Primary Immunodeficiency In Children Research Articles

Primary immunodeficiency in the 9-year child

Primary immunodeficiency conditions are a heterogeneous group of disorders caused by defects in various parts of the immune system, manifested in the form of recurrent infectious and autoimmune diseases of varying severity. The authors describe own clinical observation to determine the principles of diagnosis and treatment of primary immunodeficiency in children in modern conditions. The average age of diagnosis of an immunodeficiency condition has been established to be best over 30 days, but often this time increases to several years. The data of the enrolment of primary immunodeficiency states of the Republic of Dagestan on the diagnosis and permanent replacement therapy of immunodeficiency states is also presented.

Ураження суглобів у пацієнтів з первинними імунодефіцитами

Purpose - to analyse the leading markers of primary immunodeficiencies in children with joint syndrome based on a clinical case study. The article presents literature data on one of the immunopathological syndromes - autoimmune syndrome - in children with primary immunodeficiencies. Mechanisms of autoimmunity and frequency of joint lesions are discussed. It is emphasized that mostly lesions of the musculoskeletal system are observed in patients with primary disorders of antibody formation and in certain primary combined immunodeficiencies. It was noted that there are specific features of damage to the musculoskeletal system in various nosological units of primary immunodeficiencies. Basic ideas about modern opportunities and problems of treatment of joint lesions in children with primary immunodeficiencies are given. The main clinical manifestations of Nijmegen syndrome in children are described. A case of joint damage in a child with Nijmegen syndrome is given. Conclusions. The system of treatment of autoimmune pathology in the setting of primary genetically determined disorders of the immune system requires further improvement, given the increasing survival rate of patients with primary immunodeficiencies, and in recent years there is a need to develop consensus recommendations for their management, which will improve their quality of life. The research was carried out in accordance with the principles of the Helsinki Declaration. The informed consent of the patient was obtained for conducting the studies. No conflict of interests was declared by the authors.

The Radiological Manifestations of Phagocytic Primary Immunodeficiencies in Children.

Primary immunodeficiencies are a diverse group of rare genetic disorders, among which phagocytic dysfunction impairs neutrophil function in a wide range of inherited disorders. Due to the heterogeneity of the disorders a multidisciplinary approach is often required for early diagnosis and initiation of appropriate treatments. The aim of this study was to evaluate the imaging findings in children admitted with phagocytic primary immunodeficiencies. Thirty-five children who fulfilled the inclusion criteria for phagocytic dysfunction were enrolled in this study. The patients were under close observation and monitoring from January 2011 until data locking in December 2017. The diagnosis of phagocytic immunodeficiency was confirmed by the patient's clinical course, presentation features, and laboratory data. Among the 35 patients studied, the most frequent condition was chronic granulomatous disease (CGD) (23 patients), followed by different types of neutropenia (8 patients) and Job's syndrome (4 patients). Mediastinal and hilar lymphadenopathies and consolidation were the most frequent presentations. There was a significant relationship between mediastinal/hilar lymphadenopathies and fungal infections. A meaningful relationship was also found between pulmonary noduleswithout halo signs in patients with concomitant tuberculosis and fungal infections. A significant correlation was found between CGD, pulmonary fibrotic changes, and mediastinal lymphadenopathies. The most frequent radiological manifestations in children included mediastinal and hilar consolidations. Physicians' awareness of the radiological and clinical manifestations of these inherited diseases may be helpful in the early diagnosis and timely initiation of specific prophylaxis measures to prevent infections and also to initiate hematopoietic stem cell transplantation as the curative management modality.

The Multifaceted Syndromic Primary Immunodeficiencies in Children.

Disorders of immunity are poorly recognised in some rare multisystem genetic conditions. We aim to describe syndromic features and immunological defects in children with syndromic primary immunodeficiencies (sPIDs). This is a retrospective descriptive study of children aged 0-18 years with sPIDs under the care of the paediatric immunology service at the Bristol Royal Hospital for Children, United Kingdom, from January 2006 to September 2021. sPIDs were identified in 36 patients. Genetic diagnoses which are not commonly associated with PIDs and not included in the International Union of Immunological Societies classification were present in 7/36 (19%): Trisomy 22, Arboleda-Tham syndrome, 2p16.3 deletion syndrome, supernumerary ring chromosome 20 syndrome, Myhre syndrome, Noonan syndrome, and trichothiodystrophy/Cockayne syndrome complex. Recurrent and/or severe infections were the most common clinical features (n = 33, 92%). Approximately half had combined immunodeficiency or antibody deficiency. The most common extra-immunological manifestations include dysmorphism (72%), disorders of nervous (78%), musculoskeletal (69%), haematology/lymphatic (58%), and gastrointestinal, hepatic/pancreatic (58%) systems. Patients with sPIDs often have multiorgan involvement and some are non-immunologically mediated. There should be a low threshold to clinically assess and investigate for disorders of immunity in any patients with syndromic features especially when they present with recurrent/severe/opportunistic infections, features of immune dysregulation, autoinflammation or lymphoproliferation.

Клінічний випадок маніфестації первинного імунодефіциту з лімфоми Беркіта

Lymphoma is a group of neoplastic diseases characterized by the clonal proliferation of lymphoid cells, manifested by the response of various stages of differentiation of normal B-lymphocytes, less often T-lymphocytes or natural killer cells. The etiology of most lymphomas is unknown. Some of the proven causal-consequence factors are: viral infections and immunodeficiency conditions. Purpose - to draw the attention of non-immunologists to the peculiarities of detecting the primary immunodeficiency (PID) states and the problem of their late diagnosis based on the data of a clinical case. Clinical case. A clinical observation of severe non-genetically differentiated PID is given. Screening signs of PID in the form of recurrent infectious respiratory tract syndrome and frequent long-term use of antibacterial drugs are highlighted, which should alert doctors to clinical and immunological markers of primary immunodeficiency. The presence of Burkitt's lymphoma in the boy also does not exclude the possibility of the manifestation of an immunodeficiency state, both secondary to the drug treatment of lymphoma, and primary, which can manifest itself in puberty. Common variable immunodeficiency is one of those PIDs that "starts" with Burkitt's lymphoma. Conclusions. The problem of low detection of probable PID in children in Ukraine is urgent. Primary care physicians are the first to be able to partially solve this problem by examining the infectious history and laboratory screening tests. There is incomplete awareness of related medical specialties regarding the signs of PID in lymphoproliferative syndrome in children. This clinical case demonstrates signs of PID at an early age. Low detection is also associated with poor capacity and quality and/or lack of immunological laboratory testing, particularly in public facilities. The research was carried out in accordance with the principles of the Helsinki Declaration. The informed consent of the of the child’s parents was obtained for the research No conflict of interests was declared by the authors.

НЕОНАТАЛЬНЫЙ СКРИНИНГ, ПОСТНАТАЛЬНАЯ ДИАГНОСТИКА И ТАКТИКА ДОКЛИНИЧЕСКОГО ЛЕЧЕНИЯ И ПРОФИЛАКТИКИ ПЕРВИЧНЫХ ИММУНОДЕФИЦИТОВ У ДЕТЕЙ (МЕТОДИЧЕСКИЕ РЕКОМЕНДАЦИИ)

For citation: S.V. Voronin, R.A. Zinchenko, I.Yu. Efimova, S.I. Kutsev, A.V. Marakhonov, A.A. Mukhina, G.A. Novichkova, D.E. Pershin, Yu.A. Rodina, A.G. Rumyantsev, A.Yu. Shcherbina. Neonatal screening, postnatal diagnosis and tactics of preclinical treatment and prevention of primary immunodeficiencies in children. Guidelines by the experts from the National Association of Experts in Primary Immunodeficiencies (NAEPID) and the Association of Medical Genetics (AMG) of Russia. Pediatria n.a. G.N. Speransky. 2023; 102 (2): 11-33. DOI: 10.24110/0031-403X-2023-102-2-11-33.

Primary Immunodeficiencies in Children Initially Admitted with Gastrointestinal/Liver Manifestations.

The gastrointestinal system is the most commonly affected organ, followed by the lungs, in patients with primary immunodeficiency disease (PID). Hence, it is common for children with PIDs to present with gastrointestinal symptoms. We aimed to analyze the clinical and histopathological findings of patients who were initially admitted to pediatric gastroenterology/hepatology clinics and subsequently diagnosed with PIDs to identify the clinical clues for PIDs. The demographic, laboratory, and histopathological findings, treatment modality, and outcomes of patients initially admitted to the pediatric gastroenterology/hepatology unit and subsequently diagnosed with PIDs were recorded. The study included 24 patients (58.3% male; median age [range]: 29 [0.5-204] months). Common clinical presentations included chronic diarrhea (n=8), colitis (n=6), acute hepatitis (n=4), and acute liver failure (n=2). The association of autoimmune diseases, development of malignant diseases, and severe progression of viral diseases was observed in 20.8%, 8.3%, and 16.6% of the patients, respectively. Antibody deficiency was predominantly diagnosed in 29.2% of patients, combined immunodeficiency in 20.8%, immune dysregulation in 12.5%, defects in intrinsic and innate immunity in 4.2%, autoinflammatory disorders in 8.3%, and congenital defects of phagocytes in 4.2%. Five patients remained unclassified (20.8%). Patients with PIDs may initially experience gastrointestinal or liver problems. It is recommended that the association of autoimmune or malignant diseases or severe progression of viral diseases provide pediatric gastroenterologists some suspicion of PIDs. After screening using basic laboratory tests, genetic analysis is mandatory for a definitive diagnosis.

The examination of family functioning in immunodeficiency patients in the context of McMaster family therapy in Turkey

ABSTRACT Immunodeficiency diseases associated with the absence or dysfunction of any of the components that make up the immune system. These diseases may create difficulties for family functionality. The study aims to examine family functionality in the context of McMaster Family Therapy in families with immunodeficiency patients. The study include 153 family members from Immunodeficiency Patients Solidarity Platform in Turkey. The sociodemographic questionnaire and McMaster Family Assessment Device were used to collect data with respect to problem solving, communication, roles, affective responsiveness and involvement, behaviour control, and general functioning. The majority of the participants are married, females, university graduates and low income. Most of them have nuclear families and a diagnosis of primary immunodeficiency in children. Areas of non-healthy family functionality include affective involvement and behaviour control. Also, problem-solving, roles, and communication create risks in terms of dysfunction.

Immune and hematological disorders in Primary Immunodeficiency in children

Abstract Primary immunodeficiency (PID) was previously considered an extremely rare pathology in childhood, now it has been established that congenital deficit of quantity and functional activity of the lymphocytes, platelets and neutrophils occurs in 1:500–1:4000 newborns. Severe chronic neutropenia in PID is characterized by a stable decrease or absence of circulating neutrophils (<500/cm) and accompanied with recurrent bacterial skin and lung infections. We identified 135 patients with PID. Patient’s examination included clinical observation, general blood test, immunological tests, X-ray of chest and ultrasound examination. We report that six children with PID had significant hematological disorders. The age of these patients was from 1 month to 13 years. Four of them were born from consanguineous marriages, 3 patients died before the age of 5 years. 2 patients with PID had congenital neutropenia, repeated skin infections, pneumonia, diarrhea, stomatitis. Two brothers with WAS syndrome had repeated bleeding, skin hemorrhages, anemia, lymphadenitis, hepatosplenomegaly. The platelet count was about 30–70/ml. Genetic analysis in these patients revealed a hemizygous c.12_13insGG mutation in exon 1 of the WAS gene. 2 children with SCID were found to be carriers of thalassemia B. All our patients showed a significant decrease in Ig classes, CD3+, CD4+, CD8+ and NBT test. We conclude that patients with suspected PID should be continuously monitored by Immunologists and Hematologists. Timely detection of hematological disorders in patients with PID allows for correct diagnosis and prevents fatal complications. Genetic testing can help in making a definitive diagnosis. Supported by Azerbaijan Medical University

Outstanding Features of COVID-19 Overlapping Primary Immunodeficiency in Children.

Outstanding Features of COVID-19 Overlapping Primary Immunodeficiency in Children.

Azithromycin and Co-Trimoxazole in Antimicrobial Prophylaxis: Special Emphasis on Primary Immunodeficiencies in Children

Patients with primary immunodeficiency diseases (PID) are prone to infectious, and they often determine the course of the disease. Antimicrobial prophylaxis for patients with PID includes co-trimoxazole, amoxicillin and macrolides. Co-trimoxazole is a widely used antimicrobial agent for pneumocystosis prophylaxis in immunocompromised patients, including patients with primary cellular immunodeficiency. Antiinflammatory effect of azithromycin made it a drug of choice in the management of chronic lung diseases in the patients with primary immunodeficiencies, especially in those with antibody deficiencies. Further randomised controlled studies are needed to define the optimal agent for all types of primary immunodeficiencies, its dose, duration of treatment, benefits and safety of long-term use.A recommendation for the prophylactic use of long-term therapy should consider the balance between benefits and risk of adverse events.
 Bangladesh Journal of Medical Science Vol.20(3) 2021 p.530-538

Granulomatous skin lesion as a manifestation of primary immunodeficiency in children

Primary immunodeficiencies (PID) compile a genetically heterogeneous group of more than 400 disorders. Most patients with PID are shown to be highly susceptible to various types of infectious diseases. However, in the past decade, non-infectious complications associated with immune dysregulation and autoimmunity have been increasingly recognized in PID. Patients with PID often have skin manifestations, that allow to suspect the diagnosis of immunodeficiency in early childhood. One of the least studied skin manifestations of PID is granulomatous dermatitis. This manuscript current research on the pathogenesis, methods of diagnosis and therapy of granulomatous dermatitis in patients with various PID.

Створення онлайн-тесту для виявлення в дітей підозри на вроджені помилки імунітету

As of 2020, more than 400 nosologies of primary immunodeficiencies are known. For most children with this pathology, the key immunological diagnosis remains unclear due to the lack of pathognomonic symptoms, as well as low medical alertness due to the relative rarity of these diseases. Primary immunodeficiencies are not fatal if diagnosed early, moreover, they are treatable with the possibility of a full life or complete recovery. Today, information technology has become an integral part of everyday life. The ability to evaluate a clinical patient record online is a modern important step. Purpose — to create an online test, available to both physicians and patients, to detect suspicious cases of primary immunodeficiencies in children based on possible clinical manifestations. Material and methods. Collection and analysis of a child's clinical record on suspicious manifestations of primary immunodeficiency, age and gender comparisons using web technologies. (PHP, MySQL). Results. International and Ukrainian developments of clinical criteria for suspected primary immunodeficiency in a child have been transformed into an online test containing 35 clinical inquiries to a child's parents or attending physician, followed by analysis of a child's gender and age. As a result, the test user receives the result of the alertness level in terms of urgency to consult a pediatric immunologist. Conclusions. The immunological online test showed considerable interest, a high detection rate of suspicious cases of primary immunodeficiency. The test can be used with patients who come for an appointment or with hospital patients. The study was carried out in accordance with the principles of the Helsinki Declaration. The study protocol was approved by the Local Ethics Committee of the institution specified in the work. Informed consent was obtained from the parents of the children for the research. The authors declare no conflicts of interest. Key words: pediatric immunology, primary immunodeficiencies, online, test, clinical criteria.

Matched versus Haploidentical Hematopoietic Stem Cell Transplantation as Treatment Options for Primary Immunodeficiencies in Children

Primary immunodeficiencies (PIDs) are inherited disorders of the immune system with allogeneic hematopoietic stem cell transplantation (HSCT) as the only curative treatment in some of them. In case an HLA-matched donor is not available, HSCT from a haploidentical family donor may be considered. We compared the outcomes of HSCT from HLA-matched unrelated or related donors (MUDs or MRDs) and mismatched related haploidentical donors (MMRDs) in patients with a variety of PIDs in 2 centers. A total of 44 pediatric patients were evaluated. We reviewed the outcomes of 25 children who underwent transplantation with HLA-matched grafts (MRD, n=13; MUD, n=12) and 19 patients receiving haploidentical stem cells. Bone marrow (BM) was transplanted in 85% (MRD) and 75% (MUD) of the matched cohort and peripheral blood stem cells (PBSCs) in 15% (MRD), 25% (MUD), and 100% (MMRD). All but 9 patients (MRD, n=6; MMRD, n=3) with severe combined immunodeficiency (SCID) received a chemotherapy-based conditioning regimen. Immune reconstitution of T, B, and natural killer cells was comparable for all groups with an advantage of recipients of MRD grafts in early CD4 reconstitution. However, deaths due to viral infections occurred more often in the haploidentical cohort. The disease-free survival was 91.7% (MRD), 66.7% (MUD), and 62.7% (MMRD), respectively. Grade II to IV acute graft-versus-host disease (GVHD) occurred in 15% (MRD), 8% (MUD), and 21% (MMRD) of the patients. Only 1 patient had severe grade IV GVHD in the MRD group, whereas no grade >II GVHD was observed in the MUD or MMRD cohort. These data indicate that in the absence of a suitable HLA-identical family donor, haploidentical HSCT may be a viable option for patients with life-threatening disease and urgent need of HSCT.

Primary immunodeficiencies, autoimmune hyperthyroidism, coeliac disease and systemic lupus erythematosus in childhood immune thrombocytopenia.

To evaluate the cumulative prevalence of coeliac disease, systemic lupus erythematosus, autoimmune hyperthyroidism and primary immunodeficiencies in children with either newly diagnosed/persistent or chronic immune thrombocytopenia (ITP). Monocentric retrospective analysis of the clinical and biochemical features of 330 consecutive patients with ITP referred to our Pediatric Hematology Unit between January 2009 and December 2018. The prevalence of systemic lupus erythematosus (0.3%), coeliac disease (0.3%) and autoimmune hyperthyroidism (0.6%) was not increased compared to general paediatric population. Of note, the prevalence of underlying primary immunodeficiencies was 2.4%, remarkably higher than the general paediatric population (P=.005). All the patients diagnosed with immunodeficiency developed either bi-/trilinear cytopenia or splenomegaly. Whilst autoimmune and immunological screening is already recommended at the onset of immune thrombocytopenia, we recommend that primary immunodeficiencies be regularly screened during follow-up, especially in case of additional cytopenia or lymphoproliferation.

Хронічний шкірно-слизовий кандидоз — нозологічна форма первинного імунодефіциту у дітей. Випадок шкірно-слизового кандидозу в дитини раннього віку

Хронічний шкірно-слизовий кандидоз — нозологічна форма первинного імунодефіциту у дітей. Випадок шкірно-слизового кандидозу в дитини раннього віку

Infectious complications after hematopoietic stem cell transplantation for primary immunodeficiency in children: A multicenter nationwide study.

The aim of this nationwide study was to evaluate the characteristics of bacterial infections (BI), invasive fungal disease (IFD), and viral infections (VI) in pediatric patients with PID after allogeneic hematopoietic stem cell transplantation (allo-HSCT). In total, 114 HSCT recipients were enrolled into the study. At least one infectious complication (IC) was diagnosed in 60 (52.6%) patients aged 0.1-17.7years, that is, 59.5% with SCID and 49.4% with non-SCID. Among 60 HSCT recipients diagnosed with at least one IC, 188 episodes of infectious complications (EIC) were recorded, that is, 46.8% of BI, 41.5% of VI, and 11.7% of proven/probable IFD. According to PID and HSCT donor type, the incidence of EIC was comparable (P=.679). The localization of infections differed significantly due to PID type (P=.002). After each HSCT donor type, the most common site of infection was GI. Overall, BI caused by Gram-positive strains (59.1%) were prevalent, especially Staphylococcaceae. The multidrug-resistant (MDR) pathogens were diagnosed in 52.3%, especially ESBL+Enterobacteriaceae. The profile of VI was comparable for SCID and non-SCID patients (P=.839). The incidence of IFD was comparable for each PID and HSCT donor type. Survival after infection was 91.5% and was comparable for PID and HSCT donor type. The rate of patients diagnosed with IC among pediatric PID-HSCT recipients did not depend on PID type, but rather on HSCT donor type. The localization of IC depended on PID and HSCT donor type. Within bacterial infections, predominated Gram-positive strains and the MDR pathogens were responsible for more than half of EIC.

The impact of combining educational program with the improving of infrastructure to diagnose on early detection of primary immunodeficiencies in children.

Early detection of primary immunodeficiency diseases (PID) is vital for adequate prevention and management of PID infectious complications. The objective of this study was to evaluate the impact of a model combining physician education and public awareness with the infrastructure to diagnose PID to improve its early detection in children. Three approaches were combined and the results were followed from February 2017 to February 2019 in Ternopil region, Ukraine: the education of primary care physicians and other specialists on early PID detection using workshops, trainings, and targeted publications; organization of public events and media appearances to raise PID awareness; performing immunological testing for patients with suspected PID. Among the 150 individuals that were screened, PID was diagnosed in 19 patients (12.7%). The majority of diagnosed PID cases were combined immunodeficiency with associated or syndromic features, followed by antibody deficiencies. Patients referred by the specialist doctors had the highest percentage of confirmed PID compared with those referred by primary care physicians (p = 0.0273) and risk group patients (p = 0.0447). Among warning signs in patients with PID, two or more pneumonias within 1year occurred most often (26.3%), followed by failure of an infant to gain weight or grow normally (21.1%). Among other signs of PID, dysmorphic features and microcephaly were the most prevalent (31.6%). In conclusion, a program combining physician education and public awareness with infrastructure needed to diagnose primary immunodeficiency diseases is an effective tool for early PID diagnosis. Physician education was a more effective tool compared with rising public awareness.

Cutaneous granulomas with primary immunodeficiency in children: a report of 17 new patients and a review of the literature.

Paediatric cutaneous granuloma with primary immunodeficiency (PID) is a rare condition. The physiopathology is unclear, and treatment is challenging. We report on 17 paediatric cases and review the literature. To make dermatologists and dermatopathologists aware of the diagnostic value of skin granulomas in paediatric PID. We collected data on 17 patients with cutaneous granulomas and PID registered with us and also reviewed 33 cases from the literature. Cutaneous granuloma was the presenting feature of the PID in 15 of the 50 collated cases. The lesions presented as red-brownish nodules and infiltrated ulcerative plaques, predominantly on the face and limbs. Scleroderma-like infiltration on a single limb was observed in 10% of the cases. The associated PID was ataxia-telangiectasia (52%), combined immunodeficiency (24%), cartilage-hair hypoplasia (6%) and other subtypes (18%). The granulomas were mostly sarcoidal, tuberculoid, palisaded or undefined subtypes. In some patients, several different histopathologic granulomatous patterns were found in the same biopsy. Some granulomas were associated with the presence of a vaccine strain of rubella virus. Cutaneous granulomas associated with a PID have a variable clinical presentation. A PID can be suspected when crusty, brownish lesions are found on the face or limbs. The concomitant presence of several histological subtypes in a single patient is suggestive of a PID.

A model for reticular dysgenesis shows impaired sensory organ development and hair cell regeneration linked to cellular stress.

ABSTRACTMutations in the gene AK2 are responsible for reticular dysgenesis (RD), a rare and severe form of primary immunodeficiency in children. RD patients have a severely shortened life expectancy and without treatment die, generally from sepsis soon after birth. The only available therapeutic option for RD is hematopoietic stem cell transplantation (HSCT). To gain insight into the pathophysiology of RD, we previously created zebrafish models for Ak2 deficiencies. One of the clinical features of RD is hearing loss, but its pathophysiology and causes have not been determined. In adult mammals, sensory hair cells of the inner ear do not regenerate; however, their regeneration has been observed in several non-mammalian vertebrates, including zebrafish. Therefore, we used our RD zebrafish models to determine whether Ak2 deficiency affects sensory organ development and/or hair cell regeneration. Our studies indicated that Ak2 is required for the correct development, survival and regeneration of sensory hair cells. Interestingly, Ak2 deficiency induces the expression of several oxidative stress markers and it triggers an increased level of cell death in the hair cells. Finally, we show that glutathione treatment can partially rescue hair cell development in the sensory organs in our RD models, pointing to the potential use of antioxidants as a therapeutic treatment supplementing HSCT to prevent or ameliorate sensorineural hearing deficits in RD patients.