Assessing the need for home-based end-of-life palliative care in pediatric cancer care

Background: Palliative care is underrepresented in our community at large. End-of-life care is offered mainly in palliative care hospices or hospitals worldwide. As access to such a facility is often sparse, and since many of them are located far away from home, most families wish to go home if a curative treatment option does not exist. Aims and Objectives: The study was done to analyze the preferences for the location of end-of-life care for families of children with cancer. We analyze the reasons for the same and offer suggestions for improving this situation. Materials and Methods: Parents of 77 children who died following a diagnosis of childhood cancer between 2019 and 2023, either due to progressive or refractory disease or due to toxic death, were interviewed to understand their choice of location for end-of-life care. The interview was done telephonically or face to face. Results: 41 out of 77 deaths were anticipated, and out of these, we observed that only 3 (7.3%) opted for a formal palliative care center. Fifteen families (36%) opted for end-of-life treatment in the hospital, and 23 families (56%) went home despite having no support at home for palliation. The decision is taken considering the practical needs of the rest of the family, although it is more difficult to implement. The reasons behind the decision are analyzed here. Conclusion: We recommend that integrated home-based palliation for end-of-life care in children be developed instead of hospice support. Hospices that take care of adults may be used with children where required. A multidisciplinary team that can support the needs of families and can visit them at home needs to be developed around centers managing children with cancer

Clinical and Immunological Phenotype of Patients With Primary Immunodeficiency Due to Damaging Mutations in NFKB2

Non-canonical NF-κB-pathway signaling is integral in immunoregulation. Heterozygous mutations in NFKB2 have recently been established as a molecular cause of common variable immunodeficiency (CVID) and DAVID-syndrome, a rare condition combining deficiency of anterior pituitary hormone with CVID. Here, we investigate 15 previously unreported patients with primary immunodeficiency (PID) from eleven unrelated families with heterozygous NFKB2-mutations including eight patients with the common p.Arg853* nonsense mutation and five patients harboring unique novel C-terminal truncating mutations. In addition, we describe the clinical phenotype of two patients with proximal truncating mutations. Cohort analysis extended to all 35 previously published NFKB2-cases revealed occurrence of early-onset PID in 46/50 patients (mean age of onset 5.9 years, median 4.0 years). ACTH-deficiency occurred in 44%. Three mutation carriers have deceased, four developed malignancies. Only two mutation carriers were clinically asymptomatic. In contrast to typical CVID, most patients suffered from early-onset and severe disease manifestations, including clinical signs of T cell dysfunction e.g., chronic-viral or opportunistic infections. In addition, 80% of patients suffered from (predominately T cell mediated) autoimmune (AI) phenomena (alopecia > various lymphocytic organ-infiltration > diarrhea > arthritis > AI-cytopenia). Unlike in other forms of CVID, auto-antibodies or lymphoproliferation were not common hallmarks of disease. Immunophenotyping showed largely normal or even increased quantities of naïve and memory CD4+ or CD8+ T-cells and normal T-cell proliferation. NK-cell number and function were also normal. In contrast, impaired B-cell differentiation and hypogammaglobinemia were consistent features of NFKB2-associated disease. In addition, an array of lymphocyte subpopulations, such as regulatory T cell, Th17-, cTFH-, NKT-, and MAIT-cell numbers were decreased. We conclude that heterozygous damaging mutations in NFKB2 represent a distinct PID entity exceeding the usual clinical spectrum of CVID. Impairment of the non-canonical NF-κB pathways affects function and differentiation of numerous lymphocyte-subpopulations and thus causes a heterogeneous, more severe form of PID phenotype with early-onset. Further characteristic features are multifaceted, primarily T cell-mediated autoimmunity, such as alopecia, lymphocytic organ infiltration, and in addition frequently ACTH-deficiency

X-linked agammaglobulinemia (XLA) : Phenotype, diagnosis, and therapeutic challenges around the world

Background: X-linked agammaglobulinemia is an inherited immunodeficiency recognized since 1952. In spite of seven decades of experience, there is still a limited understanding of regional differences in presentation and complications. This study was designed by the Primary Immunodeficiencies Committee of the World Allergy Organization to better understand regional needs, challenges and unique patient features. Methods: A survey instrument was designed by the Primary Immunodeficiencies Committee of the World Allergy Organization to collect both structured and semi-structured data on X-linked agammaglobulinemia. The survey was sent to 54 centers around the world chosen on the basis of World Allergy Organization participation and/or registration in the European Society for Immunodeficiencies. There were 40 centers that responded, comprising 32 countries. Results: This study reports on 783 patients from 40 centers around the world. Problems with diagnosis are highlighted by the reported delays in diagnosis>24 months in 34% of patients and the lack of genetic studies in 39% of centers Two infections exhibited regional variation. Vaccine-associated paralytic poliomyelitis was seen only in countries with live polio vaccination and two centers reported mycobacteria. High rates of morbidity were reported. Acute and chronic lung diseases accounted for 41% of the deaths. Unusual complications such as inflammatory bowel disease and large granular lymphocyte disease, among others were specifically enumerated, and while individually uncommon, they were collectively seen in 20.3% of patients. These data suggest that a broad range of both inflammatory, infectious, and autoimmune conditions can occur in patients. The breadth of complications and lack of data on management subsequently appeared as a significant challenge reported by centers. Survival above 20 years of age was lowest in Africa (22%) and reached above 70% in Australia, Europe and the Americas. Centers were asked to report their challenges and responses (n = 116) emphasized the difficulties in access to immunoglobulin products (16%) and reflected the ongoing need for education of both patients and referring physicians. Conclusions: This is the largest study of patients with X-linked agammaglobulinemia and emphasizes the continued morbidity and mortality of XLA despite progress in diagnosis and treatment. It presents a world view of the successes and challenges for patients and physicians alike. A pivotal finding is the need for education of physicians regarding typical symptoms suggesting a possible diagnosis of X-linked agammaglobulinemia and sharing of best practices for the less common complications.Peer reviewe

DIAMOND BLACKFAN ANEMIA: A TERTIARY CARE CENTRE EXPERIENCE

Introduction: Diamond Blackfan anemia (DBA) is a rare congenital hypoplastic anemia that usually presents early in infancy. Methods: All consecutive children of DBA attending the Department of Hematology OPD, AIIMS were included in the study. This is a retrospective study, with few cases enrolled prospectively, over the last 3 years. Aim: To study the clinical profile & treatment response of Diamond Blackfan anemia patients at our center. Results: 10 patients were included in the study; male: female ratio was 9:1. Median age was 2.5 yrs, ranging from 4 months to 8 yrs. Anemia requiring frequent blood transfusions was the predominant complaint since infancy. Two children were siblings.Abnormal phenotypic features were observed in 60%. The craniofacial abnormalities seen included triangular facies with DBA phenotype 50 % (5), microcephaly 10 %( 1), low set ears 10 %( 1), low hairline 10 %( 1), wide spaced teeth 10%( 1), malar prominence 10 %( 1), wide spaced toes 10 %( 1), growth failure 30%( 3) and wide spaced nipple10 % (1). Out of 10 patients, 5(50%) are transfusion independent on steroids, 4 patients had partial response with steroids and 1 had partial response on cyclosporine with occasional transfusions and the other 3 are transfusion dependent and on iron chelation. Conclusion: DBA is a rare congenital hypoplastic anemia. About 50% of patients have a good response to steroids

Retrospective analysis of 60 patients with Hemophagocytic Lymphohistiocytosis (HLH): focus on genetic variants associated with secondary/late onset disease

Hemophagocytic lymphohistiocytosis (HLH) is a rare disorder of uncontrolled cytotoxic T-lymphocyte and macrophage activation associated with extreme inflammation, which if left untreated is invariably fatal. HLH can be classified either as primary (familial) or secondary (acquired). Genetic mutations underlie primary HLH which typically occurs in young children, while secondary HLH is associated with infections, metabolic disease, and malignancies and manifests later in life. Both categories of HLH affect the function of T-lymphocytes and natural killer (NK) cells. Homozygous null mutations in several genes including PRF1, UNC13D (MUNC13-4), STX11, and STXBP2 (MUNC18-2) have been described in cases of primary HLH, where consanguinity has been shown to play a role. These mutations contribute to an uncontrolled inflammatory response, over production of interferon gamma (IFNγ) and pro-inflammatory cytokines leading to macrophage activation and eventually to tissue and organ damage. While no known genetic mutations have been described in patients with acquired HLH, an underlying genetic predisposition has been suggested. In an effort to better understand the genetic and clinical correlates of this disease, we performed retrospective analyses of 60 suspected HLH cases that were submitted by physicians for genomic analysis to our diagnostic laboratory. High throughput exome sequencing of the 60 HLH samples was carried out on an Illumina HiSeq 2500 platform, followed by bioinformatics analysis. Our data showed that 1) 34% of the patients had homozygous mutations in known HLH-associated genes, the majority of which were in the Perforin1 (PRF1) gene (70%) followed by mutations in the UNC13D (20%) and STXBP2 (10%) genes. Most patients with homozygous PRFI mutations were products of consanguineous marriages. The parents of these patients while being carriers, however, remained unaffected. 2) 18% of our patients had mutations in other congenital immune deficiency syndromes that are known to lead to HLH. 3) The remaining 48% of the patients lacked any known HLH-associated mutation. Our data suggest that heterozygous mutations in novel genes may contribute to predisposing patients to secondary HLH, particularly since most of these genes are associated with T-lymphocyte activation, which plays a vital role in the etiology of this devastating disease