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UNASSIGNED: CVID is the commonest and most symptomatic primary immune deficiency of adulthood. NHLs are the most prevalent malignancies in CVID. The cross-talk between tumor cells and immune cells may be an important risk factor in lymphomagenesis.
UNASSIGNED: The present review highlights immune cell, genetic and histopathological alterations in the CVID-associated NHLs.
UNASSIGNED: CVID patients exhibit some notable immune defects that may predispose to lymphomas. T/NK cell defects including reduced T cells, naïve CD4+T cells, T regs, and Th17 cells, increased CD8+T cells with reduced T cell proliferative and cytokine responses and reduced iNKT and NK cell count and cytotoxicity. B cell defects include increased transitional and CD21low B cells, clonal IgH gene rearrangements, and increased BCMA levels. Increase in IL-9, sCD30 levels, and upregulation of BAFF-BAFFR signaling are associated with lymphomas in CVID. Increased expression of PFTK1, duplication of ORC4L, germline defects in TACI, NFKB1, and PIK3CD, and somatic mutations in NOTCH2 and MYD88 are reported in CVID-associated lymphomas. Upregulation of PD-L1-PD-1 pathway may also promote lymphomagenesis in CVID. These abnormalities need to be explored as prognostic or predictive markers of CVID-associated NHLs by large multicentric studies.

BACKGROUND: People with a rare disease commonly experience long delays from the onset of symptoms to diagnosis. Rare diseases are challenging to diagnose because they are clinically heterogeneous, and many present with non-specific symptoms common to many diseases. We aimed to explore the experiences of people with myositis, primary immunodeficiency (PID), and sarcoidosis from symptom onset to diagnosis to identify factors that might impact receipt of a timely diagnosis.
METHODS: This was a qualitative study using semi-structured interviews. Our approach was informed by Interpretive Phenomenological Analysis (IPA). We applied the lens of uncertainty management theory to tease out how patients experience, assess, manage and cope with puzzling and complex health-related issues while seeking a diagnosis in the cases of rare diseases.
RESULTS: We conducted interviews with 26 people with a rare disease. Ten participants had been diagnosed with a form of myositis, 8 with a primary immunodeficiency, and 8 with sarcoidosis. Time to diagnosis ranged from 6 months to 12 years (myositis), immediate to over 20 years (PID), and 6 months to 15 years (sarcoidosis). We identified four themes that described the experiences of participants with a rare disease as they sought a diagnosis for their condition: (1) normalising and/or misattributing symptoms; (2) particularising by clinicians; (3) asserting patients\' self-knowledge; and (4) working together through the diagnosable moment.
CONCLUSIONS: Managing medical uncertainty in the time before diagnosis of a rare disease can be complicated by patients discounting their own symptoms and/or clinicians discounting the scale and impact of those symptoms. Persistence on the part of both clinician and patient is necessary to reach a diagnosis of a rare disease. Strategies such as recognising pattern failure and accommodating self-labelling are key to diagnosis.

The life expectancy and the risk of developing cardiovascular diseases in patients with inborn errors of immunity are systematically increasing. The aim of the study was to assess cardiovascular risk factors and to evaluate the heart in echocardiography in patients with primary antibody deficiency (PAD). Cardiac echography and selected cardiovascular risk factors, including body mass index, sedentary lifestyle, nicotine, glucose, C-reactive protein, lipid profile, uric acid level, certain chronic diseases, and glucocorticoid use, were analyzed in 94 patients >18 years of age with PAD. Of the patients,25.5% had a cardiovascular disease (mostly hypertension, 18%), 10.5% smoked, 17% were overweight, 14% were obese, and 15% were underweight. Abnormal blood pressure was found in 6.5% of the patients. Lipid metabolism disorders were found in 72.5% of in the studied cohort, increased total cholesterol (45.5%), non-high-density lipoprotein (HDL) (51%), low-density lipoprotein (LDL) (47%), and triglycerides (32%) were observed. Furthermore, 28.5% had a decrease in HDL and 9.5% had a history of hyperuricemia. The average number of risk factors was 5 ± 3 for the entire population and 4 ± 2 for those under 40 years of age. Elevated uric acid levels were found de novo in 4% of participants. In particular, 74.5% of the patients had never undergone an echocardiogram with a successful completion rate of 87% among those tested. Among them, 30% showed parameters within normal limits, primarily regurgitation (92.5%). New pathologies were identified in 28% of patients. Prevention in patients with PAD, aimed at reducing cardiovascular risk, should be a priority.

BACKGROUND: People who are immune-deficient/disordered (IDP) are underrepresented in COVID-19 studies. Specifically, there is limited research on post-SARS-CoV-2 infection outcomes, including viral persistence and long-term sequelae in these populations.
OBJECTIVE: This review aimed to examine the published literature on the occurrence of persistent SARS-CoV-2 positivity, relapse, reinfections, variant coinfection, and post-acute sequelae of COVID-19 in IDP. Although the available literature largely centred on those with secondary immunodeficiencies, studies on people with inborn errors of immunity are also included.
METHODS: PubMed was searched using medical subject headings terms to identify relevant articles from the last 4 years. Articles on primary and secondary immunodeficiencies were chosen, and a special emphasis was placed on including articles that studied people with inborn errors of immunity. The absence of extensive cohort studies including these individuals has limited most articles in this review to case reports, whereas the articles focusing on secondary immunodeficiencies include larger cohort, case-control, and cross-sectional studies. Articles focusing solely on HIV/AIDS were excluded.
BACKGROUND: Scientific literature suggests that IDP of any age are more likely to experience persistent SARS-CoV-2 infections. Although adult IDP exhibits a higher rate of post-acute sequelae of COVID-19, milder COVID-19 infections in children may reduce their risk of experiencing post-acute sequelae of COVID-19. Reinfections and coinfections may occur at a slightly higher rate in IDP than in the general population.
CONCLUSIONS: Although IDP experience increased viral persistence and inter-host evolution, it is unlikely that enough evidence can be generated at the population-level to support or refute the hypothesis that infections in IDP are significantly more likely to result in variants of concern than infections in the general population. Additional research on the relationship between viral persistence and the rate of long-term sequelae in IDP could inform the understanding of the immune response to SARS-CoV-2 in IDP and the general population.

BACKGROUND: Primary immune deficiencies (PID) encompasses genetic disorders that result in recurrent infections and immune dysregulation, often increasing the risk of malignancies. The aim of this study is to determine the quality of life, depression, and anxiety in parents of children with PID.
METHODS: Various validated assessment tools, including the Beck Depression Inventory (BDI), State and Trait Anxiety Inventory (STAI), the 36-item Short Form Survey (SF-36), and a demographic form, were employed to gather data from 85 parents of 64 PID patients and 85 parents of 75 healthy children.
RESULTS: The findings reveal that parents of PID patients exhibited higher BDI, STAI-S, STAI-T, and fatigue subdomain of SF-36 (p = .013, p = .013, p = .027, p = .000). Both parents had lower energy levels than the normal population, but mothers experienced higher levels of anxiety and depression. PID mothers\' had higher scores than fathers of PID patients with healthy children in BDI, STAI-S, and STAI-T (p = .002, p = .010, p = .001). Mothers of PID patients reported lower scores in RLEP, E/F, EWB, P, and GH compared to fathers (p = .009, p = .005, p = .034, p = .001, p = .003). Additionally, the study found that STAI-T influenced all subdimensions of HRQOL. These results highlight the substantial emotional and psychological burden placed on parents caring for children with PID.
CONCLUSIONS: The study underscores the importance of supporting caregivers to enhance the overall well-being of both parents and children with PID. Such support can potentially alleviate depression and anxiety levels among parents, ultimately improving their quality of life and aiding in the management of children with PID.

Activated phosphoinositide 3-kinase delta syndrome (APDS) is a rare genetic disorder that presents clinically as a primary immunodeficiency. Clinical presentation of APDS includes severe, recurrent infections, lymphoproliferation, lymphoma, and other cancers, autoimmunity and enteropathy. Autosomal dominant variants in two independent genes have been demonstrated to cause APDS. Pathogenic variants in PIK3CD and PIK3R1, both of which encode components of the PI3-kinase, have been identified in subjects with APDS. APDS1 is caused by gain of function variants in the PIK3CD gene, while loss of function variants in PIK3R1 have been reported to cause APDS2. We conducted a review of the medical literature and identified 256 individuals who had a molecular diagnosis for APDS as well as age at last report; 193 individuals with APDS1 and 63 with APDS2. Despite available treatments, survival for individuals with APDS appears to be shortened from the average lifespan. A Kaplan-Meier survival analysis for APDS showed the conditional survival rate at the age of 20 years was 87%, age of 30 years was 74%, and ages of 40 and 50 years were 68%. Review of causes of death showed that the most common cause of death was lymphoma, followed by complications from HSCT. The overall mortality rate for HSCT in APDS1 and APDS2 cases was 15.6%, while the mortality rate for lymphoma was 47.6%. This survival and mortality data illustrate that new treatments are needed to mitigate the risk of death from lymphoma and other cancers as well as infection. These analyses based on real-world evidence gathered from the medical literature comprise the largest study of survival and mortality for APDS to date.

Leukocyte adhesion deficiency-III (LAD-III) is a rare recessive autosomal disorder characterized by bleeding syndrome of Glanzmann-type and life-threatening infections. The main etiology of this condition is variations in the FERMT3 gene, which encodes kindlin-3, an integrin-binding protein. This protein is responsible for the activation of fibrinogen receptors and integrin-mediated hematopoietic cell adhesion. So far, only limited cases of LAD-III have been reported. This case report discusses a two-year-old male infant from the Asir region, Saudi Arabia, who was referred to the pediatric hematology service due to recurrent ecchymosis and epistaxis. He was born at full term with a history of transient tachypnea of the newborn and recurrent bronchiolitis. The patient exhibited normal platelet count and coagulation profiles alongside a familial history of bleeding disorders, including a cousin with a similar condition. The patient also presented with hypospadias and café-au-lait spots. Laboratory findings revealed anemia, microcytosis, and hypochromia indicative of iron deficiency anemia. Whole exome sequencing (WES) identified a homozygous variant of uncertain significance in the FERMT3 gene, associated with autosomal recessive LAD-III. The patient was subsequently referred to an immunology subspecialty for further investigation and bone marrow transplant preparation. This case underscores the importance of comprehensive clinical and genetic evaluations in pediatric patients with unexplained bleeding tendencies.

BACKGROUND: Primary immunodeficiency diseases (PID) are defined by recurrent infections, allergies, autoimmunity, and malignancies. Neurologic symptoms are one of the major components of some immunodeficiency syndromes, such as Ataxia-Telangiectasia (AT), Nijmegen breakage syndrome (NBS), and Purine Nucleoside Phosphorylase (PNP) deficiency, which are considered as the primary involvement. Various pathological mechanisms, DNA repair disorders, metabolic abnormalities, and autoimmune phenomena have also been linked with neurological conditions.
METHODS: We retrospectively assessed the neurological involvement in 108 patients out of 6000 with PID in this study.
RESULTS: The female/male ratio of the cases was 49/59, and the median age was 13 years (min = 1; max = 60). Neurological problems were detected at a median age of 7 years (min = 0.5; max = 30). Di George Syndrome (DGS) and CVID (common variable immunodeficiency) were the most common diseases in our cohort (n = 31, 30% and n = 30, 27%, respectively). The most frequent outcomes were cognitive delay (n = 63, 58%), epilepsy (n = 25, 23%), and ataxia (n = 20, 18%). Central nervous system involvement was found in 99% of the patients (n = 107), and peripheral nervous system complication was found in only one patient with CVID and chronic inflammatory demyelinating polyneuropathy (CDIP). Cranial MRI was found to be abnormal in 74% (n = 80) of the patients. MRI findings included cerebellar atrophy (n = 33, 34%), white matter lesion (n = 27, 28.4%), cerebral atrophy (n = 21, 22.3%), gray matter lesion (n = 6, 6.3%), hydrocephalus (n = 5, 5,3%), and pituitary gland lesion (n = 3, 3.2%), intracranial hemorrhage (n = 3, 3%), intracranial vasculitis (n = 3, 2.7%), and arterio-venous malformation (n = 1, 0,9%). Primary involvement (a component of the disease) was 60% (n = 65), and secondary (infection or autoimmunity) and tertiary involvements (structural or incidental lesions) contributed 20% (n = 20) each in the patients.
CONCLUSIONS: In this study, we describe the various neurologic findings of patients with PID. The neurologic presentation may represent the initial manifestation of certain types of PID. Early diagnosis and treatment are essential to prevent or reduce further neurologic damages.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type 1 (APS-1), is a rare genetic disorder caused most often by biallelic mutations in the AIRE gene. Classic clinical findings of the disease are chronic mucocutaneous candidiasis and autoimmunity that primarily targets endocrine tissues, such as hypoparathyroidism and adrenal insufficiency. Recently, however, it has been appreciated that enamel hypoplasia, together with intestinal malabsorption and a characteristic APECED rash, is a prominent early disease manifestation of APECED which can aid in the diagnosis of disease before other potentially life-threatening disease manifestations occur. To demonstrate this point, we present data from a cohort of APECED patients, approximately 70% of who present with enamel dysplasia at an early age. Importantly, early life presentation with enamel dysplasia was predictive of likelihood of development of a subsequent APECED diagnosis. Furthermore, we present a case of a patient with APECED and severe enamel defects and discuss the utility of medical-dental professional co-operation in the diagnosis and management of this complex disorder.