Primary Immunodeficiency Research Articles

COVID-19 in children with somatic pathology

The coronavirus infection is a pressing issue in modern healthcare, yet the characteristics of the SARS-CoV-2 infection course in children with comorbidities remain insufficiently studied. The aim of this study was to evaluate the clinical form, severity, and duration of SARS-CoV-2 virus shedding in pediatric patients with somatic diseases, depending on the comorbid pathology. Materials and Methods. A comprehensive single-center retrospective study was conducted, analyzing 314 medical records of patients hospitalized in the infectious diseases department of the Russian Children’s Clinical Hospital in Moscow over 11 months in 2022. The inclusion criterion was the presence of a laboratory-confirmed COVID-19 diagnosis. Results. Children with comorbidities were found to be predisposed to a more severe course of SARS-CoV-2 infection compared to the pediatric population in general. Children with hematological diseases were at the highest risk of adverse outcomes from COVID-19. Patients with oncological and hematological diseases and primary immunodeficiencies shed the SARS-CoV-2 virus significantly longer than patients with other somatic pathologies. The duration of SARS-CoV-2 RNA detection in patients with severe COVID-19 was significantly longer, which also correlated with the severity of the underlying somatic disease. Conclusion. Children with comorbidities are at risk for a more severe and prolonged course of SARS-CoV-2 infection.

Innate immunodeficiencies: a group of primary immunodeficiencies predisposing exclusively to common diseases

Abstract Background Innate immune deficiencies can impair both cellular and humoral immune responses. In contrast, other immune functions may appear normal, leading to increased susceptibility to specific pathogens, such as severe viral infections or Mendelian Susceptibility to Mycobacterial Disease (MSMD). Studying these deficiencies is essential for understanding the pathophysiology of these infectious diseases. Main body While primary immunodeficiencies (PIDs) generally cause vulnerability to multiple infections, innate immunodeficiencies increase susceptibility to specific pathogens, despite normal immune responses to others. Patients with these deficiencies show normal immunoglobulins and lymphocyte subpopulations, complicating diagnosis. This review highlights genetic susceptibility to mycobacteria, pneumococci, herpes simplex virus, and candidiasis, emphasizing recognizing this subset of PIDs. Conclusion This review highlights the diverse spectrum of genetic mutations contributing to defects in innate and intrinsic immunity, including Mendelian susceptibility to mycobacterial disease (MSMD), chronic mucocutaneous candidiasis, and predispositions to invasive bacterial and viral infections. Identifying key mutations in pathprovideh such as TLR3, IFN signaling, and IL-17A/F immunity provides valuable insights into the pathogenesis of these conditions. Our findings underscore the need for early genetic diagnosis and targeted interventions, particularly in regions with high undiagnosed cases, to reduce the morbidity and mortality associated with defects in innate and intrinsic immunity.

Inflammatory Bowel Disease in Activated PI3Kδ Syndrome: An Uncommon Complication of a Rare Condition

Background/Objectives: Monogenic primary immunodeficiencies represent a group of disorders with varying levels of severity, many of which remain poorly understood. Activated phosphoinositide-3 kinase delta syndrome (APDS) is a rare genetic condition resulting from dominant point mutations in the phosphoinositide-3 kinase delta (PI3Kδ) gene, which leads to hyperactivation of the PI3Kδ enzyme, primarily expressed in T and B lymphocytes. Children with this mutation often have recurrent sinopulmonary infections and immunodeficiency. Additional complications may include increased susceptibility to herpes virus infections, lymphoid hyperplasia, and autoimmune conditions. In this case, report, we describe the clinical course of a young boy diagnosed with APDS who developed unclassified inflammatory bowel disease (U-IBD) and explore a personalized treatment approach. Methods: We detail the clinical course of a 12-year-old boy with APDS who presented with fever, diarrhea, anemia, and significant weight loss. Diagnostic evaluations, including endoscopy and histological analysis, led to a diagnosis of U-IBD. Genetic testing confirmed a heterozygous PIK3CD mutation (c.G3061A, p.E1021K). Results: Although APDS is characterized by a broad spectrum of immune dysregulation, the occurrence of IBD in this context is rare. We managed the patient’s IBD with exclusively enteral nutrition to induce remission, followed by a maintenance regimen combining the Crohn’s Disease Exclusion Diet (CDED) and mesalamine, achieving sustained long-term clinical remission. Conclusions: This case underscores the importance of personalized treatment approaches in managing the complex manifestations of APDS.

CXCR4 antagonism ameliorates leukocyte abnormalities in a preclinical model of WHIM syndrome

BackgroundWHIM (Warts, Hypogammaglobulinemia, Infections, and Myelokathexis) syndrome is an ultra-rare, combined primary immunodeficiency and chronic neutropenic disorder characterized by a range of clinical presentations, including peripheral neutropenia, lymphopenia, and recurrent infections. WHIM syndrome is most often caused by gain-of-function mutations in the gene encoding C-X-C chemokine receptor 4 (CXCR4). As such, inhibition of CXCR4 with XOLREMDI® (mavorixafor), an orally bioavailable CXCR4 antagonist, demonstrated clinically meaningful increases in absolute neutrophil and lymphocyte counts and concomitant reduction in infections in patients with WHIM syndrome, resulting in its recent U.S. Food and Drug Administration approval. The impact of CXCR4 antagonism on other aspects of the pathobiology in WHIM syndrome, such as lymphopoiesis and leukocyte trafficking between primary and secondary lymphoid organs, is less understood.MethodsIn the current study, the effects of CXCR4 antagonism on leukocyte trafficking and distribution in primary and secondary lymphoid organs were investigated in a mouse model of WHIM syndrome carrying the heterozygous Cxcr41013 mutation. Cxcr4+/1013 and Cxcr4 wild-type mice received the orally bioavailable CXCR4 antagonist X4-185. Blood, spleen and bone marrow samples were collected for numeration, flow cytometry, and functional studies.ResultsCxcr4+/1013 mice exhibited profound peripheral blood leukopenia as seen in patients with WHIM syndrome. CXCR4 antagonism corrected circulating leukopenia and mobilized functional neutrophils without disrupting granulopoiesis in the bone marrow of Cxcr4+/1013 mice. Furthermore, Cxcr4+/1013 displayed aberrant splenic T and B-cell counts and frequency. Treatment with X4-185 normalized splenic T-cell abnormalities, correcting the reduced CD8+ T-cell numbers, restoring the CD4/CD8 T-cell ratio, and ameliorating peripheral blood T-cell lymphopenia. In addition, CXCR4 antagonism was able to correct the abnormal frequencies and numbers of splenic marginal zone and follicular B cells in Cxcr4+/1013 mice, and ultimately normalize B-cell lymphopenia in the peripheral circulation.ConclusionsOur study provides comprehensive evidence that oral dosing with a CXCR4 antagonist can effectively correct WHIM-associated neutrophil and lymphocyte abnormalities in a mouse model of WHIM syndrome. These findings extend our understanding of how targeting the dysregulated CXCR4 signaling pathway can ameliorate the pathogenesis of WHIM syndrome.

Transient biopsy-proven progressive multifocal leukoencephalopathy-immune reconstitution inflammatory syndrome (PML-IRIS) in an elderly woman without known immunodeficiency: a case report

BackgroundProgressive multifocal leukoencephalopathy (PML) is a severe opportunistic brain disease caused by lytic JC polyomavirus (JCPyV) replication in oligodendrocytes. Although JCPyV infection is common in the general population, PML almost exclusively occurs in patients immunocompromised due to untreated HIV/AIDS, haematological malignancies, primary immunodeficiencies, solid organ transplantation, or immunomodulatory treatment of autoimmune diseases. There is no effective antiviral treatment, and recovery depends on immune reconstitution. Paradoxically, initiation of antiretroviral therapy for HIV/AIDS or interruption of immunomodulating treatment can worsen the clinical manifestations due to immune reconstitution inflammatory syndrome (IRIS). Here, we report an unusual case of spontaneous IRIS in a 76-year-old immunocompetent woman, unmasking PML and leading to unexpected recovery.Case presentationThe patient was admitted to the hospital due to psychosis, speech impairment, and behavioral changes over the last three months. She had previously been healthy, except for a cerebellar stroke secondary to paroxysmal atrial fibrillation. Magnetic resonance imaging (MRI) revealed multiple contrast-enhancing white matter lesions suspicious of cancer metastases. Due to suspicion of edema, dexamethasone was administered, and the patient was released while waiting for a stereotactic brain biopsy. Eight days later, she suffered tonic seizures and was readmitted. Intravenous levetiracetam gave rapid effect, but the patient was paranoid and non-cooperative, and dexamethasone was unintentionally discontinued. Ten days later, the brain biopsy revealed demyelination, abundant perivascular T cells, macrophages, and scattered JCPyV-infected oligodendrocytes, rendering the diagnosis of PML-IRIS. The cerebrospinal fluid contained low amounts of JCPyV-DNA, and plasma contained high levels of anti-JCPyV immunoglobulin G. Despite extensive immunological testing, no evidence of immunodeficiency was found. The patient gradually recovered clinically and radiologically. More than 19 months after diagnosis, the patient has only a slight impairment in language and behavior.ConclusionsAn apparently immunocompetent elderly person developed clinically symptomatic PML, which spontaneously resolved with symptoms and signs of IRIS. The atypical MRI lesions with contrast enhancement and the lack of known immunological risk factors for PML delayed the diagnosis, eventually proved by biopsy. PML and PML-IRIS should be considered in the differential diagnosis of patients presenting CNS symptoms and focal lesions with contrast enhancement on MRI.

Hyperactivation of the PI3K Pathway in Inborn Errors of Immunity: current understanding and therapeutic perspectives

Abstract Phosphoinositide-3-kinase (PI3K) pathway function is crucial to normal development, differentiation and function of immune cells including B, T and NK cells. Following the description of two cohorts of patients with a primary immunodeficiency with gain-of-function variants in the PIK3CD gene a decade ago, the disease entity activated PI3K delta syndrome (APDS) was named. Since then, many more patients with PIK3CD variants have been described, and loss-of-functions variants in PIK3R1 and PTEN have also been linked to APDS. Importantly, the availability of small molecules that inhibit the PI3K pathway have enabled targeted treatment of APDS patients. In this review, we define (1) the PI3K pathway and its role in inborn errors of immunity; (2) the clinical and immunological presentation of APDS1 (PIK3CD GOF), APDS2 (PIK3R1 LOF) and related disorders; (3) Diagnostic approaches to identify and functionally validate the genetic causes of disease; (4) therapeutic interventions to target PI3K hyperactivation; and finally (5) current challenges and future perspectives that require attention for the optimal treatment of patients with APDS and APDS-L diseases.

Early diagnosis of immunodeficient patients with partial albinism: The role of hair study and peripheral blood smear.

Primary immunodeficiency diseases (inborn errors of immunity) with partial albinism are a group of autosomal recessive syndromes including Chediak Higashi Syndrome (CHS), Griscelli Syndrome type 2 (GS2), Hermansky-Pudlak Syndromes type 2 and 10 (HPS2, HPS10), Vici syndrome and P14/LAMTOR2 deficiency. Twenty-five patients including 10 CHS, 10 GS2, and 5 HPS2 were evaluated in this study within the last 10 years. Five cases with oculocutaneous albinism (OCA) and 5 healthy subjects without albinism were used as two control groups. Genetic analyses were performed by whole exome or panel sequencing or targeted Sanger sequencing. Subsequently, leukocyte granules in peripheral blood smear and hair shaft were examined as screening tests. Giant granules were only presented in the leukocytes cytoplasm of 10/10 CHS patients. The uneven cluster of pigments and giant melanin granules in hair samples were observed in 10/10 GS2 and 10/10 CHS patients, respectively. In both 5/5 OCA and 5/5 HPS2 patients, there were regular pigments in the middle of hair shafts. Genetic analyses were performed for all patients, revealing 7 novel variants in LYST gene for CHS patients and 4 novel variants in AP3B1 for HPS2 patients. Receiving hematopoietic stem cell transplantation (HSCT) in a timely manner is crucial in CHS and GS2 patients; therefore, screening tests may provide a vital clue for early diagnosis in these patients. However, the final confirmation of CHS, GS2, and HPS2 disorders is done by genetic assay.

Protective antibody concentrations in primary immunodeficiency following infusion with 5% or 10% intravenous immunoglobulin.

Background: Inadequate production of immunoglobulin G (IgG) antibodies renders patients with primary immunodeficiency susceptible to infection by numerous pathogens, some of which can lead to severe asthma exacerbation and possible death. These patients who are immunocompromised are often reliant on intravenous immunoglobulin (IVIG) therapies, which provide passive antibodies against various respiratory pathogens, including measles virus and encapsulated bacteria. Objective: We conducted a subanalysis of data from a multicenter, multinational, phase III, open-label bioequivalence study to compare protective concentrations of IgG antibodies provided by a 5% and a 10% IVIG product in patients with primary immunodeficiency. Methods: Patients on stable 21- or 28-day regimens of previous IVIG products were assigned to receive study treatment (adults: 5% IVIG and 10% IVIG; children: 10% IVIG) at doses of 300-800 mg/kg per infusion. Trough concentrations of total IgG, IgG subclasses, measles-neutralizing antibodies, and IgG against Haemophilus influenzae type b and Streptococcus pneumoniae serotypes were evaluated. Results: A total of 48 patients (33 adults ages 16-55 years; 15 children ages 2-15 years) were enrolled and received treatment. No statistically significant differences in trough concentrations of total IgG, IgG subclasses, measles-neutralizing antibodies, or IgG directed at encapsulated bacteria were observed between the 5% and 10% formulations in analyses by age (adult or pediatric) or infusion schedule (every 21 or 28 days). All evaluated patients had trough IgG concentrations above accepted thresholds for protection against disease. Conclusion: These findings support the conclusion that, at dose levels and infusion schedules prescribed in clinical practice, this 5% and 10% IVIG product provided consistent, predictable, and bioequivalent IgG concentrations for adult and pediatric patients with primary immunodeficiency disease. Both formulations delivered trough antibody concentrations of total IgG, measles-neutralizing antibodies, and antibodies against encapsulated bacteria that are above thresholds accepted as protective.Clinical trial NCT01963143, <ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="http://www.clinicaltrials.gov">www.clinicaltrials.gov</ext-link>.

Job’s syndrom. Case reports

Primary immunodeficiencies with impaired humoral link are genetically determined diseases characterized by impaired antibody formation. The article presents information about an orphan disease – hyperimmunoglobulinemia E syndrome (hyper-IgE), or Job’s syndrome, which is characterized by elevated IgE levels in the blood serum, recurrent infections and various clinical manifestations (specific abnormalities of connective tissue, skeleton, tooth enamel, neurological disorders, etc.). Historical aspects of Job’s syndrome are described, the importance of immunoglobulins E in the human immune system is shown. It is noted that genetic testing, including sequencing of the STAT3 and DOCK8 genes, plays a decisive role in confirming the diagnosis. Low prevalence of Job’s syndrome is the reason for late diagnosis. Clinical cases of Job’s syndrome, a variant of primary immunodeficiency confirmed genetically, are presented.

Competency of Jeffrey Modell Foundation warning signs and routine laboratory tests in suspecting primary immunodeficiencies: A cross-sectional multi-centric prospective study from eastern India.

To test the efficaciousness of the 10 warning signs of Jeffrey Modell Foundation (JMF) and routine laboratory tests in predicting Primary Immunodeficiencies (PIDs). Hospitalized children <12 years age satisfying at least two of 10 warning signs were subjected to routine and confirmatory tests. Of 35 204 admitted patients, 66 satisfied the JMF criteria and 34 had PID. Also, 59% were infants, with a female preponderance. The most common immunodeficiency disorder group were antibody deficiencies and phagocyte defects (35.3%). Chronic granulomatous disease (CGD) was the commonest overall (29.4%). The need for intravenous antibiotics was the most sensitive (91%) criterion for predicting PID. When combined with positive family history of PID, sensitivity (94%) increased further. The two most specific indicators were recurrent ear infections (88%), and family history of PID (88%). The best positive predictor was family history of PID (69%), and the best negative predictor was recurrent sinus infections (58%). Significant association was found between persistent oral thrush and PID (p .043), and insufficient weight gain and antibody deficiencies (p .037). Absolute neutrophil count, CRP, and elevated ESR were also significantly associated with PIDs (p-values being .036, .011, and .014 respectively). Out of all 10 JMF criteria, the three most important ones to predict PID were need for IV antibiotics, family history of PID, and recurrent ear infections.

OA26 Atypical Multisystem Inflammation related to infection or just plain old polyarteritis nodosa?

Abstract Introduction We present the case of a 5-year-old boy with episodes of pyrexia of unknown origin associated with polyarthritis, central neuroinflammation and mucocutaneous manifestations. His skin biopsy demonstrated a nodular vasculitis which could be consistent with polyarteritis nodosa. Interestingly though, he had additional atypical rashes, ocular inflammation and evidence of acute and past streptococcal infection and his fever and CRP normalised prior to corticosteroid initiation. Case description A five-year-old British African male presented with five-week history of persistent fever, headaches, joint pain and bilateral eye pain. He was transferred to a tertiary paediatric infectious disease’s unit due to unrelenting fever with no fixed pattern, despite nine days of broad-spectrum intravenous antibiotics. He was diagnosed with neuroinflammation of uncertain aetiology, evidenced by leptomeningeal enhancement and bilateral papillitis on brain MRI. CSF microbiology and autoimmune profiles were negative. There was no evidence of primary malignancy. The fever resolved with pulsed IV methylprednisolone and the child was discharged home on a weaning regime of oral prednisolone. After stopping steroid treatment, he represented with high-grade fever, limping, anterior uveitis and new-onset non tender cutaneous lesions, plaques over eyelids and cheek and annular lesions over arms, legs and buttocks. Repeat MRI of the brain and spine showed resolution of previous neuroinflammation. Blood tests revealed raised ANA, IgG and ASOT titre, and his throat swab was positive for Group A Streptococcus. He completed 10 days of intravenous antibiotics and oral high dose ibuprofen (10 mg/kg TDS). On review by tertiary paediatric rheumatology, he was identified to have pleomorphic skin rash and subcutaneous nodules. Skin and deep tissue biopsy confirmed lobular and septal panniculitis with necrotising vasculitis, consistent with a nodular vasculitis. Treatment with high-dose steroid and mycophenolate mofetil (MMF) was initiated, but his CRP and fever had resolved prior to his first dose. He experienced improvement in systemic symptoms and arthritis; however, skin lesions persisted, with appearance of new lesions and hyperpigmentation, on reduction of steroid dose. His course was complicated by acute varicella infection, requiring oral aciclovir. Further treatment trials included topical tacrolimus and topical corticosteroids for his skin lesions. At one biopsy site, he experienced significant delay in wound healing. The genetic panel for primary immunodeficiency panel (R15) demonstrated no pathological variants. Discussion This case report highlights that, whilst the biopsy may be consistent with nodular vasculitis, such as PAN, the clinical manifestations are not perfectly aligned. Discussion within the rheumatology community would support optimal patient care. Childhood-onset Polyarteritis Nodosa (c-PAN) is a rare systemic vasculitis. Although the aetiology is unknown, associations with infections like group A streptococcus and hepatitis B suggest a postinfectious autoimmune response. There are no clear genetic links to PAN, but PAN-like vasculitis is part of reported monogenic autoinflammatory conditions. Key atypical features in this case include uveitis at presentation, nonspecific central neuroinflammation, unusual cutaneous lesion morphology, improvement of acute phase reactants before immunomodulatory treatment, and delayed biopsy wound healing. While ocular findings in PAN may include episcleritis, scleritis, keratitis, retinal vascular occlusions, and ocular ischemic syndrome, uveitis has not been reported in c-PAN. The patient also showed nonspecific inflammatory changes on initial MRI. Neurological involvement in c-PAN typically includes cerebrovascular accidents, cranial nerve palsies, and mononeuritis multiplex, with meningeal involvement being less common (reported 4% in a study of 69 children). Additionally, the patient experienced delayed wound healing following the biopsy, which is undocumented in c-PAN, but may be related to immune modulating treatment. A positive streptococcal throat swab could suggest an immune reaction as part of bacterial tonsilitis, or Acute Rheumatic Fever. However, he did not meet Jones Criteria, there was no response to prolonged antibiotics and the chronic remitting nature made these less likely. An autoinflammatory disorder, Deficiency of Adenosine Deaminase 2 (DADA2), was also considered but he had no evidence of livedo racemosa, strokes and no CECR1 mutation was identified. Our case has been discussed within a multidisciplinary team and we speculate that it could represent a previously undefined immune sensitivity within the autoimmune, autoinflammatory and immune deficiency spectrum giving an exaggerated response to infection. Key learning points • This case presents a significant diagnostic challenge due to its atypical clinical features and inconclusive extensive investigations, including immunologic testing, tissue biopsy, and genetic analysis. • While the patient’s symptoms improved with high-dose steroids and MMF, the recurrence of symptoms upon tapering steroids underscores the persistent inflammatory nature of the disease. • The detection of group A Streptococcus in the patient’s throat swab suggests a potential postinfectious autoimmune trigger, highlighting the role infections can play in the pathogenesis of vasculitis. The negative results from the R15 Primary Immunodeficiency panel suggest that more advanced genetic and immunologic testing may be beneficial. • We invite discussion on whether additional genetic or immunologic testing could optimise this patient’s care and contribute to the broader understanding of atypical vasculitis syndromes.

Pulmonary manifestations in hyper IgE syndrome: A case series and review of Indian literature.

Recurrent pulmonary infections starting from childhood often prompt evaluation for primary immunodeficiency disorders (PIDs). Hyper IgE syndrome (HIES) is a less common PID characterised by recurrent skin and pulmonary infections associated with elevated IgE levels. Staphylococcal infections are more commonly seen in these individuals, resulting in structural lung abnormalities such as pneumatoceles and bronchiectasis. The associated non-immunologic features (characteristic facies, retained primary dentition, scoliosis, osteopenia, and hyperextensible joints) should raise suspicion of this syndrome. We present four cases of HIES and review the pulmonary manifestations in this disease as reported in the Indian literature.

The paradigm of possibilities leading to the formation of autoimmune and infectious phenotypes of common variable immune deficiency

The term variable in the definition of CVID is associated with the heterogeneity of the genetic nature and clinical manifestation of this variant of PI. Deciphering of the mechanisms or identifying biomarkers of clinical heterogeneity may be important in the timely diagnosis and prognosis of the course of CVID. The purpose of the study was to identify distinctive features in the parameters of the innate and adaptive immune response of the patients with infectious and autoimmune manifestations of CVID in remission and clinical manifestation. Fifteen patients, 11 women and 4 men with an average age 39.7±11.7 years were examined, and they were divided into two subgroups depending on clinical verification: infectious phenotype (10 people) and autoimmune phenotype (5 people). In the absence of clinical signs of activation of autoimmune pathology or exacerbation of chronic infectious processes, peripheral blood monocytes became the application point of distinctive values. An increase in the number of TLR9-expressing monocytes has been shown in patients with autoimmune clinical verification of CVID. The differences in the parameters of the immune status of patients conducted during the period of clinical manifestation consisted of a decrease in the relative content and absolute number of T regulatory lymphocytes, and an increase in the number of monocytes containing TLR9, TLR2 and HLA-DR in patients with an autoimmune phenotype relative to the subgroup with infectious manifestation. The data obtained reflect the involvement of the immunoregulatory potential of the immune system in the clinical manifestation of primary immunodeficiency, even under the conditions of pathogenetic substitution therapy. The evidence of the stated position is a decrease in immunosuppression in autoimmune manifestation due to a decrease in the number of peripheral T-regulatory cells and a smaller proportion of monocyte cells belonging to the M2 suppressive category. Attention is also drawn to the increased potential of primary response to patterns of various nature in autoimmune manifestation due to an increase in the number of monocytes expressing Toll-like receptors of various specificity. The presented results can be proposed as a diagnostic and prognostic indicator of the difference in clinical phenotypes of CVID.

Primary Immunodeficiency in ICU: A Retrospective Multicentric Study.

Primary Immunodeficiency in ICU: A Retrospective Multicentric Study.

Dissecting Secondary Immunodeficiency: Identification of Primary Immunodeficiency within B-Cell Lymphoproliferative Disorders

Distinguishing between primary (PID) and secondary (SID) immunodeficiencies, particularly in relation to hematological B-cell lymphoproliferative disorders (B-CLPD), poses a major clinical challenge. We aimed to analyze and define the clinical and laboratory variables in SID patients associated with B-CLPD, identifying overlaps with late-onset PIDs, which could potentially improve diagnostic precision and prognostic assessment. We studied 37 clinical/laboratory variables in 151 SID patients with B-CLPD. Patients were classified as “Suspected PID Group” when having recurrent-severe infections prior to the B-CLPD and/or hypogammaglobulinemia according to key ESID criteria for PID. Bivariate association analyses showed significant statistical differences between “Suspected PID”- and “SID”-groups in 10 out of 37 variables analyzed, with “Suspected PID” showing higher frequencies of childhood recurrent-severe infections, family history of B-CLPD, significantly lower serum Free Light Chain (sFLC), immunoglobulin concentrations, lower total leukocyte, and switch-memory B-cell counts at baseline. Rpart machine learning algorithm was performed to potentially create a model to differentiate both groups. The model developed a decision tree with two major variables in order of relevance: sum κ + λ and history of severe-recurrent infections in childhood, with high sensitivity 89.5%, specificity 100%, and accuracy 91.8% for PID prediction. Identifying significant clinical and immunological variables can aid in the difficult task of recognizing late-onset PIDs among SID patients, emphasizing the value of a comprehensive immunological evaluation. The differences between “Suspected PID” and SID groups, highlight the need of early, tailored diagnostic and treatment strategies for personalized patient management and follow up.

Primary immunodeficiency in children: agammaglobulinemia (Bruton’s disease)

Primary Immunodeficiencies (PID) are a group of congenital immune system disorders caused by the loss, reduction, or impaired functioning of one or more components of the immune system. This article presents a detailed characterization of Bruton’s disease, the most common manifestation of inherited agammaglobulinemia, as well as modern approaches to its diagnosis and treatment. A clinical observation of the manifestation of primary immunodeficiency in a 3-year-old boy is described, while the diagnosis of “Primary Immunodeficiency: Bruton’s disease” was only established at the age of 8. The results of an 8-year follow-up of the patient are presented, and the difficulties of early diagnosis are analyzed. It is shown that a sequential diagnostic search allowed for the diagnosis of PID and the determination of the appropriate therapeutic strategy.

Mavorixafor: A spotlight on the clinical aspects and prospects of the first USFDA-approved treatment for the primary immunodeficiency WHIM syndrome

WHIM syndrome (WHIMS) is an extremely rare, severe, and potentially fatal genetic condition that affects the immune system, leading to warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM). Effective therapy for WHIMS requires regular monitoring, medical intervention, and a collaborative approach to treatment. Due to the limited therapeutic options, addressing WHIMS is an unmet medical need. The United States Food and Drug Administration (USFDA) recently granted approval for mavorixafor as the first treatment for WHIMS. This review focuses on the pharmacological characteristics, clinical investigations, associated inventions, and prospects of mavorixafor. The literature for this article was searched on PubMed, reputable websites (USFDA and X4 Pharmaceuticals) and free patent databases like Espacenet. WHIMS is distinguished by severe neutropenia and hypogammaglobulinemia, which increases the risk of developing cancer. Mavorixafor enhances the movement of neutrophils and lymphocytes from the bone marrow (BM) to the bloodstream. Hence, it could be beneficial for managing medical illnesses characterized by a decrease in the quantity of neutrophils and lymphocytes in the bloodstream. X4 Pharmaceuticals has submitted patent applications for the utilization of mavorixafor in the treatment of diverse cancer types, inflammatory ailments, B-cell dysfunction, Waldenstrom's macroglobulinemia, and primary immunodeficiency disorders. This suggests that mavorixafor can effectively treat various disorders either alone or when used in conjunction with other medications. It will be intriguing to observe the future approvals of mavorixafor for various disorders.Keywords: Mavorixafor; WHIM syndrome; Cancer; Immunodeficiency; Patent; Prospect

Nephrotic Syndrome and Recurrent Infection

Nephrotic syndrome is characterized by the leakage of protein from the blood into the urine along with the triad of proteinuria, albuminuria, and peripheral edema. Loss of protein leads to the loss of immunoglobulin and complements. X-linked agammaglobulinemia (XLA), or Bruton disease, is a primary immunodeficiency disease caused by a defect in the development of B cells in the bone marrow and a low serum level of immunoglobulins. The present case involves a 12-year-old boy with nephrotic syndrome, osteomyelitis, and recurrent infections. We discovered that he had XLA. This report underscores the importance of considering inborn errors of immunity in cases of protein loss, such as nephrotic syndrome.

Development of an Expert-Based Scoring System for Early Identification of Patients with Inborn Errors of Immunity in Primary Care Settings - the PIDCAP Project.

Early diagnosis of inborn errors of immunity (IEIs) has been shown to reduce mortality, morbidity, and healthcare costs. The need for early diagnosis has led to the development of computational tools that trigger earlier clinical suspicion by physicians. Primary care professionals serve as the first line for improving early diagnosis. To this end, a computer-based tool (based on extended Jeffrey Modell Foundation (JMF) Warning Signs) was developed to assist physicians with diagnosis decisions for IEIs in the primary care setting. Two expert-guided scoring systems (one pediatric, one adult) were developed. IEI warning signs were identified and a panel of 36 experts reached a consensus on which signs to include and how they should be weighted. The resulting scoring system was tested against a retrospective registry of patients with confirmed IEI using primary care EHRs. A pilot study to assess the feasibility of implementation in primary care was conducted. The scoring system includes 27 warning signs for pediatric patients and 24 for adults, adding additional clinically relevant criteria established by expert consensus to the JMF Warning Signs. Cytopenias, ≥ 2 systemic infections, recurrent fever and bronchiectasis were the leading warning signs in children, as bronchiectasis, autoimmune diseases, cytopenias, and > 3 pneumonias were in adults. The PIDCAP (Primary Immune Deficiency "Centre d'Atenció Primària" that stands for Primary Care Center in Catalan) tool was implemented in the primary care workstation in a pilot area. The expert-based approach has the potential to lessen under-reporting and minimize diagnostic delays of IEIs. It can be seamlessly integrated into clinical primary care workstations.

The EuroFlow PIDOT external quality assurance scheme: enhancing laboratory performance evaluation in immunophenotyping of rare lymphoid immunodeficiencies.

The development of External Quality Assessment Schemes (EQAS) for clinical flow cytometry (FCM) is challenging in the context of rare (immunological) diseases. Here, we introduce a novel EQAS monitoring the primary immunodeficiency Orientation Tube (PIDOT), developed by EuroFlow, in both a 'wet' and 'dry' format. This EQAS provides feedback on the quality of individual laboratories (i.e.,accuracy, reproducibility and result interpretation), while eliminating the need for sample distribution. In the wet format, marker staining intensities (MedFIs) within landmark cell populations in PIDOT analysis performed on locally collected healthy control (HC) samples, were compared to EQAS targets. In the dry format, participants analyzed centrally distributed PIDOT flow cytometry data (n=10). We report the results of six EQAS rounds across 20 laboratories in 11 countries. The wet format (212 HC samples) demonstrated consistent technical performance among laboratories (median %rCV on MedFIs=34.5 %; average failure rate 17.3 %) and showed improvement upon repeated participation. The dry format demonstrated effective proficiency of participants in cell count enumeration (range %rCVs 3.1-7.1 % for the major lymphoid subsets), and in identifying lymphoid abnormalities (79.3 % alignment with reference). The PIDOT-EQAS allows laboratories, adhering to the standardized EuroFlow approach, to monitor interlaboratory variations without the need for sample distribution, and provides them educational support to recognize rare clinically relevant immunophenotypic patterns of primary immunodeficiencies (PID). This EQAS contributes to quality improvement of PID diagnostics and can serve as an example for future flow cytometry EQAS in the context of rare diseases.