Covid-19 and cardiac involvement in childhood: state of the art.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was first described in a cluster of patients in Wuhan, China, in December of 2019. Over the past few months, COVID-19 has rapidly spread worldwide becoming the first pandemic of the 21st century. COVID-19 results in mild symptoms in most infected children but can cause acute cardiac injury and death. In comparison to younger children, teenagers and infants are at higher risk for morbidity and mortality, with particular risk factors including pre-existing conditions like cardiovascular disease. Since this is an emerging infectious disease, there are limited data about the effects of this infection on patients especially in the pediatric population. We summarize here with the data on cardiovascular involvement in children and adolescents.

Hypertension in childhood.

Hypertension is a growing health problem in children, and it is an important parameter of cardiovascular risk for adults. It is classified as primary (influenced by obesity, sedentary lifestyles and poor-quality food) or secondary to underlying causes. The AAP 2017 guidelines recommend measuring blood pressure every year from the age of three and in children under the age of three only if they have known risk factors. The measurement of infantile hypertension is relatively complicated and instable and, for this reason, ambulatory blood pressure monitoring (ABPM) and multiple office BP measurement (mOBPM), especially in infants who are not collaborating are indicated. High blood pressure may have an adverse effect on the heart, the vessels, the kidney, and the central nervous system so it is important recognize it and act promptly. Hypertension is initially treated with lifestyle changes such as weight loss, a healthy diet, and regular exercise, but, if non-pharmacological interventions have failed, a pharmacological treatment with angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, calcium channel blockers, thiazide diuretics and/or beta blocker may be indicated.

Cardiovascular risk factors in childhood obesity.

Childhood obesity is the "disease of the century". This article reviews the early cardiovascular risk factors and the recommendations to prevent them in the overweight and obese children. A comprehensive search of published literature was carried out to identify all articles published on this topic in English and Italian from 1999 to 2020.

Cardiac malformations in children with congenital hypothyroidism.

Congenital hypothyroidism (CH) is the most common endocrine disease in children, according to literature, infants with CH have an increased risk of associated congenital malformations (CM), especially cardiac defects (CD), compared to the general population. We retrospectively analyzed medical records of 255 patients with a positive screening result for CH in the period 1991-2016 followed at our Center. At the time of enrollment, the clinical examination included looking for the presence of heart murmurs and dysmorphic features. In all patients an echocardiography with cardiological evaluation were performed. Of all patients, 191 were included in the final analysis. Of these, 51.3% (98/191) presented an eutopic normally sized thyroid gland while 48.7% (93/191) showed a thyroid dysgenesis. Among the studied infants, 13.6% (26/191) presented CD. The most frequent cardiac anomaly was atrial septal defect (ASD) which was found in 65.4% (17/26) of patients with CD. Other defects were ventricular septal defect (VSD), patent ductus arteriosus (PDA), pulmonary valve stenosis (PvS), transposition of the great vessels (TGV), aortic valve stenosis (AvS). Six patients had multiple defects. In the analysed group, there was no significant relation with sex, type of CH, median blood-TSH (b-TSH) and serum-TSH (s-TSH) values and frequency of CD. There is a high prevalence of CD in CH, indicating the need of routine echocardiography in these patients to achieve an early diagnosis and management of CD.

Antihistamines in children and adolescents: A practical update.

Histamine is a chemical mediator, released predominantly by tissue mast cells, circulating basophils, and neurons, which are activated in response to various immunological and non-immunological stimuli. Histamine has to bind to specific receptors to exert its physiological and pathophysiological functions. Endogenous histamine is the main mediator of the immediate allergic response, which moreover, performs other multiple functions, including regulation of gastric secretion, neurotransmission in the central nervous system, and immunomodulatory activity. The involvement of histamine in various disorders and the importance of receptors in the clinical features have relevant implications in clinical practice. Anti-H1 antihistamines contrast the histamine-dependent effects, mainly concerning nasal symptoms and cutaneous itching and wheal. Antihistamines are among the most prescribed drugs in pediatric care. This review updates the practical use of antihistamines in children and adolescents.

Failure to thrive: the importance of measuring the electrolytes.

Diabetes insipidus (DI) is characterized by hypoosmotic polyuria related to deficiency of arginine-vasopressin (AVP) secretion (centraldiabetesinsipidus, CDI) or renalinsensitivity to AVP (nephrogenicdiabetesinsipidus, NDI). We report a case of a child with congenital NDI.

Nephrotic syndrome: immunological mechanisms.

Nephrotic Syndrome (NS) is a rare diseases (around 2-7 cases per 100.000 children per year) characterized by proteinuria ≥50 mg/kg/day (or ≥40 mg/m2/h) or a proteinuria/creatininuria ratio >2 (mg/mg); hypoalbuminaemia less than 25 g/l and edema. The protein leakage, with the consequent hypoalbunaemia and edema, due to podocyte alterations may be caused by genetic diseases, immunological mechanisms, infections, toxins or malignancy. However, most commonly the exact etiology is unknow. The idiopathic NS may be classified based on response to corticosteroid therapy or the hytological appearance. The first classification identifies steroid-resistant NS (no response after 4 weeks of steroid therapy); frequently relapsing NS (≥ 2 relapses in first 6 months or ≥4 relapses in 1-year); steroid dependent NS (relapses during steroid decalage or within 2 weeks from steroid therapy interruption). The hystological classification is based on light and electron microscopy after renal biopsy, which is indicated in case of onset disease before 1 year or after 12 years of age. Macroscopic hematuria: persistent hypertension and/or microscopic hematuria and/or low plasma C3 renal failure not related to hypovolemia; steroid resistence: secondary or relatedsyndromes NS. Minimal change disease (MCD) is the most common form of idiopahtic NS in children, with good response to steroid treatment, and it is characterized by normal glomerular appearance on light microscopy and evidence of podocyte foot alterations on electron microscopy, due to immunological related damage. Focal segmental glomerulosclerosis (FSGS) is described inidiopahtic NS, particularly in steroiddependent or steroid-resistant forms, and is characterized by evidence of focal glomerular damage with secondary sclerosis and adhesion with Bowman's capsule; the electron appearance is the same of MCD one. Recent authors hypotizethat the FSGS is an evolution of MCD. These 2 idiopathic NS forms may be expression of the same immunological disease, with 2 different severity grades; so they may be considered different moments of the same disease spectrum. Less common idiopathic NS forms are membrano proliferative glomerulonephritis; membranous nephropathy; IgM-nephropathy; C1q nephropathy and thin basement membrane disease (1, 2, 3).

Renal anomalies in newborns with vacterel association: case series and literature review.

Nocturnal enuresis (NE) was defined by the World Health Organization (ICD-10) and the American Psychiatric Association (DSM-5) as bed-wetting in children aged >5 years. In cases of mental retardation, the developmental age may be equivalent to 5 years. In this review, we focus on the current knowledge about the etiology of enuresis and the most recent therapeutical options. Both non-pharmacological and pharmacological therapies are included, although the relative effectiveness of each remains uncertain. To date, motivational, alarm and drug therapies are the mainstay of treatment. Alarm therapy remains the first-line treatment modality for NE, while desmopressin is the most commonly used medical treatment.

Cardiac dysfunction in children with essential obesity: preliminary data.

Obesity in children has been recognized as a major underlying factor of the pathogenesis of several diseases and a reduced life expectancy. This study aims to verify if clinical parameters, such as waist circumference and/or body mass index and biohumoral and inflammatory parameters can help predict cardiac structural and functional alterations, through an echocardiogram test in obese children and adolescents. Children were prospectively enrolled at the AUOC outpatients' department of Emergency Paediatrics, University Hospital, Messina, from June to December 2017. Clinical, metabolic parameters and an inflammation marker (HMGB1) were evaluated and a transthoracic echocardiogram was carried out. Twenty-two obese subjects were prospectively enrolled.HMGB1 values were 12.6 ± 2ng/ml, significantly higher compared to a previously studied healthy control group. A significant positive correlation was found both between total cholesterol levels and HMGB1 values (r=0.846, p=0.000) and between LDL cholesterol and HMBG1 values (r=0.663, p=0.001). No correlation was found between clinical, biohumoral and echocardiograph parameters. In obese children cardiac parameters obtained from echocardiogram tests may be in the normal range. However, other parameters may be altered in the early phase, showing that infantile obesity can compromise myocardial functions, even in the absence of comorbidities. Furthermore, the evaluation of concentrations of HMBG1 could explain how an initial inflammation can trigger the condition of meta-inflammation.

Local therapy with ozone in the management of the exit site in a patient undergoing peritoneal dialysis.

The natural history of children with end stage renal disease is dialysis until a transplant can be done. There are two types of dialysis: hemodialysis and peritoneal dialysis (1). Peritoneal dialysis is preferred in young children because getting the vascular access for hemodialysis is challenging (2). Catheters should be surgically placed in a paramedian or lateral abdominal region with an extremity located in Douglas' pouch.

GSTP1 gene methylation and AHR rs2066853 variant predict resistance to first generation somatostatin analogs in patients with acromegaly.

PURPOSE: Biomarkers of clinical and therapeutic outcome in acromegaly are needed. Polymorphisms or epigenetic changes of detoxification genes, such as those coding for the aryl hydrocarbon receptor (AHR) and the glutathione-S-transferase-P1 (GSTP1), could have a role in GH secreting pituitary tumors' pathophysiology and clinical expression. In this study, we assessed the contribution of GSTP1 gene promoter methylation status, per se or in combination with the occurrence of the AHR gene rs2066853 variant, on clinical features and response to somatostatin analogs (SSA) treatment in acromegaly patients. METHODS: This is an observational, retrospective study, carried out in the Endocrine Unit of an Italian University Hospital. We enrolled 77 wild-type AIP gene acromegaly patients, who have been screened for germline AHR rs2066853 variant and GSTP1 gene promoter methylation. Clinical and biochemical parameters were compared after patients' stratification according to GSTP1 methylation status and the presence of AHR rs2066853. We also evaluated the response to SSA treatment in 71 cases. RESULTS: 17 patients carried the AHR rs2066853 variant and 26 had methylated GSTP1 (GSTP1-methyl) gene promoter. GSTP1-methyl patients showed a higher prevalence of diabetes mellitus (p = 0.01), colonic polyps (p = 0.05), and were more resistant to SSA (p = 0.02) as compared to GSTP1 unmethylated patients (GSTP1-unmethyl). Patients GSTP1-unmethyl and AHR wild-type were the most sensitive to SSA treatment, while those with both GSTP1-methyl and AHR rs2066853 variant were all resistant to SSA (p = 0.01). CONCLUSIONS: In acromegaly, GSTP1 gene methylation associates with resistance to SSA treatment, especially in patients carrying also the AHR rs2066853 variant, and with increased prevalence of colonic polyps and diabetes mellitus.

Pilot study shows right ventricular diastolic function impairment in young children with obstructive respiratory disease.

AIM: This study determined cardiovascular impairment in young children with obstructive respiratory disease who were assessed using the opening interrupter technique (RINT). METHODS: This pilot study enrolled 41 children who had been referred to pulmonology and allergology specialists at the University of Catania, Italy, from March to July 2017: 23 (mean age 4.13 ± 0.62 years) had chronic coughs and wheezing and 18 controls (mean age 4.27 ± 0.66 years) had obstructive chest disease, but were otherwise healthy. Airway resistance was evaluated using RINT and cardiac function by studying the ejection fraction, pulmonary artery systolic pressure (PASP), tricuspid annular plane systolic excursion and tricuspid flow propagation velocity (TFPV). RESULTS: The RINT and PASP values were significantly higher in the patient group when compared to the controls, but the TFPV values were lower. A direct and significant Spearman's correlation coefficient (r) between RINT and PASP values was observed (r = 0.81). We found a significant inverse correlation between RINT and TFPV (r = -0.83), as well as TFPV and PASP (r = -0.78). CONCLUSION: This study showed that children with obstructive respiratory diseases had a major risk of cardiovascular impairment. Impaired diastolic function of the right ventricle occurred very early when airway resistance was abnormally increased.

Lack of clear and univocal genotype-phenotype correlation in familial Mediterranean fever patients: A systematic review.

Familial Mediterranean fever (FMF) is the most common autosomal recessive autoinflammatory disease. To date, following the isolation of more than 280 MEFV sequence variants, the genotype-phenotype correlation in FMF patients has been intensively investigated; however, an univocal and clear consensus has not been yet reached. Thus, the aim of this systematic review was to analyze the available literature findings in order to provide to scientific community an indirect estimation of the impact of genetic factors on the phenotypic variability of FMF. This systematic review has been conducted according to the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) guidelines. The p.M694V mutation was reported to have a relatively severe clinical course, similarly, patients homozygous for M694I and M680I, or carrying a combination of both at codons 694 and 680, have a severe disease. Also, patients homozygous for M694V and V726A variants experienced more severe clinical picture. Conversely, heterozygous p.V726A and p.E148Q genotypes have been correlated with a milder disease course. At present, doubts remain on the potential pathogenic role of E148Q variant. The heterogenity in clinical FMF manifestations reflects the changes occuring in repertoire of mutations. We believe that clinical criteria and gene tests, enhancing each other, could better support the diagnosis of FMF.

Different concentration of human cord blood HMGB1 according to delivery and labour: A pilot study.

OBJECTIVE: Oxidative stress is involved in several maternal conditions characterized both by an increase in free radicals synthesis and a parallel decrease in the antioxidant activity. Parturition induces considerable oxidative stress and many inflammatory mediators, among which HMGB1, are involved from the beginning of pregnancy to the birth of the infant. We evaluated serum cord blood HMGB1 levels in a population of neonates to investigate correlation with mode of delivery, as well as the influence of labour. SETTING AND PATIENTS: The study subjects were 325 neonates delivered at University Hospital "G. Martino" of Messina over an 18-month period. Following cord separation, venous blood sampling was performed on umbelical cords. RESULTS: In the cord venous blood, we found HMGB1 values significantly more elevated in spontaneous vaginal group when compared to elective or emergency caesarean section group. Regarding labour, umbilical cord venous blood HMGB1 levels were significantly higher in the spontaneous and induced labour group, compared to non-labouring women. CONCLUSION: These results could highlight a possible role of HMGB1 during birth time related to mode of delivery and labour.

Serum IL-10, IL-17 and IL-23 levels as "bioumoral bridges" between dyslipidemia and atopy.

BACKGROUND: Although several studies suggest a possible link between dyslipidemia and atopy, literature findings are still unclear. OBJECTIVE: The aim of the study was to investigate the relationship between dyslipidemia and atopy in a pediatric population affected by dyslipidemia or dyslipidemia/atopic predisposition. MATERIALS AND METHODS: Children with dyslipidemia, dyslipidemia and atopy as well as healthy children were recruited. Serum total IgE, IL-10, IL-17, and IL-23 levels as well as fasting lipid values (total cholesterol, LDL, HDL and triglycerides) were performed on all enrolled children. RESULTS: The present study evaluated 23 patients affected by dyslipidemia, 26 patients affected by atopy and dyslipidemia and, 22healthy children. Serum total IgE levels significantly related also with serum cholesterol levels: positively with total cholesterol (p<0.05), LDL (p<0.05), and tryglicerides (p<0.001), but negatively with HDL (p<0.05). Serum levels of IL-10 were lower in children with atopy and dyslipidemia than patients with dyslipidemia (p<0.001). Serum IL-10 levels significantly related also with serum cholesterol levels: negatively with total cholesterol (p<0.001), LDL (p<0.05), and triglycerides (p<0.05), but positively with HDL (p<0.05). Serum IL-17 and IL-23 levels showed the same trend. They were significantly higher in children with atopy and dyslipidemia than patients with dyslipidemia (p<0.001). In particular, serum IL-17 and IL-23 values positively correlated with serum total IgE levels (p<0.05); serum total cholesterol levels (p<0.001); serum LDL levels (p<0.001); serum triglycerides levels (p<0.05). Although not statistically significant, an inverse correlation has been noted between serum IL-17, IL-23 and HDL levels. CONCLUSIONS: These findings support the notion that dyslipidemia and atopic predisposition share the same immune pathways as well as they offer new insights in the complex crosstalk between hyperlipidemia and atopy.

Human herpesviruses-6 and -7 encephalitis in immunocompetent infants: are they really so uncommon?

Human herpesviruses-6 and -7 (HHV-6 and 7) are considered uncommon causes of central nervous system infection and may occasionally cause encephalitis in young infants, however, the clinical syndrome and incidence are not well defined. In immunosuppressed hosts, reactivation is associated with a worse outcome such as encephalitis, hepatitis, or graft rejection. In immunocompetent hosts, this persistent infection is generally of no consequence. We report 4 cases of immunocompetent critically ill children, affected by HHV-6 and -7 encephalitis, admitted to our Pediatric Intensive Care Unit. In three patients, herpesvirus polymerase chain reaction in blood and cerebrospinal fluid was positive for HHV- 6, while one patient was positive for HHV-7. In our cases, a typical clinical picture of viral infection was not present but neurological symptoms were predominant. In all 4 children, neurological involvement rapidly regressed after acyclovir therapy. In this report, we offer evidence that HHV-6 and -7 primary infections can cause several clinical manifestations, such as encephalitis, also in immunocompetent hosts. In our experience, children with neurological symptoms suggestive of viral encephalitis should be fully investigated for these two viruses.

Pneumomediastinum, subcutaneous emphysema and pneumorrhachis in asthmatic children.

Pneumomediastinum (PM), subcutaneous emphysema (SE) and pneumorrhachis (also known as epidural air (EDA) or epidural emphysema) are very rare findings in children. PM is defined as the passage of air from intra-alveolar space to interstitium and, later, to the mediastinum. From the mediastinum, the air may catch up subcutaneous tissue (usually of the neck) and/or epidural space via the cervical fascial planes and neural foramina, forming respectively SE and EDA. The PM can be divided in spontaneous (or idiopathic) and secondary PM. Only few studies have evaluated the exact incidence of PM and its complications in children, and to define the correct diagnostic work up, treatment and outpatient follow-up. We report the case of a 9-year-old child with undiagnosed asthma that, during severe asthmatic flare secondary to acute infection of high airway, developed PM, SE and EDA.

ALMOND MILK: A POTENTIAL THERAPEUTIC WEAPON AGAINST COW’S MILK PROTEIN ALLERGY.

Food allergy is defined as an adverse health effect arising from a specific immune response that occurs reproducibly following exposure to a given food. Cow’s milk protein allergy results from an immunological reaction to one or more milk proteins. The principle key in the treatment of cow’s milk protein allergy is the dietary elimination of cow’s milk protein. Although hydrolyzed and elemental formulas are appropriate replacements, other milk products, including almond milk adequately integrated, could be administered. Here, in the light of encouraging results from our study, we focused on the anti-inflammatory and anti-oxidant properties of almond milk and we also believe that almond milk might be considered as a potential alternative in cow’s milk protein allergy treatment.

ATOPIC DERMATITIS: MELATONIN AS POTENTIAL TREATMENT.

Atopic dermatitis (AD) is a chronic relapsing-remitting inflammatory skin disorder, characterized by a skin barrier dysfunction resulting in epidermal damage and altered permeability to allergens and microbes. Traditionally, the immunological mechanism involving the Th1-Th2 paradigm is considered central in the pathogenesis of AD. However, oxidative stress is, currently, recognized as a fundamental predisposing stimulus for AD. Several therapeutic approaches have been proposed as treatment, including the use of melatonin. This indolamine, through widespread expression and pleiotropic activity of the cutaneous melatoninergic system, may counteract environmental and endogenous stressors, regulate the immune response, decrease oxidative stress, and, finally, promote skin integrity. In the light of its pleiotropic effects, melatonin could represent a potential and alternative therapeutic approach in patients with AD.

POTENTIAL USE OF MELATONIN IN PROCEDURAL ANXIETY AND PAIN IN CHILDREN UNDERGOING BLOOD WITHDRAWAL.

The recognition of the value of pain, especially in the pediatric population, has increased over the last decade. It is known that pain-related anxiety can increase perceived pain intensity. There are several different approaches to the treatment of pre-procedural anxiety and procedural pain in children. Melatonin, a neurohormone with the profile of a novel hypnotic-anaesthetic agent, plays an important role in anxiolysis and analgesia. This study investigated the effects of oral melatonin premedication to reduce anxiety and pain in children having blood samples taken. The investigations were carried out on 60 children, aged 1-14 years, divided into 2 equal groups. Using a computer-generated randomization schedule, patients were given either melatonin orally (0.5 mg/kg BW, max 5 mg) or placebo 30 min before blood draw. Pre-procedural anxiety was assessed using the scale from the Children’s Anxiety and Pain Scales, while procedural pain used the Face, Legs, Activity, Cry and Consolability assessment tool for children under the age of 3 years, Faces Pain Scale-Revised for children aged 3-8 years and Numeric Rating Scale for children over the age of 8 years. Oral administration of melatonin before the blood withdrawal procedure significantly reduced both anxiety (p<0.0005) and pain levels than placebo (p<0.0002 for children under 3 years and p<0.0039 for children over 3 years). These data support the use of melatonin for taking blood samples due to its anxiolytic and analgesic properties. Further studies are needed to support the routine use of melatonin to alleviate anxiety and pain in pediatric patients having blood samples taken.