New agents for invasive mycoses in children

PURPOSE OF REVIEW: Invasive fungal infections are an important cause of morbidity and mortality in immunocompromised children of all ages. This review summarizes information on new antifungal agents, including current data on their clinical use in children, as well as alternative strategies such as antifungal combination and immunomodulation therapy. RECENT FINDINGS: Novel antifungal agents, such as the echinocandins and the second-generation triazoles, were recently introduced that exhibit promising efficacy against Candida spp., Aspergillus spp., and other opportunistic fungal pathogens. These compounds are generally well tolerated and show substantial efficacy as salvage treatment and equal or even superior efficacy compared with older azoles or amphotericin B as first-line or empiric therapy for fungal infections. Clinical studies of pharmacokinetics and efficacy of the new agents in the pediatric population are, however, limited. SUMMARY: The response rates observed with the recently introduced drugs, although superior in some cases compared with older antifungal agents, are still far from satisfactory. The development of new antifungal compounds as well as the use of alternative approaches of combination therapy and immunomodulation should be pursued through well-designed laboratory and clinical studies in pediatric patients.     

Hematopoietic stem cell transplantation for curing children with severe autoimmune diseases: Is this a valid option?

The cure of children with severe AD, especially patients with severe, progressive, and therapy-resistant autoimmunity, represents a challenge for current medical practice. The idea of HSCT as a promising therapeutic opportunity was borne accidentally from finding patients who, after undergoing HSCT for a hematological indication, were cured of a concomitant AD. Thus, over the last two decades, HSCT has been extensively investigated, and it has become an appealing therapy for rheumatological (juvenile rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis) and hematological diseases (immune cytopenias). Recently, interesting results have been also described in type 1 diabetes mellitus and Crohn's disease. Although the use of HSCT has been steadily rising in the last few years, many questions are still open, especially after the discoveries of many new biological agents. Given the low incidence of ADs in children, most of the data about the use of the HSCT for these diseases are taken from a mixed cohort of adults and children. The aim of this review is to summarize the published studies and to try to answer the question as to whether this procedure can be considered a promising approach.     

Newer therapies for cystic fibrosis

Cystic fibrosis is the most common lethal inherited disease in Caucasians in the UK, with an incidence of approximately one in 2500 live births. It is a heterogeneous disease which reflects different mutations in the cystic fibrosis transmembrane conductance regulator gene, modifier genes and environmental influences. The median life expectancy of children with cystic fibrosis born in the UK is approximately 30 years. Longer survival is the result of improvements in basic therapies including airway clearance, aggressive use of antibiotics and optimizing nutrition. Care given in a specialist centre has also been shown to improve survival. Despite this progress, pulmonary disease still accounts for most of the morbidity and is the cause of death in over 90% of patients with cystic fibrosis. This review will focus on newer therapies aimed at pulmonary disease which are now being used in the clinical setting, and other novel therapies which are still at the research stage.     

Treating the wheezing infant

The management of infants and small children with asthma is a challenging task because of the many issues unique to this age group that deserve special consideration. The diagnosis of asthma is limited by inherent difficulties in obtaining objective measures of lung function and airway inflammation. In persistently symptomatic patients, the decision to initiate controller therapy is not as great an issue as it is in infants and young children with recurrent episodic wheeze in whom early intervention may allow a window of opportunity potentially to alter the course of the disease. The reality is that even if atopy has been consistently implicated in the development of persistent asthma, there is not a well-established set of criteria by which patients who are likely to benefit from early intervention controller therapy can be identified. Hence, large prospective studies need to be performed evaluating the impact of early pharmacologic intervention on the natural history of infantile asthma. Many areas needing investigation involve what medications to use, how best to deliver the medications, and how to monitor the response to treatment. Only a few medications have been approved for use in this population. Long-term studies evaluating available drugs such as inhaled glucocorticoids, LABAs, and the leukotriene-modifying agents in young children still need to be performed.     

Tobacco addiction in young people: the paediatrician's role

Smoking is the leading cause of preventable deaths worldwide. Both first- and second-hand tobacco smoking are a major cause of morbidity in children. Smoking has both a health and an economic impact. Whilst there has been legislation in the UK that has impacted tobacco use, there remain about 88,000 children who start smoking each year in the UK. There is an increasing focus to treat tobacco addiction as a disease, and the dependency is more likely to start in the adolescent years. The paediatrician has an important role in systematically identifying smokers and offering highly cost-effective treatments to smokers in order to improve the chances of quitting and thus reduce the consequences that come along with smoking. This article discusses the importance of recognizing nicotine addiction, the increasing use of electronic cigarettes, the benefits of nicotine replacement therapy and behavioural support in smoking cessation in the paediatric population. We explore the WHO Framework Convention of Tobacco Control and the relevance of it to the paediatrician's role.     

Application of stem cell transplant for brain tumors

Abstract:  Brain tumors are the second most common malignancy in children and the most common solid tumor. The majority of children are treated with surgery alone or in combination with radiation and/or chemotherapy. Recently investigators have used high dose chemotherapy with autologous stem cell rescue (ASCR) in patients with malignant brain tumors. This approach has been most successful in chemosensitive tumors including medulloblastoma, supratentorial primitive neuroectodermal tumors (SPNET) and central nervous system germ cell tumors (CNS GCT). In addition, the use of high dose chemotherapy has enabled the reduction and in many cases elimination of radiation therapy to very young children. To date there have been no prospective randomized studies comparing high dose chemotherapy and ASCR with conventional therapy. Radiation therapy is often not an option for patients with recurrent disease and conventional dose chemotherapy rarely if ever results in long-term survival. Unfortunately, the majority of studies using conventional therapy in order to delay irradiation in young children newly diagnosed with malignant brain tumors have been unsuccessful. Although the numbers are small, preliminary data suggest that not only is survival but also quality of life is superior with the use of high dose chemotherapy. Future studies will most likely include the use of new agents as part of the cytoreduction. In addition, through the use of peripheral blood stem cells and improvements in supportive care, multiple courses of high dose chemotherapy can be administered. High dose chemotherapy with ASCR is a foundation upon which many different types of therapies can be built. Several possibilities include the use of anti-angiogenesis agents, monoclonal antibodies and biologic response modifiers.     

New modalities for preventing and treating influenza

Influenza continues to plague children and adults annually, causing moderate to severe disease and, in some cases, leading to death caused by primary or secondary infection. New epidemiologic studies confirm that the impact of influenza on children is great. Public health officials expect a pandemic that is likely to dramatically increase the morbidity and mortality from influenza. New modalities that have arisen for prevention and treatment include the cold-adapted nasal vaccine and new neuraminidase inhibitors (oseltamivir and zanamivir), which have been approved for use in children. Like older agents (amantadine and rimantadine), the neuraminidase receptor agents must be used within the first 2 days of illness to be effective for therapy. Correct and early diagnosis is, therefore, necessary. The greatest advantages of newer agents are the additional efficacy against influenza B virus and the low frequency of drug resistance. Shortened illness and a reduction in minor complications are the main observed benefits of therapy. Because new agents are much more expensive than are older ones, dynamic cost-benefit analysis specific for children is needed to determine the utility of these drugs. Vaccination remains the most cost-effective approach to influenza disease. Universal vaccination of children remains a consideration for the future. Copyright © 2001 by W.B. Saunders Company     

Hypertension in children: an update on treatment strategies

PURPOSE OF REVIEW: Hypertension is among the more prevalent treatable diseases that afflict children. Pediatric hypertension carries significant short-term morbidity and long-term risk for the development of cardiovascular disease. This review addresses issues significant to the chronic management of hypertension and discusses common pharmacological agents currently used to treat elevated blood pressure in children. RECENT FINDINGS: The recent change in the Federal 2002 Best Pharmaceuticals for Children Act has led to the study and approval of new antihypertensive medications for use in pediatrics. Several antihypertensive medications are commercially available in liquid form or can be extemporaneously compounded for flexible dosing and ease of administration. SUMMARY: The availability of normative blood pressure data and several pharmacologic antihypertensive agents makes early detection and treatment of hypertension in children a realizable goal. The long-term effect of chronic antihypertensive therapy on growth, as well as the prevention of future development of cardiovascular disease, is not fully understood.     

Adaptation of the Manchester-Minneapolis Quality of Life instrument for use in the UK population.

INTRODUCTION: The availability of health-related quality of life (HRQL) measures that are reliable, valid, brief and comprehensible and appropriate for use with UK children is limited. We report the validation of a HRQL measure suitable for UK use in healthy children, children with chronic disease conditions and socially disadvantaged children. PATIENTS: A total of 1238 children took part in the study, including healthy children as controls (n = 824) and five exemplar groups: children diagnosed with asthma (n = 87), diabetes (n = 103) or inflammatory bowel disease (IBD; n = 69), children in remission from cancer (n = 68) and children in public care (n = 87). METHODS: In phase I, the Manchester-Minneapolis Quality of Life instrument (MMQL) Child Form was translated into UK English. In phases II and III, the questionnaire was shortened and validated. RESULTS: MMQL was anglicised and shortened to five components comprising 29 items. Good internal reliability was found with alpha reaching at least 0.69 for all subscales. Construct validity was established through moderate correlations with comparable PedsQL subscales (Pearson's r ranged from 0.38 to 0.58, p<0.01). Discriminant validity was also demonstrated in children with asthma and IBD, children in remission from cancer and children in public care, all of whom reported significantly lower HRQL than healthy children. Children with diabetes showed similar HRQL to their healthy peers. Good reproducibility and moderate responsiveness were demonstrated for the new measure. CONCLUSIONS: The anglicised and shortened MMQL was shown to be valid and reliable and could be a valuable new tool for the assessment of HRQL in children.     

Coeliac disease

The incidence of coeliac disease remains high in the UK. This review describes the pathophysiology and presentation of children with coeliac disease. We discuss the new diagnostic process, which is now guided by the presence or absence of symptoms. New guidelines allow a secure diagnosis to be made in some children with the use of serological testing and genotyping, in place of duodenal biopsy.     

Exclusive enteral nutrition in the treatment of children with Crohn's disease in Sweden: a questionnaire survey

Aim: The general use of exclusive enteral nutrition (EEN) as therapy for children with Crohn’s disease (CD) in Sweden has not previously been studied. Thus, the aim of this study was to investigate how EEN is used as therapy in Sweden for children with CD. Methods: A questionnaire was sent to all 37 paediatric units in Sweden that treat children with inflammatory bowel disease. Results: The response rate was 78%, which covers nearly 90% of Sweden’s paediatric population between 0 and 17 years of age. Ninety‐six per cent of the units used EEN as a treatment option for children with CD, and 65% of the units used EEN as their primary therapy in newly diagnosed CD. The standard duration of EEN was 6 weeks, but the questionnaire revealed a span of 4–8 weeks. The use of polymeric formula was just as common as a combination of polymeric and elemental formulas. Fifty‐seven per cent used oral nutrition supplements, and 81% allowed some extent of concomitant feeding, the addition of food and fluids, during EEN. All units used enteral nutrition to some extent as maintenance therapy after EEN was discontinued. Conclusions: In Sweden, EEN is used as therapy for children with Crohn′s disease (CD), but the EEN protocols vary as to choice of formula and type of food and fluids allowed during EEN. Standardized EEN protocols would enable multicentre studies in Sweden, with the objective of investigating how EEN treatment can be improved and employed in the most efficient way.     

Non-Hodgkin's lymphoma: current management

Around 100 new cases of non-Hodgkin's lymphoma are diagnosed each year in the UK, accounting for 7% of childhood cancer. Immunophenotype and stage are used to determine treatment, current treatment resulting in more than 70% long-term survival. The extent of disease at diagnosis is the most important prognostic factor. Patients with localized disease have an excellent prognosis regardless of histology, with a 5-year survival rate of around 90%. The use of intensive multi-agent chemotherapy has improved the outcome for patients with more advanced disease. However, children who relapse after intensive treatment have a poor outcome despite aggressive attempts at salvage treatment. Future advances in treatment require multinational trials in order that treatment can be refined to reduce toxicity for those children with an expected good outcome, and to develop new strategies for children who relapse.     

A discourse: the 2002 Wataru W. Sutow lecture. Hodgkin disease in children--perspectives and progress

THE PIONEER: Wataru W. Sutow, 1912-1981, was a remarkable and pivotal leader in pediatric oncology. Early in his medical career, he conducted important clinical and anthropometric studies among Japanese and Marshall Island children exposed to atomic radiation. These studies established standards for childhood growth and development still in use today. Dr. Sutow pioneered the multidisciplinary approach to childhood cancer by combining multidrug chemotherapy protocols with surgery and radiotherapy in the common childhood solid tumors. The textbook "Clinical Pediatric Oncology," of which he was the senior editor, served to define the discipline of pediatric oncology and educate a new era of oncologists in the curative treatment for childhood cancer. THE PAST AND PRESENT: The first edition of "Clinical Pediatric Oncology," published in 1973, demonstrated that only children with early-stage localized Hodgkin disease had a realistic opportunity for cure. Soon the use of combined-modality therapy consisting of low-dose, involved-field radiation plus multi-agent chemotherapy emerged, and made the goal of cure realistic for all patients. This approach is now universal. Today, the 5-year relative survival rate for American children with Hodgkin disease, who are under 14 years of age, is 94%, a dramatic and remarkable achievement. FUTURE: Management of children with Hodgkin disease now involves clinical staging and risk-adapted, combined-modality therapy. Clinical and translational research initiatives that hold promise for children with Hodgkin disease in the future include: use of the WHO Classification System combining morphologic and biologic criteria; noninvasive staging procedures with increased sensitivity and specificity; development of a useful prognostic index to define groups for risk-adapted therapy; high-dose therapy with stem cell transplantation; and novel therapies.     

Pharmacology considerations for antiretroviral therapy in human immunodeficiency virus (HIV)-infected children

The contemporary treatment of the child infected with human immunodeficiency virus (HIV) unavoidably requires combination therapy with antiretroviral agents and may include additional drugs for the prevention and treatment of opportunistic infections or other disease states. The current guidelines for the treatment of the HIV-infected child recommend that the same principles of treatment for adults should apply to children. However, the pharmacokinetic and pharmacodynamic characteristics of many agents and regimens used in adults have not been defined adequately in children, and large-scale clinical trials to establish safety and show efficacy have not been completed. Therefore, the clinician will be required to use agents with incomplete knowledge about their pharmacologic properties. The purpose of this article is to provide an overview of the pediatric pharmacologic principles, a review of the pharmacologic characteristics of selected antiretroviral agents in children, and a prospectus on the design of drug dosing regimens in children.     

Management of acute renal failure in children

The term acute kidney injury (AKI) has replaced acute renal failure, recognizing that an acute decline in renal function is often secondary to an injury or insult. The incidence of AKI was 8 per million total population in a UK retrospective study. AKI is classified into three groups: pre-renal, intrinsic renal and obstructive post-renal AKI. Haemolytic uraemic syndrome and acute tubular necrosis (ATN) are the most common causes in children. This review discusses the clinical evaluation, investigation and management of AKI and its associated complications. The prognosis for AKI depends upon the underlying cause. It is good for ATN and interstitial nephritis but AKI following cardiac surgery has the worst outcome. Other poor prognostic factors include multiorgan failure, inotropic support, ventilation and need for dialysis therapy. AKI due to primary renal disease is not common but is the cause for the majority of children who need chronic dialysis therapy. All children with AKI who require renal replacement therapy need long-term follow-up to monitor blood pressure, proteinuria and renal function.     

儿童心力衰竭药物治疗进展与展望

儿童心力衰竭（心衰）是儿科领域急危重症，多数心衰患儿经过传统抗心衰药物治疗后病情仍进展，亟待拓展新的治疗靶点药物。近年来心衰药物治疗领域取得了较大的进展，针对病理生理学发病机制为靶点的新型抗心衰治疗药物在临床上取得了较好的疗效，提供了新的治疗选择。该文通过综述儿童心衰的最新药物治疗进展，并对药物治疗前景进行展望，以期为儿童心衰的药物治疗提供参考。     

Inadequate therapy and poor symptom control among children with asthma: findings from a multistate sample.

OBJECTIVES: Asthma continues to cause significant morbidity in children. We hypothesized that many children still do not use recommended preventive medications, or they have ineffective symptom control despite preventive medication use. The aim of this study was 1) to describe the use of preventive medications among children with persistent asthma, 2) to determine whether children using preventive medications have adequate asthma control, and 3) to identify factors associated with poor control. METHODS: The State and Local Area Integrated Telephone Survey (SLAITS) Asthma Survey provided parent-reported data for children aged <18 years with asthma from a random-digit dial survey implemented in Alabama, California, Illinois, and Texas. We focused this analysis on children with persistent symptoms and/or children using preventive asthma medications (N = 975). Children with inadequate therapy had persistent symptoms and no preventive medication use. Children with suboptimal control had persistent symptoms or > 1 attack in the previous 3 months despite preventive medication use; children in optimal control had intermittent symptoms, < or = 1 attack, and reported using preventive medication. Demographic and asthma-related variables were compared across groups. RESULTS: Among children with persistent asthma, 37 per cent had inadequate therapy, 42.9 per cent had suboptimal control, and only 20.1 per cent had optimal control. In multivariate regression, black race (odds ratio [OR], 2.0; 95 percent confidence interval [CI] 1.1-3.5), Hispanic ethnicity (OR, 1.8; 95 per cent CI, 1.1-2.9), and discontinuous insurance status (OR, 2.4; 95 per cent CI, 1.4-4.3) were associated with inadequate therapy. Potential explanations for poor control included poor adherence, exposure to smoke and other triggers, and lack of written action plans. CONCLUSIONS: Inadequate asthma therapy remains a significant problem. A newly highlighted concern is the substantial number of children experiencing poor symptom control despite reported use of preventive medications.     

Newer treatments for HIV in children

PURPOSE OF REVIEW: Several new antiretroviral agents have been introduced into pediatric and adult use. This review will summarize information about these new agents and other recent advances in the care of HIV-infected children. RECENT FINDINGS: New drugs like tenofovir, emtricitabine, and enfuvirtide are being rapidly introduced into antiretroviral treatments for adult patients. In addition, some well-established drugs are being modified to make them more convenient (specifically didanosine and stavudine). Unfortunately, pediatric data lag for these new agents, in some cases because of complicated pharmacokinetics in children. At the same time, critical information on how to use established drugs like nelfinavir and efavirenz in younger children is slowly becoming available. Although antiretroviral treatment in children has often been initiated at standard doses of milligrams per kilogram, and susceptibility to drug was presumed in individuals without a previous history of exposure, recent data show that some primary infections are caused by drug-resistant virus, and there is a tremendous variability in serum drug levels in children. Researchers and clinicians should consider the role of baseline antiretroviral susceptibility testing and therapeutic drug monitoring to identify the optimal treatment for each child. SUMMARY: New therapeutic options for children with HIV infection are becoming available as the pharmacokinetics and best strategies for use of newer drugs are studied.     

神经母细胞瘤相关的眼阵挛-肌阵挛综合征研究进展

眼阵挛-肌阵挛综合征(OMS)是一种罕见的神经系统疾病,临床以不自主、快速、无规律眼球运动,肌阵挛,共济失调为特征,常有发育和行为异常后遗症。OMS与恶性肿瘤相关,在儿童,约50%的OMS并神经母细胞瘤(NB),NB是儿童常见的一种颅外恶性实体肿瘤。伴有OMS的NB患儿大多数能长期存活。其确切发病机制尚不十分清楚,多数学者认为是一种自身免疫性疾病。关于OMS的治疗,目前尚无统一的治疗方法,多应用免疫抑制剂和免疫调节剂。由于切除肿瘤、免疫抑制治疗未能有效阻止神经系统发育与行为异常后遗症的发生,如何通过有效的治疗改变预后,其观点仍有争议。