Pediatric and Hereditary Mastocytosis.

To a large extent, the clinical picture of pediatric mastocytosis depends on the age at which it is diagnosed. A neonate with diffuse cutaneous mastocytosis may frequently present in a severe state requiring treatment. Toddlers may require long-term anti-mediator therapy, and this may lead to concerns such as organizing preschool education due to the need for epinephrine injections. A teenager may have to face cutaneous disease persistence or a diagnosis of systemic mastocytosis. Further studies are needed to refine the available treatment options and prognosis for different age groups.

COVID-19 in unvaccinated patients with inborn errors of immunity-polish experience.

At the beginning of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic, patients with inborn errors of immunity (IEI) appeared to be particularly vulnerable to a severe course of the disease. It quickly turned out that only some IEI groups are associated with a high risk of severe infection. However, data on the course of Coronavirus Disease 2019 (COVID-19) in patients with IEI are still insufficient, especially in children; hence, further analyses are required. The retrospective study included 155 unvaccinated people with IEI: 105 children and 50 adults (67.7% and 32.3%, respectively). Male patients dominated in the study group (94 people, 60.6%). At least two comorbidities were found in 50 patients (32.3%), significantly more often in adults (56% vs. 21%). Adult patients presented significantly more COVID-19 symptoms. Asymptomatic and mildly symptomatic course of COVID-19 was demonstrated in 74.8% of the entire group, significantly more often in children (88.6% vs. 46%). Moderate and severe courses dominated in adults (54% vs. 11.4%). Systemic antibiotic therapy was used the most frequently, especially in adults (60% vs. 14.3%). COVID-19-specific therapy was used almost exclusively in adults. In the whole group, complications occurred in 14.2% of patients, significantly more often in adults (30% vs. 6.7%). In the pediatric group, there were two cases (1.9%) of multisystem inflammatory syndrome in children. Deaths were reported only in the adult population and accounted for 3.9% of the entire study group. The death rate for all adults was 12%, 15.4% for adults diagnosed with common variable immunodeficiency, 12.5% for those with X-linked agammaglobulinemia, and 21.4% for patients with comorbidity. The results of our study imply that vaccinations against COVID-19 should be recommended both for children and adults with IEI. Postexposure prophylaxis and early antiviral and anti-SARS-CoV-2 antibody-based therapies should be considered in adults with IEI, especially in those with severe humoral immune deficiencies and comorbidity.

COVID-19-related Gastrointestinal Bleeding in a Pediatric Patient With ALL.

Coronavirus disease 2019 (COVID-19) is a contagious disease caused by severe acute respiratory syndrome coronavirus-2. Patients with hematologic malignancies have been shown to have higher risk of mortality due to COVID-19 than reported in the general adult population. Reports on acute lymphoblastic leukemia and COVID in children are scarce. We present a case of an 11-year-old male patient undergoing treatment for B-cell acute lymphoblastic leukemia with an atypical course of COVID-19. The patient received a positive result of the syndrome coronavirus-2 polymerase chain reaction test performed due to epidemiologic reasons. The chemotherapy was continued since the patient had no clinical signs of COVID-19. The disease started with intensive gastrointestinal bleeding, followed by severe respiratory tract infection over 2 weeks later.

Molecular Background, Clinical Features and Management of Pediatric Mastocytosis: Status 2021.

Pediatric mastocytosis is a heterogeneous disease characterized by accumulation of mast cells in the skin and less frequently in other organs. Somatic or germline mutations in the KIT proto-oncogene are detected in most patients. Cutaneous mastocytosis is the most common form of the disease in children. In the majority of cases, skin lesions regress spontaneously around puberty. However, in few patients, mastocytosis is not a self-limiting disease, but persists into adulthood and can show signs of systemic involvement, especially when skin lesions are small-sized and monomorphic. Children with mastocytosis often suffer from mast cell mediator-related symptoms. Severe hypersensitivity reactions can also occur, mostly in patients with extensive skin lesions and blistering. In a substantial number of these cases, the triggering factor of anaphylaxis remains unidentified. Management of pediatric mastocytosis is mainly based on strict avoidance of triggers, treatment with H1 and H2 histamine receptor blockers, and equipment of patients and their families with epinephrine auto-injectors for use in severe anaphylactic reactions. Advanced systemic mastocytosis occurs occasionally. All children with mastocytosis require follow-up examinations. A bone marrow investigation is performed when advanced systemic mastocytosis is suspected and has an impact on therapy or when cutaneous disease persists into adulthood.

Natural evolution in pediatric cutaneous mastocytosis: 10-year follow-up.

BACKGROUND: Mastocytosis is a heterogeneous group of myeloproliferative disorders characterized by accumulation of clonal mast cells in various tissues. The aim of this study was to determine the symptoms evolution and outcome after 10 years observation. METHODS: Fifty-five children with mastocytosis were included in the study group and monitored concerning mast cell mediator-related symptoms (MC MRSs) and clinical course of the disease for a period of ≥10 years. RESULTS: Patients presented with a maculopapular cutaneous form of mastocytosis (MPCM) (n = 47) and diffuse cutaneous mastocytosis (DCM) (n = 8). The complete remission (CR) of skin lesions occurred in 10.3% of children after 10 years observation; no remission (NR) was observed in 17.9% children. The CR of skin specific MC MRS occurred in 69.2% children with MPCM and in 14.3% with DCM. CONCLUSION: Most children with cutaneous mastocytosis (CM) eventually experience a major or partial regression of skin lesions, although complete regression before puberty is rare. The spontaneous remission of skin specific MC MRS is less frequent in children with DCM.

[New biochemical markers of ethyl alcohol abuse - new possibilities in clinical practice]. / Mozliwosci praktycznego zastosowania nowych wskazników biochemicznych naduzywania alkoholu etylowego.

Alcohol ranks as one of the leading behavioral threats to health and life in developed countries. Alcohol abuse triggers serious social and economic effects: it contributes to higher prevalence of work-related and road accidents, as well as absence from work. The diagnosis and treatment of alcoholism still remain very difficult. Hence, the use of objective biochemical markers of alcohol abuse may contribute to earlier detection, more effective therapy and reliable teetotalism control. The aim of this study is to present the sensitive and specific biomarkers of alcohol abuse available in Poland, with particular emphasis on the practical use possibilities. Such tests may be widely used, e.g., in driving license regranting cases involving drivers whose licenses were suspended for driving when intoxicated, for the early detection of persons abusing alcohol in employment-related health controls, for abstinence monitoring during withdrawal treatment, for detecting alcohol consumption in transplant settings, for assessing the prevalence of alcohol drinking in pregnancy, as well as in autopsical examinations. The standardization of biomarkers measurement methods is essential. Moreover, concomitant disorders may pose a significant problem in the proper outcome analysis. Despite these limitations, objective biochemical markers of ethyl alcohol abuse may become helpful tools in medical care. They can play a particular role in occupational medicine diagnostics, contributing to the higher level of safety on public roads and to worker safety. Med Pr. 2021;72(2):173-84.

Changes in Novel AKI Biomarkers after Exercise. A Systematic Review.

More than 100 substances have been identified as biomarkers of acute kidney injury. These markers can help to diagnose acute kidney injury (AKI) in its early phase, when the creatinine level is not increased. The two markers most frequently studied in plasma and serum are cystatin C and neutrophil gelatinase-associated lipocalin (NGAL). The former is a marker of kidney function and the latter is a marker of kidney damage. Some other promising serum markers, such as osteopontin and netrin-1, have also been proposed and studied. The list of promising urinary markers is much longer and includes cystatin C, NGAL, kidney injury molecule-1 (KIM-1), liver-type fatty-acid-binding protein (L-FABP), interleukin 18, insulin-like growth factor binding protein 7 (IGFBP-7), tissue inhibitor of metalloproteinases-2 (TIMP-2) and many others. Although these markers are increased in urine for no longer than a few hours after nephrotoxic agent action, they are not widely used in clinical practice. Only combined IGFBP-7/TIMP-2 measurement was approved in some countries as a marker of AKI. Several studies have shown that the levels of urinary AKI biomarkers are increased after physical exercise. This systematic review focuses on studies concerning changes in new AKI biomarkers in healthy adults after single exercise. Twenty-seven papers were identified and analyzed in this review. The interpretation of results from different studies was difficult because of the variety of study groups, designs and methodology. The most convincing data concern cystatin C. There is evidence that cystatin C is a better indicator of glomerular filtration rate (GFR) in athletes after exercise than creatinine and also at rest in athletes with a lean mass lower or higher than average. Serum and plasma NGAL are increased after prolonged exercise, but the level also depends on inflammation and hypoxia; therefore, it seems that in physical exercise, it is too sensitive for AKI diagnosis. It may, however, help to diagnose subclinical kidney injury, e.g., in rhabdomyolysis. Urinary biomarkers are increased after many types of exercise. Increases in NGAL, KIM-1, cystatin-C, L-FABP and interleukin 18 are common, but the levels of most urinary AKI biomarkers decrease rapidly after exercise. The importance of this short-term increase in AKI biomarkers after exercise is doubtful. It is not clear if it is a sign of mild kidney injury or physiological metabolic adaptation to exercise.

Tumor Suppressors-HTRA Proteases and Interleukin-12-in Pediatric Asthma and Allergic Rhinitis Patients.

Background and objective: Allergy belongs to a group of mast cell-related disorders and is one of the most common diseases of childhood. It was shown that asthma and allergic rhinitis diminish the risk of various cancers, including colon cancer and acute lymphoblastic leukemia. On the other hand, asthma augments the risk of lung cancer and an increased risk of breast cancer in patients with allergy has been observed. Thus, the relation between allergy and cancer is not straightforward and furthermore, its biological mechanism is unknown. The HTRA (high temperature requirement A) proteases promote apoptosis, may function as tumor suppressors and HTRA1 is known to be released by mast cells. Interleukin-12 (Il-12) is an important cytokine that induces antitumor immune responses and is produced mainly by dendritic cells that co-localize with mast cells in superficial organs. Material and methods: In the present study we have assessed with ELISA plasma levels of the HTRA proteins, Il-12, and of the anti-HTRA autoantibodies in children with allergy (40) and in age matched controls (39). Children are a special population, since they usually do not have comorbidities and take not many drugs the processes we want to observe are not influenced by many other factors. Results: We have found a significant increase of HTRA1, 2 and 3, and of the Il-12 levels in the children with atopy (asthma and allergic rhinitis) compared to controls. Conclusion: Our results suggest that the HTRA1-3 and Il-12 levels might be useful in analyzing the pro- and antioncogenic potential in young atopic patients.

Mast cells in mastocytosis and allergy - Important player in metabolic and immunological homeostasis.

The role of mast cell (MC) activity in pathophysiology is complex and challenging and its clinical effects are difficult to predict. Apart from the known role of MCs in basic immunological processes and allergy, underlined is their importance in bone mineralization and in regulation of autoimmune reactions. Mast cell mediators, especially those released from mast cells in degranulation, but also those released constitutively, are important both in metabolic and immunological processes. Mastocytosis is a heterogeneous group of disorders characterized by accumulation of MC in one or more organs. There are scientific data indicating that mastocytosis patients are at increased risk of osteoporosis in the systemic form of the disease and children with cutaneous mastocytosis have a higher rate of hypogammaglobulinemia. Moreover, the origin of osteoporosis in patients with allergy is no longer considered as linked to steroid therapy only, but to the mast cell mediators' activity as well. There are indications that osteoporosis symptoms in this group of patients may develop independently of the cumulative steroids' dose. Thus, the influence of mast cells on metabolic and immunologic processes in allergic patients should be investigated. The assessment of mast cell activity and burden in mastocytosis may be used to guide clinical management of patients with allergy.

Immune response against HtrA proteases in children with cutaneous mastocytosis.

Mast cells play an important role in both, the innate and adaptive immunity, however, clonal proliferation of abnormal mast cells in various organs leads to mastocytosis. A skin variant of the disease, cutaneous mastocytosis (CM) is the most frequent form of mastocytosis in children. HtrA proteases are modulators of important cellular processes, including cell signaling and apoptosis, and are related to development of several pathologies. The above and the observation that mast cells constitutively release the HtrA1 protein, prompted us to investigate a possible involvement of the HtrA proteins in pediatric CM. Levels of the serum autoantibodies (IgG) against the recombinant HtrA proteins (HtrA1-4) in children with CM (n=36) and in healthy controls (n=62) were assayed. Anti-HtrA IgGs were detected using enzyme linked immunosorbent assay (ELISA) and Western-blotting. In the CM sera, levels of the anti-HtrA1 and anti-HtrA3 autoantibodies were significantly increased when compared to the control group, while the HtrA protein levels were comparable. No significant differences in the anti-HtrA2 IgG level were found; for the anti-HtrA4 IgGs lower levels in CM group were revealed. In healthy children, the IgG levels against the HtrA1, -3 and -4 increased significantly with the age of children; no significant changes were observed for the anti-HtrA2 IgG. Our results suggest involvement of the HtrA1 and HtrA3 proteins in pediatric CM; involvement of the HtrA4 protein is possible but needs to be investigated further. In healthy children, the autoantibody levels against HtrA1, -3 and -4, but not against HtrA2, increase with age.

The Possible Role of Gene Variant Coding Nonfunctional Toll-Like Receptor 2 in the Pathogenesis of Mastocytosis.

BACKGROUND: Data on the genetic predisposition to mastocytosis are scarce. The aim of this work was to study the association of single nucleotide polymorphisms of Toll-like receptor (TLR)-2, TLR-4, and TLR-9 genes in Polish patients with mastocytosis. OBJECTIVES: The study comprised 137 patients with mastocytosis (102 cutaneous [60 children and 42 adults] and 35 systemic cases); 171 disease-free individuals were used as controls. METHOD: The frequency of polymorphisms R753Q (rs5743708) of TLR-2, 896 A>G (rs496790) of TLR-4, and -1237C>T (rs5743836) of TLR-9 genes were determined with the use of the amplification refractory mutation system polymerase chain reaction method. RESULTS: It was found that the R753Q TLR-2 gene polymorphism was significantly more frequent in patients with mastocytosis in comparison to healthy controls (p = 0.037) and in the group of SM versus controls (p = 0.0076). The presence in the genotype 753Q variant of TLR-2 gene increased the risk of mastocytosis more than 2-fold (OR 2.51; p = 0.04), and the risk of SM more than 4-fold (OR 4.22; p = 0.01). TLR-4 and TLR-9 polymorphisms were not associated with mastocytosis. CONCLUSIONS: Our results suggest that the R753Q polymorphism of the TLR-2 gene may be involved in the pathogenesis of mastocytosis.

The role of regulatory T cells and genes involved in their differentiation in pathogenesis of selected inflammatory and neoplastic skin diseases. Part I: Treg properties and functions.

Regulatory T cells (Treg) can be divided into two types: the natural cells (tTreg), which arise in the thymus, and the induced cells (iTreg), which are produced in peripheral tissues during immune response. The most recently published studies indicate that the supervisory functions of these cells are weakened in the pathogenesis of autoimmune and neoplastic diseases of the skin. This may be a result of the domination of other immune cells in the skin, such as Th1/Th17/Th22 and Tc1 type in psoriasis and Th2 in atopic dermatitis. The excessive activity of Treg cells can lead to immunosuppression and decrease in the number of Th1 cells, which promote the development and progression of skin cancers. In the case of cutaneous T-cell lymphomas, there are suggestions that tumor progression is associated with the acquisition of the suppressor phenotype of malignant cells. There is genetic background of Treg dysfunction in skin disorders. This article describes the types and functions of Treg cells.

Association between uridin diphosphate glucuronosylotransferase 1A1 (UGT1A1) gene polymorphism and neonatal hyperbilirubinemia.

OBJECTIVE: To assess the prevalence of UGT1A1*28 and UGT1A1*60 polymorphisms of UGT1A1 gene and their association with hyperbilirubinemia. STUDY DESIGN: The study was performed at a single centre - at the Department of Obstetrics of the Medical University of Gdansk in Poland. DNA was isolated from Guthrie cards of 171 infants. Only full term newborns (gestational age 38-42 weeks) were included in the study. Fluorescent molecular probes were used for UGT1A1 promoter variation analysis. The presence of UGT1A1*28 polymorphism was detected with a dual-probe system, and UGT1A1*60 with a SimpleProbe™. RESULT: Homozygous UGT1A1*28 and UGT1A1*60 genotypes were detected in 14.6% and 20.5% of the newborns, respectively. Homozygous (G/G) genotypes of UGT1A1*60 polymorphism were found in all of the UGT1A1*28 (i.e. (TA)7/(TA)7) homozygotes. More than 80% (55/66) of the children with "wild" type UGT1A1*28 genotype (where no polymorphism was detected) (i.e. (TA)6/(TA)6) carried the "wild" (T/T) genotype of UGT1A1*60 as well. The UGT1A1*28 polymorphism was detected more often among neonates with elevated bilirubin. Hyperbilirubinemia was diagnosed more frequently in boys. CONCLUSION: Polymorphisms of the UGT1A1 gene frequently co-exist in neonates. The presence of UGT1A1*28 polymorphism and male gender seem to predispose to neonatal hyperbilirubinemia.

The role of regulatory T cells and genes involved in their differentiation in pathogenesis of selected inflammatory and neoplastic skin diseases. Part II: The Treg role in skin diseases pathogenesis.

Regulatory FOXP3+ T cells (Tregs) constitute 5% to 10% of T cells in the normal human skin. They play an important role in the induction and maintenance of immunological tolerance. The suppressive effects of these cells are exerted by various mechanisms including the direct cytotoxic effect, anti-inflammatory cytokines, metabolic disruption, and modulation of the dendritic cells function. The deficiency of Treg cells number or function are one of the basic elements of the pathogenesis of many skin diseases, such as psoriasis, atopic dermatitis, bacterial and viral infections. They also play a role in the pathogenesis of T cell lymphomas of the skin (cutaneous T cell lymphomas - CTCL), skin tumors and mastocytosis. Here, in the second part of the cycle, we describe dysfunctions of Tregs in selected skin diseases.

The role of regulatory T cells and genes involved in their differentiation in pathogenesis of selected inflammatory and neoplastic skin diseases. Part III: Polymorphisms of genes involved in Tregs' activation and function.

Regulatory T cells (Tregs) represent a cell type that promotes immune tolerance to autologous components and maintains immune system homeostasis. The abnormal function of Tregs is relevant to the pathogenesis of several skin diseases like psoriasis, atopic dermatitis, systemic lupus erythematosus, cutaneous T-cell lymphomas, and skin cancer and is also important in rheumatoid arthritis, diabetes and other autoimmune diseases. In this review, we will summarize the role of mutations and/or polymorphisms of genes involved in Tregs development, and functions in the pathogenesis of selected skin diseases.

The Extracellular Bacterial HtrA Proteins as Potential Therapeutic Targets and Vaccine Candidates.

BACKGROUND: An increasing resistance of bacteria to the commonly used antimicrobials forces to search for alternative or supportive ways to cure infections. Targeting virulence factors is one of such approaches. The bacterial HtrA proteins are strongly involved in virulence and the lack of functional HtrA in many cases impairs invasiveness of pathogens. HtrAs act by protecting the cells under stressful conditions as well as they take direct part in invasion of the host. The latter function is played predominantly by the recently identified extracellular fraction of HtrA. This review aims to evaluate HtrAs as therapeutic targets, including design of chemical inhibitors and vaccines. METHODS: We undertook a thorough search of bibliographic databases for peer-reviewed scientific literature. RESULTS: One hundred and sixty-four papers were included in the review. First, we briefly summarized key structural and functional properties of known HtrA proteins with the special focus on the extracellular HtrA fraction. Then we provided an overview of efforts and advancements to target HtrAs of pathogenic bacteria as a promising antimicrobial therapy. In some cases, encouraging results were obtained and application of HtrAspecific inhibitors protected tissues from damage and killed bacteria. Also promising reports concerning the use of HtrA as a protective antigen in several disease models have recently been published. CONCLUSION: The findings of this review suggest that the exported HtrA proteins are very attractive therapeutic targets due to their accessibility, significance in virulence and immunogenicity. However, further extensive studies are still needed to develop a safe antimicrobial treatment.

Transient hypogammaglobulinaemia of infants in children with mastocytosis - strengthened indications for vaccinations.

Mastocytosis is a disease caused by the accumulation of mast cells (MC) in the skin and/or in other tissues. Both the cutaneous form of the disease (CM) predominating in children and the systemic form (SM) typical for adults are associated with the occurrence of MC mediator-related symptoms. The release of mediators can be induced by physical stimuli and/or specific triggering factors. The routine vaccination program performed in the majority of children in infancy can be considered as an additional factor provoking exacerbation of CM. Conscious of the important role of MC in the innate immunity, we have analysed retrospective data concerning the levels of immunoglobulins, an adaptive factor, in a group of 74 infants and toddlers with CM. The values corresponding to transient hypogammaglobulinaemia of infants (THI) were found in 8 (10.81%) of cases. Classification of the antibody deficiency was done according to the working definitions for clinical diagnosis of primary immunodeficiency of the European Society of Immunodeficiencies (ESID) Registry - version May 11, 2015. Following the retrospective data, the final diagnosis of THI cannot be made due to the young age of the study group. The percentage may significantly exceed the published incidence of THI, i.e. about 0.11%. The results of our study may indicate, importantly, a higher incidence of THI in childhood-onset mastocytosis than in the general paediatric population and strengthen indications for vaccinations. In conclusion, we suggest that THI may be considered as a new aspect of paediatric mastocytosis that requires further investigation.