Corrigendum: Hematological profile, inflammatory markers and serum liver enzymes in COVID 19 positive children vs. COVID 19 negative ones-a comparative study.

[This corrects the article DOI: 10.3389/fped.2024.1334591.].

Hepatitis B in Pediatric Population: Observational Retrospective Study in Romania.

Hepatitis B virus (HBV) is a frequent cause of chronic hepatitis worldwide, with an estimated 5.6 million children under 5 years being infected. In Romania, there are no available epidemiology reports on large cohorts in children. We aimed to assess the profile of pediatric chronic HBV infection in southern Romania. We conducted an observational retrospective study on 506 HBV-infected children. Based on alaninaminotransferase (ALT), HBV serology and viremia, we identified four states of the disease. We correlated age, gender, household HBV infection, coinfection with other viruses and laboratory parameters. Most patients were in a positive HBV envelope antigen (HBeAg) immune-active state (65.4%). Age at diagnosis was significantly lower for those with household infection (p < 0.05). ALT values were not significantly different between positive or negative HBeAg patients in the immune-active state (p = 0.780). ALT values were higher in patients with hepatitis D virus (HDV)-associated infection (p < 0.001). Children with a household HBV infection had a high viraemia more frequently when compared to those with no infected relative (79.3% vs. 67.4%) (p < 0.001), but the ALT values were not significantly different (p = 0.21). Most of the patients are in an immune-active state (high ALT, high viremia). The percentages of HBV- and HDV-associated infections are high, but lower than the reported prevalence in Romania in the general population.

Hematological profile, inflammatory markers and serum liver enzymes in COVID 19 positive children vs. COVID 19 negative ones-a comparative study.

Background: Complete blood count, C-reactive protein and transaminases are routine laboratory parameters investigated in children with infections, including COVID 19. We aimed to evaluate the diagnostic accuracy of these parameters in children diagnosed with COVID 19. Methods: At the time of admission, children with COVID 19 suggestive symptoms were tested RT-PCR for SARS CoV-2 and were allocated to either the study group (RT-PCR SARS CoV-2 positive) or control group (RT-PCR SARS CoV-2 negative). All children were evaluated by complete blood count, CRP, and transaminases. Results: When comparing the two groups, we identified significantly lower values for leukocytes (p < 0.001), neutrophils (p < 0.001), lymphocytes (p < 0.001) and thrombocytes (p = 0.014), but no significantly different values for CRP (p = 0.916) and monocytes (p = 0.082). A diagnostic score for COVID-19 was compiled using the abovementioned parameters-presence of fever, number of lymphocytes and aspartate-aminotransferase. Performance was tested, showing a positive discrimination value (AUC of 0.703)-81.5% sensitivity, 50.6% specificity. Conclusions: The leukocytes, neutrophils and lymphocytes have significantly lower values in COVID-19 children. The proposed score based on the presence of fever the values of lymphocytes and AST has a good sensitivity in predicting COVID-19 infection.

From Severe Anemia to Intestinal Hemangiomatosis, a Bumpy Road-A Case Report and Literature Review.

Gastrointestinal hemangiomas (GIH) are unusual vascular tumors found anywhere alongside the GI tract, the small bowel being the most common site. Diagnosis requires good clinical insight and modern imaging. This is a comprehensive review of the literature, starting from a new pediatric case diagnosed through exploratory laparotomy after complex imaging techniques failed. This research was conducted on published articles from the past 25 years. We identified seventeen original papers (two series of cases with three and two patients, respectively, and fifteen case reports). The female/male ratio was 1.5. The youngest patient was a 3-week-old boy, and the was oldest a 17-year-old girl. The most common localization was the jejunum (eight cases), followed by the ileum (four), colon (three), stomach (two), and rectum (one). Seven children had cavernous and four had capillary hemangiomas. Eight patients presented gastrointestinal bleeding, seven had refractory anemia, such as our index patient, three had recurrent abdominal pain, and two had bowel obstruction. Surgical assessment was successful in fifteen cases; three cases experienced great outcomes with oral propranolol, one child was treated successfully with sirolimus, and for one patient, endoscopic treatment was the best choice. The authors present the case of a female patient admitted to the Pediatrics Department of "Grigore Alexandrescu" Emergency Children's Hospital from 25 February to 28 March 2019 for severe anemia, refractory to oral iron treatment, and recurrent blood infusions. No clear bleeding cause had been found. Although very uncommon, intestinal hemangiomas can express puzzling, life-threatening symptoms. We should keep in mind this disorder in cases of unresponsive chronic anemia.

New Perspectives of Therapies in Osteogenesis Imperfecta-A Literature Review.

(1) Background: Osteogenesis imperfecta (OI) is a rare skeletal dysplasia characterized as a heterogeneous disorder group with well-defined phenotypic and genetic features that share uncommon bone fragility. The current treatment options, medical and orthopedic, are limited and not efficient enough to improve the low bone density, bone fragility, growth, and mobility of the affected individuals, creating the need for alternative therapeutic agents. (2) Methods: We searched the medical database to find papers regarding treatments for OI other than conventional ones. We included 45 publications. (3) Results: In reviewing the literature, eight new potential therapies for OI were identified, proving promising results in cells and animal models or in human practice, but further research is still needed. Bone marrow transplantation is a promising therapy in mice, adults, and children, decreasing the fracture rate with a beneficial effect on structural bone proprieties. Anti-RANKL antibodies generated controversial results related to the therapy schedule, from no change in the fracture rate to improvement in the bone mineral density resorption markers and bone formation, but with adverse effects related to hypercalcemia. Sclerostin inhibitors in murine models demonstrated an increase in the bone formation rate and trabecular cortical bone mass, and a few human studies showed an increase in biomarkers and BMD and the downregulation of resorption markers. Recombinant human parathormone and TGF-ß generated good results in human studies by increasing BMD, depending on the type of OI. Gene therapy, 4-phenylbutiric acid, and inhibition of eIF2α phosphatase enzymes have only been studied in cell cultures and animal models, with promising results. (4) Conclusions: This paper focuses on eight potential therapies for OI, but there is not yet enough data for a new, generally accepted treatment. Most of them showed promising results, but further research is needed, especially in the pediatric field.

An Approach to Traumatic Brain Injury-Related Hypopituitarism: Overcoming the Pediatric Challenges.

Traumatic brain injury (TBI)-related hypopituitarism is a rare polymorphic complication of brain injury, with very little data, particularly concerning children and teenagers. This is a comprehensive review of the literature regarding this pathology, starting from a new pediatric case. The research was conducted on PubMed and included publications from the last 22 years. We identified nine original studies on the pediatric population (two case reports and seven studies; only four of these seven were prospective studies). TBI-related hypopituitarism is associated with isolated hormonal deficits ranging from 22.5% to 86% and multiple hormonal deficiencies from 5.9% to 50% in the studied pediatric population. Growth hormone (GH) deficiency is most often found, including the form with late occurrence after TBI; it was described as persistent in half of the studies. Thyroid-stimulating hormone (TSH) deficiency is identified as a distant complication following TBI; in all three studies, we identified this complication was found to be permanent. Adrenocorticotropic hormone (ACTH) deficiency did not relate to a certain type of brain trauma, and it was transient in reported cases. Hyperprolactinemia was the most frequent hormonal finding, also occurring late after injury. Central diabetes insipidus was encountered early post-TBI, typically with a transient pattern and did not relate to a particular type of injury. TBI-related hypopituitarism, although rare in children, should be taken into consideration even after a long time since the trauma. A multidisciplinary approach is needed if the patient is to safely overcome any acute condition.

Clinical and Evolutionary Features of SARS-CoV-2 Infection (COVID-19) in Children, a Romanian Perspective.

Background: Given the potential for additional development to clarify a better knowledge of generally influence of COVID-19 upon the pediatric population, the clinical symptoms of SARS-CoV-2 infection in children and adolescents are still being explored. Morbidity in children is characterized by a variable clinical course. Our study's goal was to compare clinical aspects of 230 pediatric patients who analyzed positive for SARS-CoV-2 and were hospitalized between April 2020 and March 2022. Methods: This retrospective study aimed to compare the clinical characteristics of coronavirus disease 2019, (COVID-19) in two groups of pediatric patients hospitalized in the infectious disease clinical ward IX at the National Institute for Infectious Diseases "Prof. Dr. Matei Bals," Bucharest, Romania. Clinical characteristics of 88 patients (first group), admitted between April−December 2020 were compared with the second group of 142 children admitted between July 2021 and March 2022. Results: Of 230 children, the median age was 4.5 years, and 53.9% were male. Fever (82.17%) and sore throat (66%) were the most common initial symptoms. Rhinorrhea (42%), cough (34%) and diarrhea (41.74%), with abdominal pain (26%) were also reported in a considerable number of cases. 88 (36.21%) patients (first group) were admitted during the second wave in Romania, mostly aged <5 years old, and experienced digestive manifestations like fever (p = 0.001), and diarrhea (p = 0.004). The second group experienced different clinical signs when compared with the first group, with higher temperature and increased respiratory symptoms analogous to persons who suffer acute respiratory viral infections. The proportion in the second group increased by 23.48% from the first group, and the 0−4 age group for both groups had symptoms for a median interval of 5 days; age (0−4-years old) and length of stay were both proportionally inversely and required longer hospitalization (5 days), for the first group. During study time, the fully vaccinated children for 5−12 years old were 10%, and for 13−18 years old, 14.35% respective. We report two Pediatric Inflammatory Multisystem Syndrome (PIMS) in the second group, with favorable evolution under treatment. Comorbidities (obesity and oncological diseases) were reported in both groups and are risk factors for complications appearing (p < 0.001). All pediatric cases admitted to our clinic evolved favorably and no death was recorded. Conclusions: Clinical characteristics of pediatric patients with COVID-19 are age-related. In the first group, 85.29% of 0−4 years old children experienced digestive symptoms, whereas in the second group 83.78% underwent mild and moderate respiratory symptoms for the 5−12 age range. The potential effects of COVID-19 infection in children older than 5 years should encourage caregivers to vaccinate and improve the prognosis among pediatric patients at risk.

Drug-Induced Hepatitis in Children: The Experience of a Single Center in Romania.

Drug-induced liver injury (DILI) is uncommon but potentially lethal. Over 6 years, 2533 children with acute liver disease were identified in our center, 48 of which suffered from toxic hepatitis, and 40 exhibited DILI (22 paracetamol-related, 14 albendazole-related). The most affected children were in the 13-17-year-old age group. The mean time between drug ingestion and disease diagnosis was 25.4 h for paracetamol-related DILI and 21.6 days for the albendazole-related group. Clinical features were mostly gastrointestinal, jaundice being reported in 30% of the cases. Regarding the type of liver injury, for 70% of the patients it was hepatocellular (mostly paracetamol toxicity), for 11% cholestatic, and for 19% mixed (albendazole-related). The mean initial ALT value was 1020 U/L for all DILIs. Coagulopathy was only identified for the acetaminophen-related group. The median number of hospitalization days was 6.9 for DILI related to acetaminophen ingestion, compared with 7 for the idiosyncratic pattern. When applying the DILI severity index, 81% of the patients were categorized as having a mild hepatic ailment, while 19% had a moderate-severe or severe disease. No deaths were reported in the study group. The diagnosis of DILI involves the exclusion of other causes of liver injury; therefore, it is considered one of the most challenging diagnoses in hepatology.

Hypertriglyceridemia Induced Acute Pancreatitis Caused by a Novel LIPC Gene Variant in a Pediatric Patient.

Hypertriglyceridemia induced acute pancreatitis is a rare cause of pancreatitis in children. Hepatic lipase deficiency is an extremely rare cause of hypertriglyceridemia, reported in only a few families to date. Hepatic lipase is the enzyme involved in the hydrolysis of triglycerides and phospholipids in remnants of triglyceride-rich lipoproteins that have a role in the conversion of very low density lipoprotein remnants to low density lipoproteins. Hepatic lipase deficiency is inherited in an autosomal recessive pattern. Detection of heterozygous carriers of hepatic lipase mutations remains accidental at the population level, as affected persons with a heterozygous state of hepatic lipase mutation do not display specific lipoprotein abnormalities and also patients with complete hepatic lipase deficiency have inconstant phenotype. The proximal promoter of the LIPC gene consists of four polymorphic sites in complete linkage disequilibrium. Five missense mutations in encoding exons have been described and proved to be responsible for hepatic lipase deficiency to date: S267F, T383M, L334F, A174T, and R186H, affecting the activity and secretion of hepatic lipase. We identified a primary disorder of the lipid metabolism as the cause of the acute episode of pancreatitis in a four years old patient, consisting of hepatic lipase deficiency caused by a novel genetic variant of the LIPC gene, a gross deletion of the genomic region encompassing exon 1. This variant was not previously described in the literature in persons with LIPC-related disorders and its significance is currently uncertain, but in the presented clinical and paraclinical context, it has the characteristics of a pathological variant inducing a hepatic lipase deficiency phenotype.

The Role of Predictive Models in the Assessment of the Poor Outcomes in Pediatric Acute Liver Failure.

OBJECTIVES: In children, acute liver failure (ALF) is a severe condition with high mortality. As some patients need liver transplantation (LT), it is essential to predict the fatal evolution and to refer them early for LT if needed. Our study aimed to evaluate the prognostic criteria and scores for assessing the outcome in children with ALF. METHODS: Data of 161 children with ALF (54.66% female, mean age 7.66 ± 6.18 years) were analyzed based on final evolution (32.91% with fatal evolution or LT) and etiology. We calculated on the first day of hospitalization the PELD score (109 children), MELD, and MELD-Na score (52 children), and King's College Criteria (KCC) for all patients. The Nazer prognostic index and Wilson index for predicting mortality were calculated for nine patients with ALF in Wilson's disease (WD). RESULTS: PELD, MELD, and MELD-Na scores were significantly higher in patients with fatal evolution (21.04 ± 13.28 vs. 13.99 ± 10.07, p = 0.0023; 36.20 ± 19.51 vs. 20.08 ± 8.57, p < 0.0001; and 33.07 ± 8.29 vs. 20.08 ± 8.47, p < 0.0001, respectively). Moreover, age, bilirubin, albumin, INR, and hemoglobin significantly differed in children with fatal evolution. Function to etiology, PELD, MELD, MELD-Na, and KCC accurately predicted fatal evolution in toxic ALF (25.33 vs. 9.90, p = 0.0032; 37.29 vs. 18.79, p < 0.0001; 34.29 vs. 19.24, p = 0.0002, respectively; with positive predicting value 100%, negative predicting value 88.52%, and accuracy 89.23% for King's College criteria). The Wilson index for predicting mortality had an excellent predictive strength (100% sensibility and specificity), better than the Nazer prognostic index. CONCLUSIONS: Prognostic scores may be used to predict the fatal evolution of ALF in children in correlation with other parameters or criteria. Early estimation of the outcome of ALF is essential, mainly in countries where emergency LT is problematic, as the transfer to a specialized center could be delayed, affecting survival chances.

The diagnostic challenges in a child with intestinal tuberculosis.

INTRODUCTION: Romania is one of the European countries with a significant burden of tuberculosis (TB). Although pulmonary TB is still highly prevalent, intestinal TB is very rare and remains a diagnosis of exclusion, especially in children. The authors aimed to raise the awareness on this pathology by discussing the challenges faced in the management of one difficult case. CASE PRESENTATION: A 3-year-old boy was hospitalized in the Pediatrics Department of Grigore Alexandrescu Emergency Children's Hospital, Bucharest, Romania, for abdominal pain and melena. On clinical examination, he was malnourished, with generalized edema and marked abdominal distension. Laboratory tests revealed iron-deficiency anemia, low plasma proteins, inflammatory syndrome and high fecal calprotectin. The abdominal ultrasound showed bowel wall thickening and diffuse edematous mesentery; the colonoscopy described multiple ulcers with edematous margins. Parenteral nutrition and complex antibiotic treatment were initiated with no effect. During the hospital stay, the medical staff observed how the mother chewed the patient's food. The child's pulmonary X-ray was normal, but the mother's was suggestive for pulmonary TB. The QuantiFERON® test was positive. Biopsy of the bowel mucosa revealed numerous granulomas; the Auramine O∕Rhodamine B staining of the specimen was positive. Specific TB treatment was started with good results: the patient resumed growth, abdominal pain and distention disappeared. CONCLUSIONS: Intestinal TB poses a diagnostic challenge, especially in the absence of pulmonary disease. It may mimic many other intestinal pathologies. Since correct treatment depends on making the correct diagnosis, a high index of suspicion must be kept when facing atypical abdominal symptoms.

Autoimmune phenomena in treated and naive pediatric patients with chronic viral hepatitis.

Chronic viral hepatitis has been incriminated for inducing autoimmune events, but it is a known fact that interferon-based therapies also promote autoimmunity. We conducted an observational prospective study which included 114 pediatric patients with chronic viral hepatitis B and C. The patients were divided in 2 groups, the first group consisted of treatment-naive patients; the second group included patients who had received interferon-based therapy. We aimed to determine whether the ones who received treatment are more predisposed to developing autoimmune manifestations when compared to those naive. Fifty percent of the study group was found to have serological autoimmune phenomenon. Our research shows that the occurrence of the autoimmune phenomenon is delayed when the patient is treated with interferon-based regimens when compared to naive patients. Hence, even though interferon treatment has been reported to promote autoimmunity, the viruses themselves are more likely to induce the appearance of autoimmune markers over time in patients who do not receive treatment.

A case report on an incidental discovery of congenital portosystemic shunt.

RATIONALE: Congenital portosystemic shunt (Abernethy malformation) is a rare entity causing the portal blood to drain directly into the systemic circulation, eluding the liver. These shunts arise through disturbances in the embryonic development. PATIENT CONCERNS: A 9-year-old male patient was referred to our department for further evaluation of a vascular malformation which was diagnosed in another facility when the patient was 2 years old, following a routine abdominal ultrasound. The patient had no complaints and the physical examination was normal at all times. DIAGNOSIS: Laboratory tests and esogastroduodenoscopy were normal. The abdominal ultrasound showed a side-to-side shunt between a short portal trunk and the inferior vena cava. A hepatic mass suggestive for focal noduar hyperplasia was seen in the left liver lobe. Abdominal angio-computed tomography (angio-CT) was performed and the ultrasonographic anomalies were confirmed. Multiple other vascular malformations were diagnosed-hepatic artery emerging from the superior mesenteric artery, with early division; hepatic veins forming a short common trunk before draining into the inferior vena cava; supranumerary right renal artery emerging from the aorta, tributary for the upper renal pole. Ecocardiography showed left superior vena cava persistence. The final diagnosis was Abernathy malformation type IB. In the meantime the patient was diagnosed with allergic asthma. INTERVENTIONS: No surgical cure was pursued because the malformation was an incidental discovery. OUTCOMES: The patient was followed-up closely from the final diagnosis (when he was 9 years old) to present (he is currently 10 years old) with no change in his status-he remained asymptomatic. LESSONS: Angio-CT should be the performed whenever a vascular malformation is suspected in order to establish a correct diagnosis, because portosystemic shunts carry a high risk of severe complications. Knowing that patients with portosystemic shunts may have pulmonary hypertension, respiratory complaints should be carefully evaluated-in this particular case, even though the most probable cause for the respiratory symptoms was pulmonary hypertension, it was ruled out by cardiac ultrasonography and further investigations confirmed the diagnosis of allergic asthma.

Adequacy of scoring systems in diagnosing paediatric autoimmune hepatitis: retrospective study using a control group children with Hepatitis B infection.

AIM: To evaluate how correct is made the diagnosis of autoimmune hepatitis (AIH) in children, comparing the adults scoring systems - the 1999 revised scoring system by International Autoimmune Hepatitis Group and the 2007 Simplified Scoring System. The inaccuracies in diagnosis have been analysed. METHODS: The two scoring systems have been applied for 28 children with AIH pre-treatment and 28 with Hepatitis B infection - matched by sex and age, all diagnosed between 2010 and 2017 in an emergency children's hospital in Bucharest, Romania. They were retrospectively followed throughout the period assessed. RESULTS: Autoimmune hepatitis was present in 85.7% cases according to the 1999 revised score, respectively, 57.0% as per the 2007 simplified score. The 2007 simplified score led to false negative results when AIH was associated with another autoimmune disease (p = 0.009). Patients who did not undergo liver biopsy were associated with a downgraded diagnosis by the 2007 simplified score (p = 0.001). CONCLUSION: There is a need for a scoring system tailored to children's characteristics. Two compulsory components of the future score might be liver biopsy and associated autoimmune disorders. The existing scores could be used in children with consideration, preferably both at once and together with liver biopsy for increased accuracy.

Genetic disorder in carbohydrates metabolism: hereditary fructose intolerance associated with celiac disease.

Celiac disease (CD) has been associated with several genetic and immune disorders, but association between CD and hereditary fructose intolerance (HFI) is extremely rare. HFI is an autosomal recessive disease caused by catalytic deficiency of aldolase B (fructose-1,6-bisphosphate aldolase). We report the case of a 5-year-old boy suffering from CD, admitted with an initial diagnosis of Reye's-like syndrome. He presented with episodic unconsciousness, seizures, hypoglycemia, hepatomegaly and abnormal liver function. The patient has been on an exclusion diet for three years, but he still had symptoms: stunting, hepatomegaly, high transaminases, but tissue transglutaminase antibodies were negative. Liver biopsy showed hepatic steatosis and mitochondrial damage. The dietary history showed an aversion to fruits, vegetables and sweet-tasting foods. The fructose tolerance test was positive, revealing the diagnostic of hereditary fructose intolerance. Appropriate dietary management and precautions were recommended. The patient has been symptom-free and exhibited normal growth and development until 10 years of age.

The role of FENO and spirometry in the evaluation of obstruction in pediatric asthma.

INTRODUCTION: The fractional exhaled nitric oxide concentration (FENO) is used as a noninvasive biomarker for asthmatic inflammation. The role in establishing an asthma diagnosis is still under research. Spirometry remains the main investigation for the diagnosis and monitoring of asthma. OBJECTIVES: The aim of the study was to assess the correlation between FENO level and the values of spirometric parameters defining airflow obstruction. MATERIALS AND METHODS: The longitudinal study included a group of 89 children admitted to the Pediatric Clinic of "Grigore Alexandrescu" Emergency Clinical Hospital for Children. The inclusion criteria were: (i) a previously known diagnosis of asthma, (ii) age range between 5 and 18 years old. All patients underwent pulmonary function testing and measurement of FENO. RESULTS: Significant correlations were identified between FENO and a part of spirometric parameters: MEF75 (p=0.007), MEF50 (p=0.0.28), MEF25 (p=0.011) and PEF (p=0.020), but not with FEV1 (p=0.090), nor FVC (p=0.308). However, multiple linear regression analysis revealed that spirometric parameters poorly predict FENO variation (R=0.062, p=0.82). In adition, binary logistic regression analysis (LR) showed that FENO can not be used as a reliable biomarker (p=0.169) for the estimation of the risk for obstructive dysfunction. CONCLUSION: The level of exhaled nitric oxide does not correlate with the values of spirometric values. More studies with a large number of patients are needed for establishing the role of FENO in the evaluation of airflow obstruction.

Clinical characteristics of rotavirus diarrhea in hospitalized Romanian infants.

Clinical characteristics of rotavirus enteritis were evaluated by comparison with acute diarrhea of other etiologies. We reviewed the medical records of children (aged 0-12 months) admitted with acute diarrhea in our hospital between January and December 2011. Of the 839 patients, 49.3% had rotavirus diarrhea. The incidence of severe disease was significantly higher for rotavirus diarrhea (65.2%, P < 0.01) than for other types of diarrheal disease.