Management of cytomegalovirus infections - Swedish recommendations 2023.

Cytomegalovirus (CMV) infection, which mostly causes a subclinical infection early in life, has important clinical consequences in certain patient groups. CMV is the most common congenital infection and can cause permanent disabilities such as hearing loss and motor- and cognitive deficits in affected infants. In allogeneic haematopoietic stem cell and solid organ transplant recipients, CMV still is an important infectious complication with a risk for life-threatening disease. The previous Swedish recommendations for the management of CMV infections were updated by an expert group under the guidance of The Swedish Reference Group for Antiviral Treatment (RAV) and published at the website of RAV in August 2023 (https://www.sls.se/rav/rekommendationer/cytomegalovirus/). We here provide a translation of the updated recommendations, with minor modifications regarding diagnosis of CMV pneumonia. In the present recommendations, we discuss aspects of old and new CMV antivirals, including dosing for different age groups, and cover the management of congenital infections and CMV in immunocompromised patients. The recommendations are evidence-graded in accordance with the Oxford Centre for Evidence-Based Medicine.

Meals are more than nutrition for children with a malignant or non-malignant disorder with a gastrostomy tube: A qualitative study.

PURPOSE: To elucidate mealtime experiences of children hospitalized with a malignant or severe non-malignant disorder -and their parents-after a gastrostomy tube insertion. METHODS: A qualitative design involving a child-centred care approach was used. Parents of children aged 1-18 years old who had received a gastrostomy tube during treatment for a malignant or non-malignant disorder were included, as were the children themselves when aged 5-18 years old. Semi-structured interviews with 21 families were carried out and a thematic analysis performed. RESULTS: The findings were presented in four themes: changed meal conditions, a troublesome sensory dimension, aggravating obstacles and solving the unmanageable. Hospitalization involves challenges regarding environmental aspects, hospital food and side effects, contributing to impaired nutritional intake and aggravated mealtime situations. CONCLUSIONS: Hospital environment and hospital food have a profound impact on children's nutritional intake and mealtime situations. In addition, sensory aspects and side effects aggravate the child's motivation to eat, resulting in demanding meals. The families described a gastrostomy tube as a valuable strategy for improving mealtime situations.

Heart failure in patients with congenital heart disease after a cancer diagnosis.

AIMS: Individuals with congenital heart disease (CHD) are at an increased risk for cancer. As cancer survival rates improve, the prevalence of late side effects, such as heart failure (HF), is becoming more evident. This study aims to evaluate the risk of developing HF following a cancer diagnosis in patients with CHD, compared with those without CHD and with CHD patients who do not have cancer. METHODS: CHD patients (n = 69 799) and randomly selected non-CHD controls (n = 650 406), born in Sweden between 1952 and 2017, were identified from the Swedish National Health Registers and Total Population Register (excluding those with syndromes and transplant recipients). CHD patients who developed cancer (n = 1309) were propensity score-matched with non-CHD patients who developed cancer (n = 9425), resulting in a cohort of 1232 CHD patients with cancer and 2602 non-CHD controls with cancer (after exclusion of individuals with HF prior to cancer diagnosis). In a separate analysis, CHD patients with cancer were propensity score-matched with CHD patients without cancer (n = 68 490). A total of 1233 CHD patients with cancer and 2257 CHD patients without cancer were included in the study. RESULTS: Among CHD patients with cancer, 73 (5.9%) developed HF during a mean follow-up time of 8.5 ± 8.7. Comparatively, in the propensity-matched control population, 29 (1.1%) non-CHD cancer patients (mean follow-up time of 7.3 ± 7.5) and 101 (4.5%) CHD patients without cancer (mean follow-up time of 9.9 ± 9.2) developed HF. CHD patients exhibited a significantly higher risk of HF post-cancer diagnosis compared with the non-CHD control group [hazard ratio (HR) 4.39, 95% confidence interval (CI) 2.83-6.81], after adjusting for age at cancer diagnosis and comorbidities. In the analysis between CHD patients with cancer and those without cancer, the results indicated a significantly higher risk of developing HF in CHD patients with cancer (HR 1.53, 95% CI 1.13-2.07). CONCLUSIONS: CHD patients face a more than four-fold increased risk of developing HF after a cancer diagnosis compared with cancer patients without CHD. Among CHD patients, the risk of HF is only modestly higher for those with cancer than for those without cancer. This suggests that the increased HF risk in CHD patients with cancer, relative to non-CHD cancer patients, may be more attributable to CHD itself than to cancer treatment-related side effects.

Corrigendum to "Risk of cancer in young and older patients with congenital heart disease and the excess risk of cancer by syndromes, organ transplantation and cardiac surgery: Swedish health registry study (1930-2017)" [The Lancet Regional Health-Europe 18 (2022) 100407].

[This corrects the article DOI: 10.1016/j.lanepe.2022.100407.].

Outcomes after cancer diagnosis in children and adult patients with congenital heart disease in Sweden: a registry-based cohort study.

OBJECTIVE: Patients with congenital heart disease (CHD) have an increased cancer risk. The aim of this study was to determine cancer-related mortality in CHD patients compared with non-CHD controls, compare ages at cancer diagnosis and death, and explore the most fatal cancer diagnoses. DESIGN: Registry-based cohort study. SETTING AND PARTICIPANTS: CHD patients born between 1970 and 2017 were identified using Swedish Health Registers. Each was matched by birth year and sex with 10 non-CHD controls. Included were those born in Sweden with a cancer diagnosis. RESULTS: Cancer developed in 758 out of 67814 CHD patients (1.1%), with 139 deaths (18.3%)-of which 41 deaths occurred in patients with genetic syndromes. Cancer was the cause of death in 71.9% of cases. Across all CHD patients, cancer accounted for 1.8% of deaths. Excluding patients with genetic syndromes and transplant recipients, mortality risk between CHD patients with cancer and controls showed no significant difference (adjusted HR 1.17; 95% CI 0.93 to 1.49). CHD patients had a lower median age at cancer diagnosis-13.0 years (IQR 2.9-30.0) in CHD versus 24.6 years (IQR 8.6-35.1) in controls. Median age at death was 15.1 years (IQR 3.6-30.7) in CHD patients versus 18.5 years (IQR 6.1-32.7) in controls. The top three fatal cancer diagnoses were ill-defined, secondary and unspecified, eye and central nervous system tumours and haematological malignancies. CONCLUSIONS: Cancer-related deaths constituted 1.8% of all mortalities across all CHD patients. Among CHD patients with cancer, 18.3% died, with cancer being the cause in 71.9% of cases. Although CHD patients have an increased cancer risk, their mortality risk post-diagnosis does not significantly differ from non-CHD patients after adjustements and exclusion of patients with genetic syndromes and transplant recipients. However, CHD patients with genetic syndromes and concurrent cancer appear to be a vulnerable group.

Hematopoietic stem cell transplantation for pediatric patients with non-anaplastic peripheral T-cell lymphoma. An EBMT pediatric diseases working party study.

Peripheral T-cell lymphomas (PTCL) other than anaplastic large-cell lymphoma are rare in children, and the role of hematopoietic stem cell transplantation (HSCT) has not been clarified yet. In a retrospective analysis of registry-data of the European Society for Blood and Marrow Transplantation we analyzed 55 patients aged < 18 years who received allogeneic (N = 46) or autologous (N = 9) HSCT for PTCL. Median age at HSCT was 13.9 years; 33 patients (60%) were in first remission, and 6 (19%) in progression at HSCT. Conditioning was myeloablative in 87% of the allogeneic HSCTs and in 27 (58.7%) based on total body irradiation. After allogeneic HSCT the 5-year overall- and progression-free survival was 58.9% (95% CI 42.7-71.9) and 52.6% (95% CI 36.8-66.1), respectively. 5-year relapse incidence was 27.6% (95% CI 15.1-41.6), the non-relapse mortality rate was 19.8% (95% CI 9.7-32.6). Five of the six patients with progression at HSCT died. Seven of nine patients after autologous HSCT were alive and disease-free at last follow-up. Our data suggest a role of allogeneic HSCT in consolidation-treatment of patients with high-risk disease, who reach at least partial remission after primary- or relapse-therapy, whereas patients with therapy-refractory or progressive disease prior to transplantation do not profit from HSCT.

Paediatric clinical trials need paediatric clinical trial budgets.

AIM: Clinical trials and the need for new treatments were recently listed among the most important factors for child health. The aim of the present study was to describe some of our experiences with budget preparations in paediatric clinical trials. METHODS: We selected 10 trials sponsored by the pharmaceutical industry at the Pediatric Clinical Research Center at Sahlgrenska University Hospital in Gothenburg, Sweden. We compared the sponsor's initial budget (budget proposal from the sponsor), with the final budget (negotiated and agreed between sponsor and site) and identified areas where discrepancies may arise. RESULTS: The mean difference in total budget amount between the initial budget and the final budget was +60% (mean 59%, range 31%-139%). The costs for preparation of the clinical trial, time spent for study activities and costs for examinations were identified as key budget items for these differences. CONCLUSION: Our findings indicate that a substantial part of the trial-related costs would not be covered by the sponsor, had the initial budget been accepted. A thorough review and budget negotiation, as well as to have a dedicated team member for this task, are essential to ensure equitable responsibility for the study-related costs and to avoid discontinuation of trials.

A retrospective case-control study of gastrostomy use in children undergoing hematopoietic cell transplantation.

BACKGROUND: Maintaining a good nutritional status during the hematopoietic cell transplantation (HCT) procedure is challenging in the pediatric population. METHODS: In a multicentric retrospective study, we compared the outcome of nutritional status and HCT-related parameters in 227 pediatric patients during and after HCT between 2005 and 2015. 112 patients received a gastrostomy before the start of HCT (GS group), and 115 did not receive a gastrostomy (NGS). Data collection was performed at HCT, 3, 6, and 12 months post-HCT. RESULTS: At time point of HCT the Standard Deviation Score (SDS) of weight was 0.17 in the NGS group, and 0.71 in the GS group (p = .01) Patients in the NGS group lost more weight during the first 3 months after HCT than patients in the GS group. At 12 months, patients in the NGS remained at a lower weight, while patients in the GS group slightly increased their weight. There were no differences between the groups in the incidence of acute graft-versus-host-disease (GvHD), overall survival, and non-relapse mortality. However, the number of febrile episodes requiring intravenous treatment with antibiotics, was higher in the GS group as compared to the NGS group, during the first 3 months post-HCT (p < .001). CONCLUSIONS: Our results indicate that gastrostomy can be utilized in children undergoing HCT without any negative effects on mortality. Therefore, the use of a gastrostomy appears to be a safe option to maintain a good nutritional status during the HCT procedure.

Improving outcomes of childhood and young adult non-Hodgkin lymphoma: 25 years of research and collaboration within the framework of the European Intergroup for Childhood Non-Hodgkin Lymphoma.

The European Intergroup for Childhood Non-Hodgkin Lymphoma (EICNHL) was established 25 years ago with the goal to facilitate clinical trials and research collaborations in the field both within Europe and worldwide. Since its inception, much progress has been made whereby major improvements in outcomes have been achieved. In this Review, we describe the different diagnostic entities of non-Hodgkin lymphoma in children and young adults describing key features of each entity and outlining clinical achievements made in the context of the EICNHL framework. Furthermore, we provide an overview of advances in biopathology with an emphasis on the role of biological studies and how they have shaped available treatments. Finally, for each entity, we describe future goals, upcoming clinical trials, and highlight areas of research that require our focus going forward.

Pain and discomfort in children with gastrostomy tubes - In the context of hematopoietic stem cell transplantation.

BACKGROUND: In children with malignant and severe non-malignant disorders undergoing hematopoietic stem cell transplantation (HSCT), treatment related pain and discomfort are common. Food consumption may become troublesome, making the use of a gastrostomy tube (G-tube) necessary and resulting in complications, why the purpose was to explore pain and discomfort during the transplantation and post-transplantation time. METHODS: This was a mixed methods study where data were collected along the child's total health-care process between 2018 and 2021. Questions with fixed answer options were used, simultaneously, semi-structured interviews were performed. In total, sixteen families participated. Descriptive statistics and content analysis were used to describe analysed data. FINDINGS: Intense pain was common during the post-surgery phase, especially in conjunction with G-tube care, which is why the children needed support to manage the situation. After the post-surgery phase when the skin has healed, most of the children experienced minor to no pain or bodily discomfort, why the G-tube became a well-functioning and supportive tool in daily life. CONCLUSIONS: This study describes variations in and experiences of pain and bodily discomfort in conjunction with G-tube insertion in a unique sample of children who had undergone HSCT. In conclusion, the children's comfort in daily life after the post-surgery phase seemed to be only marginally affected by G-tube insertion. Children with severe non-malignant disorders seemed to experience a higher frequency and intensity of pain and bodily discomfort due to the G-tube than children with malignant disorders. PRACTICE IMPLICATIONS: The paediatric care team need competence in assessing G-tube related pain and awareness that experiences may differ depending on the child's disorder.

Immunological differences between heart- and kidney-transplanted children: a cross-sectional study.

Post-transplantation lymphoproliferative disorder is a potentially mortal complication after heart transplantation in children. As the immune system plays a crucial role in the development of lymphoma, we explored the influence of thymus function in relation to immunosuppressive treatment in organ-transplanted children and healthy control subjects. A prospective case-control study was performed at a single centre, in which 36 children who had undergone heart transplantation were compared to two control groups: 34 kidney-transplanted children and 33 healthy age- and sex-matched children. T- and B-lymphocyte subtypes and monocytes were analysed by flow cytometry, and T-cell receptor excision circles were assessed using quantitative polymerase chain reaction. Heart-transplanted children had a lymphocyte profile characterised by reduced or absent thymic function with low numbers of T-cell receptor excision circles and total and naïve T cells, together with immune activation against the allograft. Despite similar immunosuppressive treatment, the kidney-transplanted group showed an activated T-lymphocyte compartment.

Use of eculizumab in children with allogeneic haematopoietic stem cell transplantation associated thrombotic microangiopathy - a multicentre retrospective PDWP and IEWP EBMT study.

Terminal complement blockade by humanised monoclonal antibody eculizumab has been used to treat transplantation-associated thrombotic microangiopathy (TA-TMA) in recent years. This retrospective international study conducted by the Paediatric Diseases (PDWP) and Inborn Error Working Party (IEWP) of the European Society for Blood and Marrow Transplantation (EBMT) describes outcome and response of 82 paediatric patients from 29 centres who developed TA-TMA and were treated with eculizumab between January 2014 and May 2019. The median time from hematopoietic stem cell transplantation (HSCT) to TA-TMA manifestation was 92 days (range: 7-606) and from TA-TMA diagnosis to the start of eculizumab treatment 6 days (range: 0-135). Most patients received eculizumab weekly (72%, n = 55) with a standard weight (kg)-based dose (78%, n = 64). Six months from beginning of eculizumab therapy, the cumulative incidence of TA-TMA resolution was 36.6% (95% CI: 26.2-47) and the overall survival (OS) was 47.1% (95% CI: 35.9-57.5). All 43 patients with unresolved TA-TMA died. The cause of death was HSCT-related in 41 patients. This study also documents poor outcome of patients without aGvHD and their frequent concomitant viral infections. Considering recent publications, intensified eculizumab dosing and complement monitoring could potentially improve upon outcomes observed in this study.

Pediatric Precursor B-Cell Lymphoblastic Malignancies: From Extramedullary to Medullary Involvement.

B-cell lymphoblastic lymphoma (BCP-LBL) and B-cell acute lymphoblastic leukemia (BCP-ALL) are the malignant counterparts of immature B-cells. BCP-ALL is the most common hematological malignancy in childhood, while BCP-LBL accounts for only 1% of all hematological malignancies in children. Therefore, BCP-ALL has been well studied and treatment protocols have changed over the last decades, whereas treatment for BCP-LBL has stayed roughly the same. Clinical characteristics of 364 pediatric patients with precursor B-cell malignancies were studied, consisting of BCP-LBL (n = 210) and BCP-ALL (n = 154) patients. Our results indicate that based on the clinical presentation of disease, B-cell malignancies probably represent a spectrum ranging from complete isolated medullary disease to apparent complete extramedullary disease. Hepatosplenomegaly and peripheral blood involvement are the most important discriminators, as both seen in 80% and 95% of the BCP-ALL patients and in 2% of the BCP-LBL patients, respectively. In addition, we show that the overall survival rates in this cohort differ significantly between BCP-LBL and BCP-ALL patients aged 1−18 years (p = 0.0080), and that the outcome for infants (0−1 years) with BCP-LBL is significantly decreased compared to BCP-LBL patients of all other pediatric ages (p < 0.0001).

Risk of cancer in young and older patients with congenital heart disease and the excess risk of cancer by syndromes, organ transplantation and cardiac surgery: Swedish health registry study (1930-2017).

Background: Increasing survival of patients with congenital heart disease (CHD) will result in an increased risk of age-dependent acquired diseases later in life. We aimed to investigate the risk of cancer in young and older patients with CHD and to evaluate the excess risk of cancer by syndromes, organ transplantation and cardiac surgery. Methods: Patients with CHD born between 1930 and 2017 were identified using Swedish Health Registers. Each patient with CHD (n = 89,542) was matched by sex and birth year with ten controls without CHD (n = 890,472) from the Swedish Total Population Register. Findings: 4012 patients with CHD (4·5%) and 35,218 controls (4·0%) developed cancer. The median follow-up time was 58·8 (IQR 42·4-69·0) years. The overall cancer risk was 1·23 times higher (95% confidence interval (CI) 1·19-1·27) in patients with CHD compared with matched controls, and remained significant when patients with syndromes and organ transplant recipients were excluded. The risk of cancer was higher in all CHD age groups, and in patients that underwent cardiac surgery during the first year after birth (Hazard Ratio 1·83; 95% CI 1·32-2·54). The highest risk was found in children (0-17 years), HR 3·21 (95% CI 2·90-3·56). Interpretation: The cancer risk in patients with CHD was 23% higher than in matched controls without CHD. The highest risk was found in children and in the latest birth cohort (1990-2017). Funding: Funding by the Swedish state (Grant Number: 236611), the Swedish Research Council (Grant Number: 2019-00193), the Swedish Childhood Cancer Fund (Grant Number: SP2017-0012) and the Swedish Heart-Lung Foundation (Grant Number: 20190724).

Patient parameters and response after administration of rituximab in pediatric mature B-cell non-Hodgkin lymphoma.

BACKGROUND: Mature aggressive B-cell lymphomas are heterogenous malignancies that make up more than half of all diagnosed non-Hodgkin lymphoma in children and adolescents. The overall survival rate increased over the last decades to 80%-90% due to fine tuning of polychemotherapy. However, new therapeutic implications are needed to further increase the overall survival. Current clinical trials analyze the therapeutic effect of rituximab in pediatric patients, while the mechanism of action in vivo is still not fully understood. METHODS: Effector molecules important for tumor defense were analyzed before and at day 5 after rituximab treatment via flow cytometry. Serum rituximab levels were measured with an ELISA. RESULTS: We evaluated patient parameters that may affect treatment response in relation to rituximab administration and serum rituximab levels. We indeed found a reduction of Fcγ receptor (FcγR) II levels after rituximab treatment in monocyte subtypes, whereas FcγRI expression was significantly increased. Serum levels of proinflammatory marker proteins S100A8/A9 and S100A12 significantly decreased after treatment to normal levels from an overall proinflammatory state before treatment. CD57, perforin, and granzyme B expression decreased after treatment, comprising a less cytolytic natural killer (NK) cell population. CONCLUSION: The highlighted effects of rituximab treatment on patient's immune response help in understanding the biology behind tumor defense mechanisms and effector function. After subsequent studies, these novel insights might be translated into patient care and could contribute to improve treatment of pediatric patients with mature aggressive B-cell lymphoma.

ICU Admission in Children With Acute Lymphoblastic Leukemia in Sweden: Prevalence, Outcome, and Risk Factors.

OBJECTIVES: Despite progress in the treatment of childhood acute lymphoblastic leukemia, severe complications are common, and the need of supportive care is high. We explored the cumulative prevalence, clinical risk factors, and outcomes of children with acute lymphoblastic leukemia, on first-line leukemia treatment in the ICUs in Sweden. DESIGN: A nationwide prospective register and retrospective chart review study. SETTING: Children with acute lymphoblastic leukemia were identified, and demographic and clinical data were obtained from the Swedish Childhood Cancer Registry. Data on intensive care were collected from the Swedish Intensive Care Registry. Data on patients with registered ICU admission in the Swedish Childhood Cancer Registry were supplemented through questionnaires to the pediatric oncology centers. PATIENTS: All 637 children 0-17.9 years old with acute lymphoblastic leukemia diagnosed between June 2008 and December 2016 in Sweden were included. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Twenty-eight percent of the children (178/637) were admitted to an ICU at least once. The Swedish Intensive Care Registry data were available for 96% of admissions (241/252). An ICU admission was associated with poor overall survival (hazard ratio, 3.25; 95% CI, 1.97-5.36; p ≤ 0.0001). ICU admissions occurred often during early treatment; 48% (85/178) were admitted to the ICU before the end of the first month of acute lymphoblastic leukemia treatment (induction therapy). Children with T-cell acute lymphoblastic leukemia or CNS leukemia had a higher risk of being admitted to the ICU in multivariable analyses, both for early admissions before the end of induction therapy and for all admissions during the study period. CONCLUSIONS: The need for intensive care in children with acute lymphoblastic leukemia, especially for children with T cell acute lymphoblastic leukemia and CNS leukemia, is high with most admissions occurring during early treatment.

Experiences before and after nasogastric and gastrostomy tube insertion with emphasis on mealtimes: a case study of an adolescent with cerebral palsy.

Purpose: Adolescents with cerebral palsy may need a feeding tube due to feeding challenges, since nutritional intake and mealtimes may be negatively affected. The purpose of the study was to describe and better understand how one adolescent with cerebral palsy and her parents experienced mealtimes before and after a nasogastric and gastrostomy tube insertion and how the use of these feeding tubes was experienced in daily life.Methods: Individual interviews were performed with one adolescent and each of her parents. In total, six interviews were conducted on two separate occasions. The qualitative approach known as Interpretive Description was used during the analysis.Results: Four thematic patterns were identified within the data: (i) struggling with nutritional intake, (ii) the paradox of using an aid, (iii) being different, and (iv) challenges of public mealtimes.Conclusions: The results showed that four themes influenced daily mealtimes in adolescents with cerebral palsy and a gastrostomy tube. Nutritional intake and mealtimes may be difficult, which is why using a gastrostomy tube can be a relief. However, the gastrostomy tube can also pose a challenge and a paradox. Time of change and acceptance seems necessary in order to meet these challenges.