Current Pediatric Reviews - Volume 16, Issue 4, 2020

Gender dimorphism in autism spectrum disorders (ASD) is well known; however, the reasons for gender differences in autism are poorly understood. There are several hypotheses that might explain male prevalence in ASD, including increased levels of androgens, “extreme male brain,” and a combination of elevated levels of prenatal testosterone in conjunction with prenatal stress. In this comprehensive review, differences in the gut microbiome and metabolome in humans and animals are described to explain gender differences in individuals with ASD, effects on behavior and social interactions and the impact of antibiotics, probiotics and fecal transplants. The bidirectional relationship between sex hormones and intestinal microbiota could also be relevant. Such interactions have been described in autoimmune diseases, but thus far, are not implicated in ASD. Since intestinal microbiota may affect behavior, it is possible that the prevalence of ASD in boys may be associated with more significant changes in the intestinal microbiome than in affected girls.

Introduction: Breast Milk (BM), containing nutrients and bioactive components, represents the best source for neonatal nutrition and determines short- and long- term benefits. Human milk oligosaccharides (HMOs) play an active role in these pathophysiological mechanisms. In fact, they influence the shaping of breastfed infant’s gut microbiota, promote intestinal development, confer protection against intestinal or systemic infections modulating immune system; moreover, HMOs determine extra-intestinal effects on several target organs, i.e reducing necrotizing enterocolitis rate or improving brain development. Aims: In this review, we analyze the great inter- and intra-individual variability of BM HMOs, investigating maternal, genetic and environmental factors modulating their composition. Moreover, we provide an update regarding HMOs’ unique properties, underlining their complex interaction with intestinal microbiota and host-derived metabolites. The possible HMOs’ influence on extraintestinal bacterial communities, potentially influencing newborns’ and even lactating mothers’ health, have been hypothesized. Finally, recognized HMOs’ crucial role, we underline the promising opportunities showed by their addition in formula milk, to make it more similar to maternal milk itself.

Background: Henoch-Schönlein purpura (HSP) is an IgA-mediated systemic smallvessel vasculitis with a predilection for the skin, gastrointestinal tract, joints, and kidneys. It is the most common form of systemic vasculitis in children. Objective: The study aimed to familiarize physicians with the etiopathogenesis, clinical manifestations, evaluation, and management of children with Henoch-Schönlein purpura. Methods: A PubMed search was conducted in January 2020 in Clinical Queries using the key terms “Henoch-Schönlein purpura” OR “IgA vasculitis” OR “anaphylactoid purpura”. The search strategy included meta-analyses, randomized controlled trials, clinical trials, observational studies, and reviews published within the past 10 years. Only papers published in the English literature were included in this review. This paper is based on, but not limited to, the search results. Results: Globally, the incidence of HSP is 10 to 20 cases per 100, 000 children per year. Approximately 90% of cases occur in children between 2 and 10 years of age, with a peak incidence at 4 to 7 years. The diagnosis should be based on the finding of palpable purpura in the presence of at least one of the following criteria, namely, diffuse abdominal pain, arthritis or arthralgia, renal involvement (hematuria and/or proteinuria), and a biopsy showing predominant IgA deposition. Most cases are self-limited. The average duration of the disease is 4 weeks. Long-term complications are rare and include persistent hypertension and end-stage kidney disease. Therapy consists of general and supportive measures as well as treatment of the sequelae of the vasculitis. Current evidence does not support the universal treatment of HSP patients with corticosteroids. Oral corticosteroids may be considered for HSP patients with severe gastrointestinal pain and gastrointestinal hemorrhage. Conclusion: Most cases of HSP have an excellent outcome, with renal involvement being the most important prognostic factor in determining morbidity and mortality. Unfortunately, early steroid treatment does not reduce the incidence and severity of nephropathy in children with HSP. In HSP children who have severe nephritis or renal involvement with proteinuria of greater than 3 months, an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker should be considered in addition to corticosteroids to prevent and/or limit secondary glomerular injury.

Background: Hiccups are a universal phenomenon. They are usually benign and selflimited. Persistent or intractable hiccups, although rare, can be debilitating and may indicate the presence of an underlying pathological process. Objective: To familiarize physicians with the pathophysiology, etiology, evaluation, and management of children with hiccups. Methods: A search was conducted on December 10, 2019, in Pubmed Clinical Queries using the key terms "hiccup" OR “hiccough” OR “singultus”. The selected publication types included all clinical trials (including open trials, non-randomized controlled trials, and randomized controlled trials), observational studies, and reviews (including meta-analysis and narrative reviews) published within the past 10 years. Only papers published in the English literature were included in this review. The information retrieved from the above search was used in the compilation of the present article. Results: Overdistension of the stomach is the most commonly identifiable cause of acute hiccups, followed by gastroesophageal reflux and gastritis. Other causes of hiccups, notably persistent and intractable hiccups, include an underlying gastrointestinal, neurological, cardiovascular, pulmonary, infectious, and psychogenic disorder. Persistent or intractable hiccups can be a harbinger of serious medical pathology. A detailed history and thorough physical examination may provide clues for the etiology of the hiccups. The treatment of hiccups should be directed at the underlying cause whenever possible. Bouts of acute hiccups less than 48 hours rarely require medical intervention as they usually resolve within minutes. Treatment may be considered when hiccups are bothersome, persistent, or intractable. Treatment modalities include lifestyle changes, physical maneuvers, pharmacotherapy and, very rarely, surgical intervention. Conclusion: Acute hiccups are usually benign and self-limiting. Persistent or intractable hiccups can be a harbinger of serious medical pathology. The underlying cause should be treated if possible. There are no formal guidelines for the treatment of hiccups. Currently, most of the methods proposed are based on case reports and anecdotal evidence. Terminating an episode of hiccups can be very challenging for a clinician but may tremendously improve the patient’s quality of life. It is hoped that future well-designed and better-powered studies will provide us with more information on the efficacy of various treatment modalities for hiccups.

Background: Acute hemorrhagic edema of infancy (AHEI), a benign and self-limited disease, can be easily mistaken to be a number of diseases with similar dermatological manifestations but with potentially adverse outcomes. Objective: This review aimed to familiarize pediatricians with the natural history, clinical manifestations, diagnosis, and management of AHEI. Methods: A PubMed search was conducted in February 2020 in Clinical Queries using the key terms “acute hemorrhagic edema of infancy“ OR “Finkelstein disease“ OR “Seidlmayer disease“. The search strategy included meta-analyses, randomized controlled trials, clinical trials, observational studies, and reviews published within the past 10 years. Only papers published in the English literature were included in this review. The information retrieved from the above search was used in the compilation of the present article. Results: AHEI, a rare cutaneous leukocytoclastic small-vessel vasculitis, typically presents with palpable purpura, peripheral acral edema, and frequently with fever, most often in children between 4 and 24 months of age. A significant number of children experience prodromal symptoms of an upper respiratory infection. Fever is typically low grade and is present in approximately 50% of cases. The cutaneous lesions are characterized by rapid onset of small erythematous macules or papules that progress to well demarcated, annular, rosette, medallion-like, or targetoid purpuric plaques or ecchymosis in 24 to 48 hours. The skin lesions are typically palpable, nonpruritic, and symmetrically distributed. Sites of predilection include the face, auricles, and extremities. Edema is typically nonpitting and asymmetrical and occurs primarily on the dorsum of the hands and feet, the face, and the auricles. In spite of the acuteness and extent of the cutaneous findings, the child looks well and nontoxic. Systemic and/or visceral involvement are rare. The differential diagnosis is broad and includes, among others, Henoch-Schin purpura. It is crucial to distinguish AHEI from the other diseases since the management of these diseases is quite different. The clinical features of mimickers of AHEI are reviewed and clues to differentiate AHEI from these mimickers are highlighted.AHEI is a benign, self-limited disease with complete spontaneous recovery in one to three weeks in the majority of cases. Conclusion: Recognizing this rare disease is important for the pediatrician to rapidly differentiate AHEI from other potentially serious diseases that require prompt therapy and monitoring. With rapid recognition of AHEI, unnecessary investigations and inappropriate interventions can be prevented and parental anxiety can be avoided.

Nonalcoholic fatty liver disease (NAFLD) is the main cause of chronic liver disease in children. With the global obesity epidemic, the prevalence of NAFLD is increasing both in industrialized and developing countries. NAFLD is a multisystem disorder and a hepatic manifestation of the metabolic syndrome. Growing scientific evidence suggests that NAFLD is an independent risk factor for cardiovascular disease. This paper briefly describes the current knowledge concerning the association between NAFLD and cardiac dysfunction in children.

Recent reports from several developed countries have documented a resurgence of bilirubin encephalopathy causing both healthcare and forensic issues. For these reasons, many national pediatric societies have issued recommendations on the diagnosis and the treatment of clinically significant neonatal hyperbilirubinemia. The differences among individual national documents may have an impact on neonatal healthcare. This paper shortly reviews the advantages and the shortcomings of the main international guidelines with a focus on the available evidence.

Background: Pneumonia is an acute infection of the lung parenchyma that is differentiated among three main diagnoses: community-acquired pneumonia (CAP), hospital-acquired pneumonia (HAP), and healthcare-associated pneumonia (HCAP). Though CAP is initially presented as a mild infection, it contributes to childhood mortality rates globally. A vast number of pathogens are the cause of CAP, but the two main causative organisms include Streptococcus pneumoniae and Haemophilus influenzae, with the former causing up to 50% of all childhood cases. In the current treatment guidelines from the Infectious Diseases Society of America (IDSA), amoxicillin is the recommended treatment choice for mild-to-moderate CAP while ampicillin is recommended for cases of severe CAP. Previous studies compared treatment between macrolides and beta-lactams to provide more information on the effectiveness in the pediatric population. Objective: The objective of this article is to systematically review the literature on the comparative efficacy of beta-lactams and macrolides in the treatment of community-acquired pneumonia among children and to evaluate the outcomes that are used to determine drug efficacy in order to provide medication recommendations. Methods: A systematic literature search was conducted in PubMed, TRIP, Cochrane and SCOPUS. Cohort studies and randomized controlled trials between the years 2000 and 2020 that compared the efficacy of amoxicillin and macrolides in treating pediatric pneumonia were included in the systematic review. Eligible patients included patients who were 17 years and younger, diagnosed with community-acquired pneumonia, and were given beta-lactams or macrolides, either as monotherapy or combination. Two reviewers were involved in the appraisal process to assess the quality of the methods used in the selected studies. Results: A total of six articles were eligible according to the inclusion criteria and quality assessment. Four articles compared beta-lactam monotherapy with beta-lactam and macrolide combination therapy, while Kogan R et al. compared macrolide therapy monotherapy with beta-lactam and macrolide combination therapy and Leyenaar JK et al. compared ceftriaxone monotherapy to ceftriaxone plus macrolide combination therapy. The studies defined treatment failure as either a change in antibiotic therapy or hospital admission within 14 days of CAP diagnosis. Three studies used the length of hospital stay as their primary outcome for comparison of treatment efficacy. Four studies showed that the use of macrolides provided better treatment outcomes by reducing hospital stay and treatment failure rates. Beta-lactam and macrolide combination therapy did not show a significant effect on treatment failure compared to beta-lactam monotherapy regimens and it did not affect mortality compared to placebo or diet alone. Within the macrolide class, azithromycin was more clinically significant compared to erythromycin. Conclusion: The use of macrolides as monotherapy or add-on therapy to beta-lactams is more effective in the treatment of community-acquired pneumonia in the pediatric population.

Background: Although LC-MS/MS is preferred as a reliable method, therapeutic enzyme drugs in the blood matrix may lead to false results. Objective: The purpose of this article is to experimentally investigate the effect of five different enzymes used in the treatment of metabolic diseases on blood immunosuppressant measurement. Methods: Five different enzyme drugs (galsulfase, alglucosidase alfa, imiglucerase, elosulfase alfa, laronidase) were added to control materials containing tacrolimus, everolimus, sirolimus, and cyclosporine A drugs. Measurements were performed using an LC-MS/MS instrument (Shimadzu 8040, Japan). The amount of deviations from the target values was calculated. Results: Blood Immunosuppressant levels significantly changed after the administration of enzyme drugs. Four different enzyme drugs led to false-positive results in the tacrolimus levels at a rate of 10.58% (95% CI, 9.83-11.32) to 37.28% (95% CI, 33.55-41.27). The highest deviations were observed with the administration of galsulfase and alglucosidase alpha in the sirolimus levels at rates of 336.54% (95% CI, 306.25-366.82) and 395.88% (95% CI, 360.25-431.50), respectively. Imiglucerase was the least effective enzyme for the sirolimus level (0.80% (95% CI, 0.71-0.89). Different deviations between the ratios of - 9.37% (95% CI, -10.40 - -8.33) and 8.33% (95% CI, 7.41-9.24) were determined at the cyclosporin A level. Conclusion: Galsulfase, alglucosidase alpha, imigluserase, elosulfase alpha and laronidase can significantly interfere with immunosuppressant measurements with LC-MS/MS. False immunosuppressant results associated with enzyme injection may result in immunosuppression failure, organ rejection. For the measurement of immunosuppressant levels, sampling should be done before the enzyme infusion. Clinicians should question the time of enzyme infusion and sampling when confounding results in immunosuppressant measurement.

Introduction: Mid-Aortic Syndrome (MAS) is a rare vascular malformation characterized by segmental narrowing of the abdominal aorta and stenosis of its principal branches. Patients affected by MAS typically present malignant renovascular hypertension, with variable clinical symptoms like claudication, abdominal angina, and headache. Moreover, they can develop other complications, such as hypertensive encephalopathy, congestive heart failure and vascular brain accidents. Hypertension with MAS is often resistant to multidrug therapy, requiring a surgical approach to treat the clinical symptoms, prevent or block organ damage and normalize the blood pressure. Case report: Here, the case of a 4-year-old boy showing elevated blood pressure with left ventricular hypertrophy leading to idiopathic MAS, who was successfully treated with percutaneous transcatheter renal angioplasty (PTRA) using an unusual, anterograde access, is reported. Discussion and Conclusion: In children and adolescents, vascular malformations like MAS must be considered as a possible cause of hypertension. PTRA is a successful therapeutic strategy in children with severe renovascular hypertension. Anterograde access, using an axillary artery, can be a valid approach for PTRA when femoral access is difficult to achieve.