Allergy, asthma and markers of infections among Albanian migrants to Southern Italy

BACKGROUND: Studies of immigrants represent an useful tool to determine the relative relevance of environmental vs genetic factors in causing the reported rapid increase of the prevalence of sensitization and allergic diseases. METHODS: A total of 152 Albanian migrants to Southern Italy responded to a questionnaire based on the European Community Respiratory Health Survey (ECRHS) and 139 of them underwent skin prick test, and 61 serological assays for total IgE and IgG antibodies against Toxoplasma gondii (TG), herpes simplex virus 1 (HSV-1), hepatitis A virus (HAV) and Helicobacter pylori (HP). RESULTS: Reported asthma was rare (2/152; 1.3%) and reported nasal allergies rather frequent (24/152; 15.8%). Sensitization to common inhalant allergens occurred in 27/139 (19.4%) subjects. The frequency of skin sensitization to pollen (P = 0.003) and that of hay fever (P = 0.004) increased with the time spent in Apulia. All the 61 sera had antibodies against HAV, 59/61 (96.7%) against HSV-1, 48/61 (78.7%) against HP and 34/61 (55.7%) against TG. The prevalence of skin sensitization and hay fever symptoms were correlated to the duration of residence in Southern Italy. CONCLUSIONS: Data presented indicate that Albanian migrants to Italy, in spite of the low prevalence of allergic diseases and sensitization in their country of origin, manifest with time an increasing prevalence of sensitization to local allergens and nasal symptoms after immigration to Italy. This would suggest a permanent role of allergen exposure and lifestyle factors in influencing the appearance of sensitization and symptoms of allergic diseases.     

Immune cells—A curse and a blessing!

Innate immune cells are crucial in the development and regulation of cardiovascular disease. In this issue, two groups, Davis et al. (2021. J. Exp. Med. https://doi.org/10.1084/jem.20201839) and Li et al. (2021. J. Exp. Med. https://doi.org/10.1084/jem.20210008) describe the impact of the innate immune system on the development of cardiovascular disease.

Inflammation resolution and tissue regeneration are fundamental for human system catabasis. The harmony between inflammation and homeostasis presents us with great challenges on a daily basis; as most recently experienced by the world, COVID-19 clearly demonstrated this challenge to us.Insights from Valbona Mirakaj.New ways of looking at inflammation are taking over the science of inflammation. As Rudolf Virchow postulated, inflammation is a pathological phenomenon, and Elie Metchnikoff considered inflammation to be an important aspect of homeostasis. These statements by the two great pioneers of the theory of inflammation lay an extremely important foundation for the way we look at and consider the pathophysiology of individual diseases.Inflammation is based on cellular dynamics that categorically recruit leukocytes to the site of the disease process. Over the past 30 yr, this aspect has been described as a key component in the pathophysiology of many diseases. A major impact of this process has been characterized especially in infectious diseases, cardiovascular diseases, and tumor immunology.The inflammatory response can be classified into four phases, namely (i) initiation of inflammation, (ii) transition, (iii) resolution, and (iv) return to homeostasis. An inflammatory stimulus triggers the release of chemical mediators such as chemokines, cytokines, and lipid mediators in the context of infection via pathogen-associated molecular patterns and in the context of sterile infection damage-associated molecular patterns. This stimulus activates the recruitment of polymorphonuclear leukocytes (PMNs) in the affected tissue in the early stages of inflammation (de Oliveira et al., 2016; Meizlish et al., 2021).The main problem with inflammation is not the frequency of its onset in early stage, but rather the frequency of its failure to resolve following this (Nathan and Ding, 2010). Checkpoints exist to balance homeostasis with so-called “physiological” inflammation before it progresses into pathological inflammation, which can transition into chronic inflammation with organ dysfunction. One of these checkpoints is placed in the field of resolution of inflammation. It had long been hypothesized that removal of the inflammatory stimulus prevents the production of chemoattractants that promote further leukocyte recruitment. Based on this statement, researchers hypothesized that simply diluting the chemoattractants in the tissue would prevent continued recruitment of inflammatory cells. Resolution of inflammation was seen as a passive event.Charles N. Serhan has been a pioneer in the field of inflammation resolution. He demonstrated in his studies of acute self-limiting responses using a systems-based approach that resolution of tissue inflammation is an active process, in which cell–cell interactions lead to the generation of endogenous active specialized pro-resolving mediators (i.e., lipoxins, resolvins, protectins, and maresins). These mediators limit further neutrophil recruitment to the tissue and enhance the efferocytosis of neutrophils by macrophages, promoting a return to homeostasis (Serhan, 2014; Serhan and Levy, 2018). At the cellular level, multifaceted immune cell dynamics proceed. PMNs exit the postcapillary venules and subsequently start efferocytosing microbes and cellular debris. At this point, neutrophils take on a pro-resolving function by first neutralizing the invaders before they get eliminated. A balance between PMN recruitment and pro-resolving actions is essential for a sufficient resolution process. However, if an imbalance occurs, resulting, for example, in an excessive infiltration of PMNs into the tissue, this mismatch may then lead to frustrated efferocytosis or an increase in cell death/necrosis (de Oliveira et al., 2016).As a result, inflammation in the tissues would worsen, which may lead to a chronic process and limitation of injury repair, resulting in loss of organ function. PMN-induced inflammation is a cornerstone of many diseases. Therefore, it is of tremendous importance to explore and understand mechanisms of PMN recruitment and further immune subsets to finely control these inflammatory events.The highly interesting work of Li et al. (2021) addresses exactly these components in a model of myocardial ischemia–reperfusion injury. In this study, the authors demonstrated that myeloid-derived netrin-1 has a central role in attenuating myocardial ischemia–reperfusion injury.Neuronal guidance proteins have recently been suggested to have immunocompetent properties in peripheral acute or chronic disease, in addition to their role in controlling axonal growth. In the process of nervous system development, a balance of chemoattractive and chemorepulsive signals guide the axons precisely to their final location to flesh out the complex neuronal system.Thus, a new approach emerged that showed that the nervous and immune systems share biological principles such as guidance mechanisms and the control of cellular migration. The study by Li et al. (2021) could show that circulating levels of netrin-1 were elevated in the blood of patients who had suffered a myocardial infarction. A hypothesis was put forward by the authors that PMNs could be an important source in this context. In murine experiments with antibody-based neutrophil depletion, they demonstrated that depletion of neutrophils before myocardial I/R revealed a significant reduction in blood netrin-1 concentrations compared with the control group. Treatment with netrin-1 protected from murine myocardial IR injury, and this effect was mediated by the myeloid-expressed adenosine 2B receptor. These results are of great importance because they show that this endogenous protein has protective properties in myocardial I/R damage. Pathophysiologically, this implies that netrin-1 supports the protective properties of an inflammatory response and, therefore, fewer adverse side effects can be expected after treatment with netrin-1.The influence of netrin-1 in the onset of acute inflammation has been described in several studies previously. Netrin-1 reduces PMN recruitment into the lung during pulmonary inflammation and also intestinal I/R injury, and thus has a protective effect on disease progression (Mirakaj and Rosenberger, 2017). In another study, Schlegel et al (2016) investigated the effect of netrin-1 in the phase of resolution in hepatic ischemia/reperfusion injury. In this work, the authors demonstrated the effect of netrin-1 on the specific cells such as monocytes and macrophages, which are, beside PMNs, central adjustors in the maintenance of tissue homeostasis and repair. In this context, netrin-1 is thought to have a dual function, an anti-inflammatory and pro-resolving one, and therefore belongs to the immunoresolvent.At the cellular level, the main actions of these immunoresolvents are in restoring barrier integrity, terminating the recruitment of neutrophils, efferocytosis and phagocytosis of apoptotic cells, pathogens, and cell debris by specialized macrophages (Serhan, 2014).The monocyte and macrophage lineages are central in inflammation resolution and tissue regeneration. Regardless of their origin, they are highly plastic and functionally diverse during the progress of pathological processes. An inflammatory stimulus induces metabolic and phenotypic changes that may allow differentiation and polarization into the classic proinflammatory M1, alternative anti-inflammatory M2, or intermediate M2 phenotype (Okabe and Medzhitov, 2016). These highly dynamic phenotype changes are evident, for example, in cardiovascular disease after myocardial infarction. Thus, cardiac macrophages exhibit dual roles. Upon injury, they respond by triggering the initial inflammatory response, and in the course of the process, they initiate tissue repair (Dick et al., 2019).The highly interesting mechanistic study by Davis et al. (2021) investigated the role of macrophages within abdominal aortic aneurysm development. Pro-inflammatory macrophages differentiate and proliferate from hematopoietic progenitor cells and show an important influence on aortic expansion. In this process, epigenetic modifications regulate the expression of immune mediators in macrophages (Kuznetsova et al., 2020). Histone demethylase, chromatin modifying–enzyme Jumonji domain–containing protein D3 (JMJD3), influences macrophage polarization after LPS stimulation. Inhibition of JMJD3 results in a reduction of cytokine production. The authors demonstrated that this mechanism is NF-κB dependent and that JMJD3 expression in macrophages is regulated via IFNβ and STAT1 pathway.In addition to epigenetics, the field of immune cell metabolism has advanced significantly. For example, macrophage metabolism is shown to be extremely plastic and often reflects pathologies associated with specific disease states. Inflammation and homeostasis—two elements in the science of inflammation—are gaining significant attention in research and have a major impact in translational medicine. Nevertheless, many questions remain to be answered. Experimental approaches to define subpopulations of immune cells in tissues and their dynamics in health and disease play an important role.Targeted personalized therapy based on temporal and spatial characteristics of the inflammatory process could be the bridge to specificity and personalized therapy.The use of newer technologies such as the application of trans-omic approaches, technologies that enable high-rate analysis of cell phenotypes would greatly expand the understanding of the biological system. In addition, there should be an increased focus on therapeutic approaches using immunoresolvents to support agnostic and pro-resolution properties in inflammation or inflammation-associated diseases.     

M-type Phospholipase A2 Receptor Autoantibodies and Renal Function in Patients with Primary Membranous Nephropathy

Background and objectives

Loss of renal function in patients with primary membranous nephropathy cannot be reliably predicted by laboratory or clinical markers at the time of diagnosis. M-type phospholipase A₂ receptor autoantibodies have been shown to be associated with changes in proteinuria. Their eventual effect on renal function, however, is unclear.

Design, setting, participants, & measurements

In this prospective, open, multicenter study, the potential role of M-type phospholipase A₂ receptor autoantibodies levels on the increase of serum creatinine in 118 consecutive patients with membranous nephropathy and positivity for serum M-type phospholipase A₂ receptor autoantibodies was analyzed. Patients were included in the study between April of 2010 and December of 2012 and observed until December of 2013. The clinical end point was defined as an increase of serum creatinine by ≥25% and serum creatinine reaching ≥1.3 mg/dl.

Results

Patients were divided into tertiles according to their M-type phospholipase A₂ receptor autoantibody levels at the time of inclusion in the study: tertile 1 levels=20–86 units/ml (low), tertile 2 levels=87–201 units/ml (medium), and tertile 3 levels ≥202 units/ml (high). The median follow-up time of all patients in the study was 27 months (interquartile range=18–33 months). The clinical end point was reached in 69% of patients with high M-type phospholipase A₂ receptor autoantibodies levels (tertile 3) but only 25% of patients with low M-type phospholipase A₂ receptor autoantibodies levels. The average time to reach the study end point was 17.7 months in patients with high M-type phospholipase A₂ receptor autoantibodies levels and 30.9 months in patients with low M-type phospholipase A₂ receptor autoantibodies levels. A multivariate Cox regression analysis showed that high M-type phospholipase A₂ receptor autoantibodies levels—in addition to men and older age—are an independent predictor for progressive loss of renal function.

Conclusions

High M-type phospholipase A₂ receptor autoantibodies levels were associated with more rapid loss of renal function in this cohort of patients with primary membranous nephropathy and therefore, could be helpful for treatment decisions.     

The Association between Patent Ductus Arteriosus and Perinatal Infection in A Group of Low Birth Weight Preterm Infants

Objective: Patent ductus arteriosus (PDA) is an extremely common occurrence in very premature infants. Untreated symptomatic PDA may be associated with chronic lung disease. PDA has a major role in neonatal mortality and morbidity. We compared the efficacy and safety of oral versus intravenous ibuprofen for the pharmacological closure of PDA in low birth weight (LBW) preterm infants. Methods: A randomized, single-blinded, controlled study was performed on premature neonates at the neonatal unit, University Hospital for Obstetrics and Gynecology “Koço Gliozheni”, Tirana, Albania from January 2010 to December 2012. The study enrolled 68 preterm infants with a confirmed and significant PDA. The preterm infants received either intravenous or oral ibuprofen randomly as an initial dose of 10 mg/kg, followed by 5 mg/kg at 24 and 48 h. Findings : 36 patients were treated with oral ibuprofen and 32 with intravenous ibuprofen during this period. After the first course of the treatment, the PDA closed in 30 (83.3%) of the patients assigned to the oral ibuprofen group versus 23 (71.8%) of those enrolled in the intravenous ibuprofen group (P=0.355). 15 patiens needed a second treatment course and they all (100%) had clinical signs of infection and positive blood culture. There was no reopening of the ductus after the closure. Conclusion: Our data indicate that, for LBW infants, the rate of early ductal closure was comparable and the adverse effects were fewer with oral ibuprofen in comparison to the intravenous route. Association of PDA with perinatal infection has a negative impact in pharmacological closure of the ductus, increasing the need for a second course of treatment or for surgery.Key Words: Prematurity, Perinatal Infection, Patent Ductus Arteriosus, Oral Ibuprofen, Intravenous Ibuprofen     

Antiphosphatidylserine/prothrombin antibodies in primary antiphospholipid syndrome

Antiprothrombin (aPT) antibodies may be detected by an enzyme-linked immunosorbent assay (ELISA) using a purified antigen or a phosphatidylserine/prothrombin complex (aPS/PT). IgG/IgM antibodies directed against aPS/PT were assessed in 158 patients with primary antiphospholipid syndrome (PAPS). They were detected in 80/158 (50.6%) PAPS patients; IgG alone was positive in 12 (7.6%), IgM alone in 36 (22.8%), and both IgG and IgM isotypes in 32 (20.2%) PAPS patients. IgG and IgM aPS/PT were significantly associated with both vascular thrombosis and pregnancy morbidity. IgG aPS/PT was significantly associated with venous thrombosis (p = 0.023), whilst IgG and IgM aPS/PT were associated with arterial thrombosis (p < 0.001 and p < 0.001, respectively). Logistic regression analysis showed that IgM and IgG aPS/PT were independent risk factors for thrombosis (odds ratio (OR) 3.5 [95% confidence interval (CI) 1.6-7.9] and OR 4.1 [95% CI 1.4-11.7], respectively) and IgM aPS/PT was an independent risk factor for arterial thrombosis (OR 2.7 [95% CI 1.1-6.7]). In conclusion, these findings indicate that aPS/PT are clinically relevant in PAPS.     

Visual and auditory hallucinations revealing cerebellar extraventricular neurocytoma: uncommon presentation for uncommon tumor in uncommon location

Objective

Visual and auditory hallucinations in relation to a cerebellar tumor are rarely reported in children. Primary origin of extraventricular neurocytoma (EVN) in the cerebellum is very rare.

Clinical Presentation

We report on a case of a cerebellar EVN in a 13-year-old girl with the initial symptoms of psychiatric manifestations for more than 2 months. Magnetic resonance imaging of the brain revealed a patchy enhanced tumor in the paramedian left cerebellar region. No obstructive hydrocephalus was noted.

Intervention

Total surgical removal of the tumor was performed. The tumor was initially diagnosed as an oligodendroglioma. After special immunohistochemical studies, the final definitive diagnosis was an EVN without isocitrate dehydrogenase mutation.

Conclusion

EVNs located in the cerebellum are extremely rare. We discuss the clinical symptoms and histological–immunohistochemical features of this rare tumor in that rare location.     

Continuous Metabolic Monitoring in Infant Cardiac Surgery: Toward an Individualized Cardiopulmonary Bypass Strategy

Cardiopulmonary bypass (CPB) in infants is associated with morbidity due to systemic inflammatory response syndrome (SIRS). Strategies to mitigate SIRS include management of perfusion temperature, hemodilution, circuit miniaturization, and biocompatibility. Traditionally, perfusion parameters have been based on body weight. However, intraoperative monitoring of systemic and cerebral metabolic parameters suggest that often, nominal CPB flows may be overestimated. The aim of the study was to assess the safety and efficacy of continuous metabolic monitoring to manage CPB in infants during open‐heart repair. Between December 2013 and October 2014, 31 consecutive neonates, infants, and young children undergoing surgery using normothermic CPB were enrolled. There were 18 male and 13 female infants, aged 1.4 ± 1.7 years, with a mean body weight of 7.8 ± 3.8 kg and body surface area of 0.39 m². The study was divided into two phases: (i) safety assessment; the first 20 patients were managed according to conventional CPB flows (150 mL/min/kg), except for a 20‐min test during which CPB was adjusted to the minimum flow to maintain MVO₂ >70% and rSO₂ >45% (group A); (ii) efficacy assessment; the following 11 patients were exclusively managed adjusting flows to maintain MVO2 >70% and rSO2 >45% for the entire duration of CPB (group B). Hemodynamic, metabolic, and clinical variables were compared within and between patient groups. Demographic variables were comparable in the two groups. In group A, the 20‐min test allowed reduction of CPB flows greater than 10%, with no impact on pH, blood gas exchange, and lactate. In group B, metabolic monitoring resulted in no significant variation of endpoint parameters, when compared with group A patients (standard CPB), except for a 10% reduction of nominal flows. There was no mortality and no neurologic morbidity in either group. Morbidity was comparable in the two groups, including: inotropic and/or mechanical circulatory support (8 vs. 1, group A vs. B, P = 0.07), reexploration for bleeding (1 vs. none, P = not significant [NS]), renal failure requiring dialysis (none vs. 1, P = NS), prolonged ventilation (9 vs. 4, P = NS), and sepsis (2 vs. 1, P = NS). The present study shows that normothermic CPB in neonates, infants, and young children can be safely managed exclusively by systemic and cerebral metabolic monitoring. This strategy allows reduction of at least 10% of predicted CPB flows under normothermia and may lay the ground for further tailoring of CPB parameters to individual patient needs.     

Rosiglitazone Dampens Pulmonary Inflammation in a Porcine Model of Acute Lung Injury

The hallmarks of acute lung injury (ALI) are the compromised alveolar-capillary barrier and the extravasation of leukocytes into the alveolar space. Given the fact that the peroxisome proliferator-activated receptor-γ agonist rosiglitazone holds significant anti-inflammatory properties, we aimed to evaluate whether rosiglitazone could dampen these hallmarks of local pulmonary inflammation in a porcine model of lung injury. For this purpose, we used a model of lipopolysaccharide (LPS, 50 μg/kg)-induced ALI. One hundred twenty minutes following the infusion of LPS, we started the exposure to rosiglitazone through inhalation or infusion. We found that intravenous rosiglitazone significantly controlled local pulmonary inflammation as determined through the expression of cytokines within the alveolar compartment. Furthermore, we found a significant reduction of the protein concentration and neutrophil activity within the alveolar space. In summary, we therefore conclude that the treatment with rosiglitazone might dampen local pulmonary inflammation during the initial stages of ALI.