Long-term follow-up in common variable immunodeficiency: the pediatric-onset and adult-onset landscape

IntroductionThe primary aim of this study is to investigate the evolution of the clinical and laboratory characteristics during the time in a longitudinal cohort of pediatric-onset and adult-onset Common Variable Immunodeficiency (CVID) patients in order to identify early predictive features of the disease and immune dysregulation complications.MethodsThis is a retrospective-prospective monocentric longitudinal study spanning from 1984 to the end of 2021. The data of pediatric-onset vs. adult-onset patients have been compared for immunological features and for infectious and non-infectious complications assessed at diagnosis and follow-up.ResultsSeventy-three CVID patients have been enrolled, with a mean of 10.0 years (SD ± 8.17) of prospective follow-up. At diagnosis, infections were observed in 89.0% of patients and immune dysregulation in 42.5% of patients. At diagnosis, 38.6% of pediatric-onset and 20.7% of adult-onset patients presented with only infections. Polyclonal lymphoid proliferation (62.1%) and autoimmunity (51.7%) were more prevalent in the adult-onset than in the pediatric-onset group (polyclonal lymphoid proliferation 52.3% and autoimmunity 31.8%, respectively). Enteropathy was present in 9.1% of pediatric-onset and 17.2% of adult-onset patients. The prevalence of polyclonal lymphoid proliferation increased during follow-up more in pediatric-onset patients (diagnosis 52.3%—follow-up 72.7%) than in adult-onset patients (diagnosis 62.1%—follow-up 72.7%). The cumulative risk to develop immune dysregulation increases according to the time of disease and the time of diagnostic delay. At the same age, pediatric-onset patients have roughly double the risk of having a complication due to immune dysregulation than adult-onset patients, and it increases with diagnostic delay. The analysis of lymphocyte subsets in the pediatric-onset group showed that CD21 low B cells at diagnosis may be a reliable prognostic marker for the development of immune dysregulation during follow-up, as the ROC curve analysis showed (AUC = 0.796). In the adult-onset group, the percentage of transitional B cells measured at diagnosis showed a significant accuracy (ROC AUC = 0.625) in identifying patients at risk of developing immune dysregulation.DiscussionThe longitudinal evaluation of lymphocyte subsets combined with clinical phenotype can improve the prediction of lymphoid proliferation and allow experts to achieve early detection and better management of such complex disorder

Invasive meningococcal disease in three siblings with hereditary deficiency of the 8th component of complement: Evidence for the importance of an early diagnosis

Deficiency of the eighth component of complement (C8) is a very rare primary immunodeficiency, associated with invasive, recurrent infections mainly caused by Neisseria species. We report functional and immunochemical C8 deficiency diagnosed in three Albanian siblings who presented with severe meningococcal infections at the age of 15 years, 4 years and 17 months, respectively. The youngest suffered serious complications (necrosis of fingers and toes requiring amputation). METHODS: Functional activity of the classical, alternative and mannose-binding lectin complement pathways was measured in serum from the 3 siblings and their parents (37-year-old woman and 42-year-old man). Forty healthy subjects (20 males and 20 females aged 4-38 years) served as normal controls. Serum complement factors were measured by haemolytic assays and immunoblotting. Sequence DNA analysis of the C8B gene was performed. RESULTS: Analyses of the three complement pathways revealed no haemolytic activity and also absence of C8beta in serum samples from all three siblings. The genetic analysis showed that the three siblings were homozygous for the p.Arg428* mutation in the C8B gene on chromosome 1p32 (MIM 120960). The parents were heterozygous for the mutation and presented normal complement activities. A 2-year follow-up revealed no further infective episodes in the siblings after antibiotic prophylaxis and meningococcal vaccination. CONCLUSIONS: Complement deficiencies are rare and their occurrence is often underestimated. In presence of invasive meningococcal infection, we highlight the importance of complement screening in patients and their relatives in order to discover any genetic defects which would render necessary prophylaxis to prevent recurrent infections and severe complications

Serial high-resolution computed tomography (HRCT) in children with chronic productive cough and bronchiectasis unrelated to cystic fibrosis: correlations with clinical evaluation

Objectives. To follow prospectively for 3 years children with chronic productive cough and non-Cystic Fibrosis bronchiectasis defined by high resolution computed tomographic scanning, in order to determine the evolution of lung damage; to compare their computed tomography scores with the results obtained with a simple clinical parameter (cough index) used to monitor the disease. Methods. We studied 22 children for 3 years, during which they underwent regular physiotherapy and antibiotic therapy for acute lower respiratory tract infections. The number of months/year of productive cough (cough index) was calculated for each patient for the 2 years before study entry and during the study. At the end of follow-up, chest high resolution computed tomographic (HRCT) was repeated. Results. During follow-up the cough index improved or remained stable in 19 children (86%); among these, HRCT scores decreased in 12, remained stable in 6 and worsened in 1. Mild and moderate bronchiectasis remained unchanged in 17 patients (77%) and completely resolved in 4. There was a close correlation between the change in cough index before and during the follow-up, and the change in HRCT scores (r = 0.66; p = 0.0008). Conclusion. The cough index significantly improved and the HRCT score of most patients improved or remained unchanged during the 3 years of systematic treatment; there was a close correlation between the change in the HRCT scores and the change in the cough index used to monitor the evolution of lung damage. Patients with a persistent productive cough do not need to repeat HRCT within a short time if the clinical symptoms improve or remain stable

Seasonal and Spatial Variations of the Oxidative Properties of Ambient PM2.5 in the Po Valley, Italy, before and during COVID-19 Lockdown Restrictions

This study describes the chemical and toxicological characteristics of fine particulate matter (PM2.5) in the Po Valley, one of the largest and most polluted areas in Europe. The investigated samples were collected in the metropolitan area of Milan during the epidemic lockdown and their toxicity was evaluated by the oxidative potential (OP), measured using ascorbic acid (OPAA) and dithiothreitol (OPDTT) acellular assays. The study was also extended to PM2.5 samples collected at different sites in the Po Valley in 2019, to represent the baseline conditions in the area. Univariate correlations were applied to the whole dataset to link the OP responses with the concentrations of the major chemical markers of vehicular and biomass burning emissions. Of the two assays, OPAA was found mainly sensitive towards transition metals released from vehicular traffic, while OPDTT towards the PM carbonaceous components. The impact of the controlling lockdown restrictions on PM2.5 oxidative properties was estimated by comparing the OP values in corresponding time spans in 2020 and 2019. We found that during the full lockdown the OPAA values decreased to 80–86% with respect to the OP data in other urban sites in the area, while the OPDTT values remained nearly constant

Seasonal and Spatial Variations of PM10 and PM2.5 Oxidative Potential in Five Urban and Rural Sites across Lombardia Region, Italy

Oxidative potential (OP) of particulate matter (PM) is gaining strong interest as a promising health exposure metric. This study investigated OP of a large set of PM10 and PM2.5 samples collected at five urban and background sites near Milan (Italy), one of the largest and most polluted urban areas in Europe, afflicted with high particle levels. OP responses from two acellular assays, based on ascorbic acid (AA) and dithiothreitol (DTT), were combined with atmospheric detailed composition to examine any possible feature in OP with PM size fraction, spatial and seasonal variations. A general association of volume-normalized OP with PM mass was found; this association may be related to the clear seasonality observed, whereby there was higher OP activity in wintertime at all investigated sites. Univariate correlations were used to link OP with the concentrations of the major chemical markers of vehicular and biomass burning emissions. Of the two assays, AA was particularly sensitive towards transition metals in coarse particles released from vehicular traffic. The results obtained confirm that the responses from the two assays and their relationship with atmospheric pollutants are assay- and location-dependent, and that their combination is therefore helpful to singling out the PM redox-active compounds driving its oxidative properties

The Impact of COVID-19 Lockdown Strategies on Oxidative Properties of Ambient PM₁₀ in the Metropolitan Area of Milan, Italy

This research investigates the impact of controlling pandemic measures on the characteristics of atmospheric particulate matter (PM), with specific concern to its toxicity, measured by its oxidative properties. The investigated PM10 samples were collected in the metropolitan area of Milan during the epidemic lockdown, and their oxidative potential (OP) was assessed using ascorbic acid (AA) and dithiothreitol (DTT) acellular assays. During the full lockdown, we estimated reductions to 46% and 60% for nitrogen dioxide (NO2) and black carbon (BC) concentrations, respectively, based on the aggregated 2018–2019 data of NO2 and BC levels, used as baseline conditions. To quantify the impact of lockdown restrictions on PM oxidative activity, we studied the OP data measured in our laboratory on PM10 filters and directly compared the results from 15–30 April 2020 with those from the same time span in 2019. The OPAA values dropped to nearly 50%, similar to the concentration decrease in Elemental Carbon (EC) and traffic related metals, as well as to the variation in NO2 level. Otherwise, the OPDTT responses decreased to nearly 75%, as described by the corresponding reduction in Organic Carbon (OC) concentration and BC level

Chemical composition and oxidative potential of atmospheric coarse particles at an industrial and urban background site in the alpine region of northern Italy

The chemical composition and oxidative potential (OP) of particulate matter (PM10) samples were investigated at an industrial (Ala) and a background (TN) site in northern Italy. Three emission sources of airborne metals were identified by Positive Matrix Factorization (PMF) analysis, i.e., the zinc coating facility located in the area, the traffic on the nearby motorway and the pesticides normally used in the extensive vineyard cultivation. PM10redox activity was measured using dithiothreitol (OPDTTV) and ascorbic acid (OPAAV) cell-free assays. Similar OPDTTVresponses were obtained at the two sites (0.60 ± 0.23 mmol min−1m−3), while higher (OPAAV) values were measured at Ala (1.4 ± 1.1 nmol min−1m−3) than at TN (0.7 ± 0.4 nmol min−1m−3). Overall, both OPDTTVand OPAAVresponses were found to be broadly correlated with several inorganic species, namely ions and soluble metals, and organic components. In particular, OPAAVresponses are mainly affected by Zn directly emitted from the zinc factory and Cu used in the vineyard cultivation. Therefore, the higher OPAAVvalues measured at Ala can be explained by the higher concentration of these metals at the industrial site

Impact Assessment of metal-rich airborne particulate on air quality and Oxidative Potential: a case study in Trentino region

The chemical composition and toxicological impact of metal rich PM10 samples was assessed in an industrial (Ala) and background (TN) sites in Trentino region. Source apportionment study using Positive Matrix Factorization assessed that the main emission sources of airborne metals at Ala are a zinc coating facility located in the area, traffic on the A-22 Brenner motorway and pesticide/fungicide spraying in the surrounding vineyard district. PM10 toxicological impact was quantified by measuring the oxidative potential OP using two a- cellular assays, i.e., dithiothreitol (DTT) and ascorbic acid (AA) assays [1]. The responses of the DTT assay (volume-normalized OPVDTT) are similar at both size (mean values ~ 0.60±0.23 nmol min-1m-3) while OPVAA values show significantly higher values at Ala (1.4±1.1 nmol AA min-1m-3) than at TN (0.7±0.4 nmol AA min-1m-3). This is consistent with the different sensitivity of the two assays towards the same redox-active species present in ambient PM, as elucidated by linear correlation analysis of OPV with the concentration of tracer pollutants and highlighted by Heat Maps representation. At the industry site OPVDTT is correlated only with potassium and rubidium (R ~ 0.8), while OPVAA almost exclusively with Cu (R= 0.88). Otherwise, at TN both OPVDTT and OPVAA are both correlated with several species (R ≥ 0.7), such as WSTC, SO42-, NH4+, K, Mn, Cu and Zn. In addition, at Ala pronounced day-of-week evolution was observed for OPVAA values confirming the contribution of heavy metals from the anthropogenic sources. In conclusion, our study clearly shows that PM10 oxidative potential is strongly enhanced by few selected metals, mainly Zn and Cu, emitted by the anthropogenic activities carried out in the investigated area, even if they only weakly impacted PM10 chemical composition. Concerning the still open question of different sensitivity of the DTT and AA assays, our results may be considered an experimental proof of the highest sensitivity of AA assay towards transition metals