significant correlation was observed between VAS for nasal obstruction and nasal airflow resistance (Spearman r = 0.879, p < 0.001) at baseline. Moreover, a significant direct relationship between these two variables was observed (r = 0.567, p < 0.001) also at the follow-up after surgery. CONCLUSION: The use of VAS for assessing the nasal obstruction appears as clinically relevant, in that it allows with good reliability to quantify this symptom in the absence of rhinomanometry in the follow-up of patients treated with turbinectomy.

Visual analog scale (VAS) and nasal obstruction in persistent allergic rhinitis.

OBJECTIVE: Nasal airflow resistance, as measured by rhinomanometry, is frequently impaired in allergic rhinitis (AR). However, rhinomanometry is scarcely available. The aim of this study was to verify the suitability of the use of visual analog scales (VAS) as a surrogate for rhinomanometry in quantifying nasal obstruction in patients with persistent allergic rhinitis. STUDY DESIGN: Prospective study on patients with allergic rhinitis. SETTING: ENT clinic. SUBJECTS AND METHODS: Fifty patients (27 males, mean age 23 years, SD 2.24) were studied. VAS for nasal obstruction and other AR symptoms and rhinomanometry were performed in all patients. RESULTS: A significant, very strong correlation has been observed between VAS for nasal obstruction and nasal airflow resistance (Spearman r = 0.879, P < 0.001). Moreover, a significant correlation exists between VAS for rhinorrhea and resistance (Spearman r = 0.313, P = 0.027). CONCLUSION: The use of VAS for assessing the nasal obstruction appears clinically relevant in that it allows, with good reliability, the quantification of this symptom in the absence of rhinomanometry.

Soluble serum HLA-G and HLA-A, -B, -C molecules in patients with seasonal allergic rhinitis exposed to pollens.

BACKGROUND: Allergic rhinitis (AR) is characterized by a Th2 polarized immune response and soluble HLA (sHLA) molecules play an immunomodulatory role in this response. Previously, it has been reported that these molecules are increased in sera of patients with pollen-induced allergic rhinitis studied outside the pollen season. To date, however, no study has investigated there in AR patients during the pollen season. OBJECTIVE: The aim of this study was to evaluate serum sHLA-G and sHLA-A, -B, -C levels in both AR patients and healthy controls. METHODS: 60 symptomatic allergic patients were enrolled. A group of 50 healthy subjects was included as a control. Serum sHLA-G and sHLA-A, -B, -C levels were determined by an immunoenzymatic method. Allergy severity was assessed by VAS for symptoms and drug use. RESULTS: Allergic patients had significantly higher levels of both sHLA-G (p<0.001) and sHLA-A, -B, -C (p=0.001) than normal controls. In addition, there was a very strong correlation between sHLA-G levels and clinical severity. CONCLUSION: The present study confirms evidence that serum sHLA-G and sHLA-A, -B, -C molecules are significantly increased in patients with pollen-induced AR also during the pollen season. Moreover, sHLA-G might be considered as a biomarker for assessing clinical severity.