Amy E. Caruso Brown

Pharmacokinetics and Safety of Intravenous Cidofovir for Life-Threatening Viral Infections in Pediatric Hematopoietic Stem Cell Transplant Recipients

ABSTRACT Children undergoing hematopoietic stem cell transplantation (HSCT) are at risk for life-threatening viral infections. Cidofovir is often used as a first-line agent for adenovirus infections, despite the absence of randomized controlled trials with HSCT patients, and as a second-line agent for resistant herpesvirus infections. The frequency and severity of adverse effects, particularly nephrotoxicity, in pediatric HSCT recipients are unclear, and pharmacokinetics (PK) of cidofovir in children have not previously been reported. This study was an open-label, nonrandomized, single-dose pilot study to determine the safety and PK of cidofovir in pediatric HSCT recipients with symptomatic adenovirus, nucleoside-resistant cytomegalovirus (CMV) or herpes simplex virus (HSV), and/or human papovavirus infections. Subsequent dosing and frequency were determined by clinical response and side effects, as assessed by the treating physician. Blood and urine samples were obtained from patients for PK studies and assessment of toxicity and virologic response. Twelve patients were enrolled (median age, 9 years; 33.5 days posttransplantation). Four of seven patients with adenovirus infection were successfully treated and eventually cleared their infections. Four of twelve patients died of disseminated viral disease and multiorgan failure. Two of twelve patients had evidence of acute kidney injury after the first dose, and one of these patients developed chronic kidney disease; two other patients developed late nephrotoxicity. The mean drug half-life was 9.5 h. There was no correlation between nephrotoxicity and plasma maximum concentration, clearance, or half-life. PK were similar to those reported for adults, although the drug half-life was significantly longer than that for adults. Cidofovir was well tolerated in the majority of patients. However, effective therapeutic strategies are urgently needed to support patients until immune reconstitution is achieved.

Reported Availability and Gaps of Pediatric Palliative Care in Low- and Middle-Income Countries: A Systematic Review of Published Data

BACKGROUND The majority of young people in need of palliative care live in low- and middle-income countries, where curative treatment is less available. OBJECTIVE We systematically reviewed published data describing palliative care services available to young people with life-limiting conditions in low- and middle-income countries and assessed core elements with respect to availability, gaps, and under-reported aspects. METHODS PubMed, CINAHL, EMBASE (1980-2013), and secondary bibliographies were searched for publications that included patients younger than 25 years with life-limiting conditions and described palliative care programs in low- and middle-income countries. A data extraction checklist considered 15 items across seven domains: access, education/capacity building, health system support, pain management, symptom management, end-of-life care, and bereavement. Data were aggregated by program and country. RESULTS Of 1572 records, 238 met criteria for full-text review; 34 qualified for inclusion, representing 30 programs in 21 countries. The median checklist score was 7 (range, 1-14) of 10 reported (range, 3-14). The most pervasive gaps were in national health system support (unavailable in 7 of 17 countries with programs reporting), specialized education (unavailable in 7 of 19 countries with programs reporting), and comprehensive opioid access (unavailable in 14 of 21 countries with programs reporting). Underreported elements included specified practices for pain management and end-of-life support. CONCLUSION Comprehensive pediatric palliative care provision is possible even in markedly impoverished settings. Improved national health system support, specialized training and opioid access are key targets for research and advocacy. Application of a checklist methodology can promote awareness of gaps to guide program evaluation, reporting, and strengthening.

Refusal of Treatment of Childhood Cancer: A Systematic Review

This systematic review illuminates the profound mismatch between the scholarly attention paid to treatment refusal for childhood cancer and what is known about refusal. CONTEXT: Refusal of treatment for childhood cancer engenders much discussion. No systematic study of this phenomenon exists in countries where access to treatment is readily available. OBJECTIVE: To identify and describe all published cases of treatment refusal for childhood cancer in the contemporary era. DATA SOURCES: We searched PubMed, Cumulative Index to Nursing and Allied Health Literature, Scopus, LexisNexis Academic, personal database, and secondary bibliographies. STUDY SELECTION: Eligible studies included at least 1 child <18 years of age and addressed refusal of medically recommended interventions intended to cure cancer. DATA EXTRACTION: Cases were analyzed with respect to key features, including demographics, rationale for refusal, legal action, and medical outcome; data were combined for multiple publications discussing the same case. RESULTS: Of 4342 unique publications identified, 579 were eligible after screening; 96 scholarly articles and 19 judicial opinions addressed 73 unique cases of treatment refusal. Most cases occurred in the United States. Rationales for refusal were broadly grouped into 4 categories. Fifty-one cases (70%) involved legal action at the time of refusal. Legal action did not reliably predict survival. LIMITATIONS: Publication bias and missing data, especially for cases without legal action, were limitations. CONCLUSIONS: We identified important gaps in the literature, including the significant variation in approaches and lack of consensus regarding the prognostic threshold necessary for compelling treatment and the absence of voices of children and adolescents who have received treatment over their families’ objections. More research reporting effective strategies for working with families who refuse is needed.

Being Persistent without Being Pushy: Student Reflections on Vaccine Hesitancy

Our goal as pediatric educators is to graduate physicians who have witnessed effective approaches and have grasped the nuances of communication strategies between vaccine-hesitant families and health care providers. We identified vaccine hesitancy as a recurring topic in 19 of 304 medical student reflective narratives addressing an issue in professionalism or systems-based practice. We conducted content analysis on the narratives in order to gain a better understanding of student perceptions of visits in which they observed a provider discussing vaccine hesitancy with a parent. We identified four major themes: perceived effectiveness of provider-family communication, student reaction to the encounter, physician approach to vaccine hesitancy, and gaps in students’ own knowledge. Most students described communication positively, despite only 4 of 19 observing eventual vaccine acceptance. Information regarding vaccines, vaccine delivery, and approaches to vaccine hesitancy needs to be introduced and enhanced in the educational curriculum of providers at all levels, including medical students, resident physicians, and attending physicians, in order to ensure that providers possess the comprehension and communication skills to ethically optimize vaccine uptake among patients.

Incidence and consequences of varicella in children treated for cancer in Guatemala

BackgroundVaricella-zoster virus infection is associated with significant morbidity and mortality in immune-compromised children, despite treatment with antiviral agents. Universal varicella vaccine programs have significantly decreased this risk in many highincome countries, but in most low-income and middleincome countries, the burden of varicella in children treated for malignancy is poorly defined.MethodsWe retrospectively reviewed records of children at the National Unit of Pediatric Oncology (UNOP) in Guatemala diagnosed with varicella between January 2009 and March 2013 in order to calculate incidence of varicella and evaluate morbidity, mortality, treatment interruption, and cost.ResultsFifty-nine cases of varicella were identified. Incidence was 23.4 cases per 1000 person-years (p-y). 66.1% of cases occurred in children with leukemia (median age 5.2 years; interquantile range 3.4-7 years) and 41.0% of these occurred during maintenance therapy. Source of exposure was identified for 14/59 (23.7%) children. Most were hospitalized (71.2%) and given intravenous acyclovir (64.4%). Eight (13.6%) children required critical care, and two (3.4%) died from disseminated varicella with multiorgan failure. Chemotherapy was delayed or omitted due to varicella in 50%. No significant differences in outcomes based on nutritional and immunologic status were detected. The minimum average cost of treatment per episode was 598.75 USD.ConclusionsVaricella is a significant problem in children treated for cancer in Guatemala, where effective post-exposure prophylaxis is limited. In the absence of universal varicella vaccination, strategies to improve recognition of exposure and the future use of novel inactivated vaccines currently under investigation in clinical trials could mitigate this burden.

Ghosts in my body: Seizure-like presentation of hypocalcemic tetany secondary to hypomagnesemia in a patient receiving cetuximab therapy for metastatic medulloblastoma.

Cetuximab, a monoclonal antibody specific for epidermal growth factor receptor, is increasingly used off-label and in early-phase trials for pediatric malignancies. Here, we report a patient with metastatic medulloblastoma receiving therapy with cyclophosphamide, vinblastine, and cetuximab. During evaluation for possible seizures, he was noted to be severely hypocalcemic, hypokalemic, and hypomagnesemic, a consequence of the blockade of renal epidermal growth factor receptor expression. His symptoms rapidly abated with intravenous electrolyte repletion. This case highlights the clinical heterogeneity of tetany and the importance of careful laboratory screening for known adverse effects of chemotherapy, particularly when newer biological agents are used off-study in combination chemotherapeutic regimens.

Should a Teenager Be Allowed to Leave the Hospital AMA to Attend His Father’s Funeral?

A teenager needs urgent medical treatment, but it will prevent him from attending his father’s funeral. His mother supports his decision. What should his doctors do? What should physicians do when an adolescent wishes to risk his physical health and leave the hospital to attend the funeral of his late father? What if the young man’s mother, and only remaining guardian, both supports and encourages such a decision? In this Ethics Rounds discussion, we examine the legality, morality, and safety of discharging a minor under such conditions.

An extravagant gift from a grateful patient

A family insists on giving their child’s doctor an extravagant gift. Should the doctor accept? BrightcoveDefaultPlayer10.1542/6138649547001PEDS-VA_2017-2837 Video Abstract Gift giving is psychologically and culturally complex. In any context, a gift can have multiple meanings. In the context of the doctor-patient relationship, the giving of gifts and decisions about whether to accept gifts raise complex ethical issues. In this essay, a number of pediatric oncologists discuss the ethical considerations that should guide physicians as they decide how to respond to an extravagant gift from a family.

Ringed sideroblasts in β-thalassemia

Symptomatic β‐thalassemia is one of the globally most common inherited disorders. The initial clinical presentation is variable. Although common hematological analyses are typically sufficient to diagnose the disease, sometimes the diagnosis can be more challenging. We describe a series of patients with β‐thalassemia whose diagnosis was delayed, required bone marrow examination in one affected member of each family, and revealed ringed sideroblasts, highlighting the association of this morphological finding with these disorders. Thus, in the absence of characteristic congenital sideroblastic mutations or causes of acquired sideroblastic anemia, the presence of ringed sideroblasts should raise the suspicion of β‐thalassemia.

Should Clinicians Intervene If They Suspect That a Caregiver Whose Child Has Cancer Is at Risk of Psychological Harm

Compelling arguments suggest that pediatric oncologists who have concerns about the mental health and well-being of a childs caregiver have a duty to intervene. These arguments are rooted in fundamental principles of beneficence, nonmaleficence, and justice. Not only do patients benefit when their parents and others caregivers are happy and healthy, but when the psychological distress of a caregiver is a consequence of the experience of illness and treatment, some of the responsibility for mitigating the harm falls to those who have an active role in directing treatment-the clinicians. However, systems to support clinicians in meeting this obligation are inadequate.