Coronavirus disease 2019 (COVID‐19), can present with a wide spectrum of severity. Elderly patients with cardiac, pulmonary and metabolic comorbidities are more likely to develop the severe ...manifestations of COVID‐19, which are observed in less than 5% of the pediatric patients. Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is able to induce an immune impairment and dysregulation, finally resulting in the massive release of inflammatory mediators, strongly contributing to the pulmonary and systemic manifestations in COVID‐19. In children, the immune dysregulation following SARS‐CoV‐2 can also be responsible of a severe disease phenotype defined as multisystem inflammatory syndrome in children. As the immune system undergoes a complex process of maturation from birth to adult age, differences in the immune and inflammatory response could have a significant impact in determining the spectrum of severity of COVID‐19. Indeed, children show a higher ability to respond to viral infections and a reduced baseline pro‐inflammatory state compared with elderly patients. Age and comorbidities contribute to disease severity through immune‐mediated mechanisms, since they are associated with a chronic increase of pro‐inflammatory mediators, and cause an enhanced susceptibility to develop an immune dysregulation following SARS‐CoV‐2 infection. Also the expression of ACE2, the receptor of SARS‐CoV‐2, varies with age, and is linked to the immune and inflammatory response through a complex, and not completely elucidated, network. This paper reviews the peculiar immunopathogenic aspects of COVID‐19, with a focus on the differences between adult and pediatric patients.
Objective
Mevalonate kinase deficiency (MKD) is a rare metabolic disease characterized by recurrent inflammatory episodes. This study was undertaken to describe the genotype, phenotype, and response ...to treatment in an international cohort of MKD patients.
Methods
All MKD cases were extracted from the Eurofever registry (Executive Agency for Health and Consumers project no. 2007332), an international, multicenter registry that retrospectively collects data on children and adults with autoinflammatory diseases.
Results
The study included 114 MKD patients. The median age at onset was 0.5 years. Patients had on average 12 episodes per year. Most patients had gastrointestinal symptoms (n = 112), mucocutaneous involvement (n = 99), lymphadenopathy (n = 102), or musculoskeletal symptoms (n = 89). Neurologic symptoms included headache (n = 43), cerebellar syndrome (n = 2), and mental retardation (n = 4). AA amyloidosis was noted in 5 patients, almost twice as many as expected from findings in previous cohorts. Macrophage activation syndrome occurred in 1 patient. Patients were generally well between attacks, but 10–20% of the patients had constitutional symptoms, such as fatigue, between fever episodes. Patients with p.V377I/p.I268T compound heterozygosity had AA amyloidosis significantly more often. Patients without a p.V377I mutation more often had severe musculoskeletal involvement. Treatment with nonsteroidal antiinflammatory drugs relieved symptoms. Steroids given during attacks, anakinra, and etanercept appeared to improve symptoms and could induce complete remission in patients with MKD.
Conclusion
We describe the clinical and genetic characteristics of 114 MKD patients, which is the largest cohort studied so far. The clinical manifestations confirm earlier reports. However, the prevalence of AA amyloidosis is far higher than expected.
During the last years, studies investigating the intriguing association between immunodeficiency and autoimmunity led to the discovery of new monogenic disorders, the improvement in the knowledge of ...the pathogenesis of autoimmunity, and the introduction of targeted treatments. Autoimmunity is observed with particular frequency in patients with primary antibody deficiencies, such as common variable immunodeficiency (CVID) and selective IgA deficiency, but combined immunodeficiency disorders (CIDs) and disorders of innate immunity have also been associated with autoimmunity. Among CIDs, the highest incidence of autoimmunity is described in patients with autoimmune polyendocrine syndrome 1, LRBA, and CTLA-4 deficiency, and in patients with STAT-related disorders. The pathogenesis of autoimmunity in patients with immunodeficiency is far to be fully elucidated. However, altered germ center reactions, impaired central and peripheral lymphocyte negative selection, uncontrolled lymphocyte proliferation, ineffective cytoskeletal function, innate immune defects, and defective clearance of the infectious agents play an important role. In this paper, we review the main immunodeficiencies associated with autoimmunity, focusing on the pathogenic mechanisms responsible for autoimmunity in each condition and on the therapeutic strategies. Moreover, we provide a diagnostic algorithm for the diagnosis of PIDs in patients with autoimmunity.
This Special issue focuses of the most relevant advances in the field of inborn errors of immunity. Indeed, as immunology is rapidly progressing, with the constant discovery of new disease entities ...and the better characterization of molecular mechanisms and targeted therapies, a continuous update is mandatory for clinician and researchers. In this Issue, the non-infectious manifestations of inborn errors of immunity (such as autoimmunity, atopy, and lymphoproliferation) are deeply discussed, as well as the impact of the novel genetic sequencing techniques in the diagnostic approach. Moreover, some well-known disorders, including common variable immunodeficiency, are extensively reviewed and revisited in a modern way. Also, diseases of recent description, including some disorders of immune dysregulation and inborn errors of immunity associated with syndromes, are described. Finally, some of the papers of this Special Issue focus in a detailed way the molecular mechanisms leading to immunodeficiency and immune dysregulation, also opening the way for further clinical and preclinical studies. As the expanding availability of immunological and genetic testing offers the opportunity to identify new disease entities and elucidate the function of new genes involved in the development and regulation of the immune response, we aim to present the most relevant innovations in this delicate field.
SARS-CoV-2 can induce an immune impairment and dysregulation, finally resulting in the massive release of inflammatory mediators (cytokine storm), strongly contributing to the pulmonary and systemic ...manifestations in severe coronavirus disease 2019 (COVID-19). As a consequence, different drugs active on the immune system have been proposed for the treatment of the disease in adults.
Children are more likely to develop a mild disease course, as the severe form of COVID-19 is identified in less than 5% of the pediatric patients. Moreover, in children a peculiar disease phenotype, defined as multisystem inflammatory syndrome in children (MIS-C) is observed, representing the most severe expression of the inflammatory dysregulation caused by SARS-CoV-2. The limited experience with the severe pediatric COVID-19 and MIS-C does not allow conclusions about the role of the immune pharmacological approach, and therefore the treatment of these conditions represents a considerable clinical challenge. The use of chloroquine, hydroxychloroquine, and colchicine in the early disease stages is not sufficiently supported by evidence, and there is an increasing interest in the role of biologic agents, including anti-IL-1 and anti-IL-6 agents, in the prevention and treatment of the severe manifestations of COVID-19.
The therapeutic approach to pediatric COVID-19 is multidisciplinary, and anti-rheumatic agents have a prominent role in severe disease. This paper reviews the rationale for the use of anti-rheumatic agents in pediatric COVID-19 and MIS-C and the clinical experience with the single drugs. Finally, the areas of potential improvement in the use of anti-rheumatic agents, including the optimization of the drug choice and the timing of administration, are discussed.
Patients with inborn errors of immunity (IEI) are susceptible to developing a severe infection-related clinical phenotype, but the clinical consequences of immune dysregulation, expressed with ...autoimmunity, atopy, and lymphoproliferation could represent the first sign in a significant percentage of patients. Therefore, during the diagnostic work-up patients with IEI are frequently addressed to different specialists, including endocrinologists, rheumatologists, and allergologists, often resulting in a delayed diagnosis. In this paper, the most relevant non-infectious manifestations of IEI are discussed. Particularly, we will focus on the potential presentation of IEI with autoimmune cytopenia, non-malignant lymphoproliferation, severe eczema or erythroderma, autoimmune endocrinopathy, enteropathy, and rheumatologic manifestations, including vasculitis and systemic lupus erythematosus. This paper aims to identify new warning signs to suspect IEI and help in the identification of patients presenting with atypical/non-infectious manifestations.
There is increasing interest in the development of cost-effective techniques for the quantification of DNA methylation biomarkers. We analyzed 90 samples of surgically resected colorectal cancer ...tissues for APC and CDKN2A promoter methylation using methylation sensitive-high resolution melting (MS-HRM) and pyrosequencing. MS-HRM is a less expensive technique compared with pyrosequencing but is usually more limited because it gives a range of methylation estimates rather than a single value. Here, we developed a method for deriving single estimates, rather than a range, of methylation using MS-HRM and compared the values obtained in this way with those obtained using the gold standard quantitative method of pyrosequencing. We derived an interpolation curve using standards of known methylated/unmethylated ratio (0%, 12.5%, 25%, 50%, 75%, and 100% of methylation) to obtain the best estimate of the extent of methylation for each of our samples. We observed similar profiles of methylation and a high correlation coefficient between the two techniques. Overall, our new approach allows MS-HRM to be used as a quantitative assay which provides results which are comparable with those obtained by pyrosequencing.
Human aging is associated with immunosenescence, a process characterized by alterations in numerical and functional features of immune system components. Dendritic cells (DCs) are the main ...antigen-presenting cells, playing a pivotal role in adaptive and innate immunity. Therefore, we investigated the distribution of human circulating DCs throughout the life, in order to contribute to the knowledge of the physiological background underlying the aging of immune system. Cytofluorimetric analysis of peripheral blood samples by all-aged healthy population showed a significant decrease of circulating DCs and of their two main subsets among age. This reduction was limited to the plasmacytoid cell subtype when young and old subjects were analyzed separately. The analysis of circulating Treg cell number in a cohort of the subjects showed a significant reduction with increasing age and a positive significant correlation to myeloid or plasmacytoid absolute numbers. In conclusion, this work provides a large set of data of normal reference values of peripheral blood dendritic cells in healthy population suitable for comparative clinical studies concerning pathological immune dysfunctions.
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