Spectrum of Primary Immunodeficiency Disorders in Hospitalized Children: Multicentric Data From Kolkata.

OBJECTIVE: To evaluate the incidence and types of primary immunodeficiency diseases (PIDs) in hospitalized children with infection. METHODS: This prospective study was conducted in five tertiary-care facilities in Kolkata over two consecutive years between November 1, 2018 and October 31, 2020. We included all children aged upto 12years who were hospitalized and screened them for PID. Children were screened for suspected IPD using Jeffrey Modell Foundation (JMF) Criteria; any child who satisfied at least 2 out of 10 warning signs was further evaluated for PIDs. RESULTS: Out of 33,204 hospital admissions, 50 children satisfied JMF criteria. Out of 50 children screened during the study period, 27 were finally diagnosed with an underlying PID, with a prevalence of 1 in 1000 hospitalized children. Majority (37.03%) of them had antibody deficiency followed by phagocytic defect (33.3%). Chronic granulomatous disease was the commonest PID followed by common variable immunodeficiency. Around 62.97% children presented with respiratory infections and overall Acinetobacter baumannii was the commonest isolated organism. CONCLUSION: Our study presents the first cohort of PID from eastern India. A methodical step-wise clinical and diagnostic approach can facilitate early diagnosis and timely therapeutic interventions.

STK4 deficiency and epidermodysplasia verruciformis-like lesions: A case report.

Serine/threonine kinase 4 deficiency (STK4 or MST1, OMIM:614868) is an autosomal recessive (AR) combined immunodeficiency that can present with skin lesions such as epidermodysplasia verruciformis-like lesions (EVLL). Herein, we describe a 17-year-old male patient born from consanguineous parents presenting with recurrent respiratory infections, verruciform plaques, poikiloderma, chronic benign lymphoproliferation, and Sjögren syndrome with suspected interstitial lymphocytic pneumonia.

Unraveling the Natural History of Good's Syndrome: A Progressive Adult Combined Immunodeficiency.

BACKGROUND: Good's syndrome (GS) is a rare immune deficiency described almost 6 decades ago. Despite numerous published individual case reports and data collected in cross-sectional studies of small cohorts, the natural history and long-term outcomes of this disease remain unknown. OBJECTIVE: We aimed to determine the clinical and laboratory evolution of 8 adults diagnosed with GS and consecutively evaluated between 1983 and 2023. METHODS: In this prospective, longitudinal cohort study, newly diagnosed patients with GS were followed through repeated measures of clinical, immune, and hematologic changes, as well as targeted genetic screening. RESULTS: All patients reported a healthy childhood and adolescence with symptom onset during the third or fourth decade of life. All presented to our center with recurrent bacterial sinopulmonary infections, thymoma, hypogammaglobulinemia, and absence of B cells. The median age of GS diagnosis was 57 years. During follow-up, immunoglobin replacement therapy effectively minimized sinopulmonary infections. However, the majority experienced severe and systemic viral or fungal infections, 3 developed basal cell carcinomas, and 5 had progressive bronchiectasis and persistent splenomegaly. The most notable clinical feature was opportunistic infections and in vitro evidence of cellular immune deficiency, which resulted in the death of 2 individuals. We also report a statistically significant, multidecade progressive decline in lymphocytes, platelets, hemoglobin, and red blood cells in our cohort, suggesting gradual bone marrow failure. CONCLUSIONS: Knowledge of the unique phenotype and temporal evolution of GS has allowed us to develop a more comprehensive diagnostic framework. It can be investigated as part of broader research into disease pathophysiology.

Whole-exome sequencing to identify undiagnosed primary immunodeficiency disorders in children with community-acquired sepsis, admitted in the pediatric intensive care unit.

BACKGROUND: Whole-exome sequencing (WES) provides a powerful diagnostic tool for identifying primary immunodeficiency diseases (PIDs). This study explores the utility of this approach in uncovering previously undiagnosed PIDs in children with community-acquired sepsis (CAS), with a medical history of recurrent infections or a family history of PIDs. METHODS: We performed WES on DNA samples extracted from the blood of the 34 enrolled patients, followed by bioinformatic analysis for variant calling, annotation, and prioritization. We also performed a segregation analysis in available family members to confirm the inheritance patterns and assessed the potential impact of the identified variants on protein function. RESULTS: From 34 patients enrolled in the study, 29 patients (85%) with previously undiagnosed genetic diseases, including 28 patients with PIDs and one patient with interstitial lung and liver disease, were identified. We identified two patients with severe combined immunodeficiency (SCID), patients with combined immunodeficiency (CID), six patients with combined immunodeficiency with syndromic features (CID-SF), four patients with defects in intrinsic and innate immunity, four patients with congenital defects of phagocyte function (CPDF), and six patients with the disease of immune dysregulation. Autoinflammatory disorders and predominantly antibody deficiency were diagnosed in one patient each. CONCLUSION: Our findings demonstrate the potential of WES in identifying undiagnosed PIDs in children with CAS. Implementing WES in the clinical evaluation of CAS patients with a warning sign for PIDs can aid in their timely diagnosis and potentially lead to improved patient care.

Evaluation of Clinical and Immunological Alterations Associated with ICF Syndrome.

PURPOSE: Immunodeficiency with centromeric instability and facial anomalies (ICF) syndrome is a rare autosomal recessive combined immunodeficiency. The detailed immune responses are not explored widely. We investigated known and novel immune alterations in lymphocyte subpopulations and their association with clinical symptoms in a well-defined ICF cohort. METHODS: We recruited the clinical findings from twelve ICF1 and ICF2 patients. We performed detailed immunological evaluation, including lymphocyte subset analyses, upregulation, and proliferation of T cells. We also determined the frequency of circulating T follicular helper (cTFH) and regulatory T (Treg) cells and their subtypes by flow cytometry. RESULTS: There were ten ICF1 and two ICF2 patients. We identified two novel homozygous missense mutations in the ZBTB24 gene. Respiratory tract infections were the most common recurrent infections among the patients. Gastrointestinal system (GIS) involvements were observed in seven patients. All patients received intravenous immunoglobulin replacement therapy and antibacterial prophylaxis; two died during the follow-up period. Immunologically, CD4+ T-cell counts, percentages of recent thymic emigrant T cells, and naive CD4+ T decreased in two, five, and four patients, respectively. Impaired T-cell proliferation and reduced CD25 upregulation were detected in all patients. These changes were more prominent in CD8+ T cells. GIS involvements negatively correlated with CD3+ T-, CD3+CD4+ T-, CD16+CD56+ NK-cell counts, and CD4+/CD8+ T-cell ratios. Further, we observed expanded cTFH cells and reduced Treg and follicular regulatory T cells with a skewing to a TH2-like phenotype in all tested subpopulations. CONCLUSION: The ICF syndrome encompasses various manifestations affecting multiple end organs. Perturbed T-cell responses with increased cTFH and decreased Treg cells may provide further insight into the immune aberrations observed in ICF syndrome.

Approach to Diagnosing Inborn Errors of Immunity.

Inborn errors of immunity are now understood to encompass manifold features including but not limited to immunodeficiency, autoimmunity, autoinflammation, atopy, bone marrow defects, and/or increased malignancy risk. As such, it is essential to maintain a high index of suspicion, as these disorders are not limited to specific demographics such as children or those with recurrent infections. Clinical presentations and standard immunophenotyping are informative for suggesting potential underlying etiologies, but integration of data from multimodal approaches including genomics is often required to achieve diagnosis.

Diagnosis of mixed infection and a primary immunodeficiency disease using next-generation sequencing: a case report.

Major Histocompatibility Complex Class II (MHC II) deficiency is a rare primary immunodeficiency disorder (PID) with autosomal recessive inheritance pattern. The outcome is almost fatal owing to delayed diagnosis and lacking of effective therapy. Therefore, prompt diagnosis, timely and effective treatment are critical. Here, we report a 117-day-old boy with diarrhea, cough, cyanosis and tachypnea who was failed to be cured by empiric antimicrobial therapy initially and progressed to severe pneumonia and respiratory failure. The patient was admitted to the pediatric intensive care unit (PICU) immediately and underwent a series of tests. Blood examination revealed elevated levels of inflammatory markers and cytomegalovirus DNA. Imaging findings showed signs of severe infection of lungs. Finally, the diagnosis was obtained mainly through next-generation sequencing (NGS). We found out what pathogenic microorganism he was infected via repeated conventional detection methods and metagenomic next-generation sequencing (mNGS) of sputum and bronchoalveolar lavage fluid (BALF). And his whole exome sequencing (WES) examination suggested that CIITA gene was heterozygous mutation, a kind of MHC II deficiency diseases. After aggressive respiratory support and repeated adjustment of antimicrobial regimens, the patient was weaned from ventilator on the 56th day of admission and transferred to the immunology ward on the 60th day. The patient was successful discharged after hospitalizing for 91 days, taking antimicrobials orally to prevent infections post-discharge and waiting for stem cell transplantation. This case highlights the potential importance of NGS in providing better diagnostic testing for unexplained infection and illness. Furthermore, pathogens would be identified more accurately if conventional detection techniques were combined with mNGS.

Good's syndrome: brief overview of an enigmatic immune deficiency.

Good's syndrome, an infrequent adult-onset immunodeficiency is characterized by the triad of thymoma, hypogammaglobulinemia, and increased susceptibility to recurrent infections. The clinical presentation is highly variable, with a spectrum ranging from recurrent bacterial and opportunistic infections to concomitant autoimmune diseases and, sometimes malignant pathologies. Due to heterogeneous clinical phenotypes and the lack of adequate diagnostic criteria, its recognition is often challenging, even delaying it by years. It is one of the most unusual, less studied form of the immune deficiency syndromes with a still unknown pathophysiology. It was initially considered a thymoma-associated variant of primary antibody deficiencies with a reduced or absent number of mature B cells, but it later emerged that significant defects of T cell-mediated immune functions are the underlying cause of opportunistic infections. On the basis of current evidence, Good's syndrome is evaluated as a distinct acquired form of combined immunodeficiency states and classified as a phenocopy of primary immunodeficiency diseases. Epigenetic and acquired genetic factors can play an ultimate role in its evolution.

Neurologic Status of Patients with Purine Nucleoside Phosphorylase Deficiency Before and After Hematopoetic Stem Cell Transplantation.

BACKGROUND: Purine nucleoside phosphorylase (PNP) deficiency is a rare autosomal recessive combined immunodeficiency. The phenotype is profound T cell deficiency with variable B and NK cell functions and results in recurrent and persistent infections that typically begin in the first year of life. Neurologic findings occur in approximately two-thirds of patients. The mechanism of neurologic abnormalities is unclear. Hematopoietic stem cell transplantation (HSCT) is the only curative treatment for PNP deficiency. METHODS: We report here six patients from five unrelated families with PNP deficiency treated in two centers in Turkey. We evaluated the neurological status of patients and compared to post-transplantation period if available. Then, we performed PubMed, Google Scholar, and Researchgate searches using the terms "PNP" and "hematopoietic stem cell transplantation" to find all reported cases of PNP transplantation and compared to our cohort. RESULTS: Six patients were treated in two centers in Turkey. One patient died from post-transplant complications. The other four patients underwent successful HSCT with good immune reconstitution after transplantation (follow-up 21-48 months) and good neurological outcomes. The other patient with a new mutation is still waiting for a matching HLA donor. DISCUSSION: In PNP deficiency, clinical manifestations are variable, and this disease should be considered in the presence of many different clinical findings. Despite the comorbidities that occurred before transplantation, HSCT currently appears to be the only treatment option for this disease. HSCT not only cures immunologic disorders, but probably also improves or at least stabilizes the neurologic status of patients.

Transition practice for primary immunodeficiency diseases in Southeast Asia: a regional survey.

Introduction: With increased diagnostic capabilities and treatment modalities in the field of primary immunodeficiencies (PID), many pediatric patients survive beyond childhood and experience a change of care to the adult-oriented healthcare system. Unfortunately, the transition pathways for PID are less clearly defined, resulting in deterioration of quality of care in adulthood. Hence, this is the first regional study to address PID clinicians' opinions on practices and challenges of transition care in 7 Southeast Asia (SEA) countries. Methods: We adopted a cross-sectional study design through an online survey platform to enquire opinions of transition practices from expert representatives in 7 SEA countries. Results: Regionally, 3 out 7 countries reported having no practice of transition care. Among cited challenges were reluctant adaptation by patients and caregivers to unfamiliarized adult healthcare systems, inadequate ratio of adult immunologists to patients and lack of facilities for transfer. Discussion and conclusion: Our study provides evidence to advocate policy makers on the importance of standardized integration of transition practice towards betterment of transiting PID patients into adulthood.

[Early detection of WHIM symdrome. A case report]. / Identificación temprana de síndrome de WHIM. Informe de un caso.

BACKGROUND: WHIM syndrome corresponds to an inborn error of innate and intrinsic immunity, characterized by: warts (Warts), Hypogammaglobulinemia, Infections and Myelocathexis, for its acronym in English. CASE REPORT: 4-year-old male, with severe neutropenia and B-cell lymphopenia from birth, without severe infections or warts; the panel genetic sequencing study of primary immunodeficiencies with the CXCR4 c.1000C>T (p.Arg334*) variant, which is associated with WHIM syndrome. CONCLUSIONS: The diagnosis of severe neutropenia from birth should include the search for inborn errors of immunity, through genetic sequencing studies, especially in asymptomatic or oligosymptomatic patients.

ANTECEDENTES: El síndrome WHIM corresponde a un error innato de la inmunidad innata e intrínseca, caracterizada por verrugas (Warts), hipogammaglobulinemia, infecciones y mielocatexis, por sus siglas en inglés. REPORTE DE CASO: Paciente masculino de 4 años, con neutropenia severa y linfopenia de células B desde el nacimiento, sin infecciones severas ni verrugas. El estudio de secuenciación genética informó la variante CXCR4 c.1000C>T (p.Arg334*), relacionada con el síndrome de WHIM. CONCLUSIÓN: El diagnóstico de neutropenia severa desde el nacimiento debe incluir la búsqueda de errores innatos de la inmunidad, mediante estudios de secuenciación genética, especialmente en pacientes asintomáticos u oligosintomáticos.

Novel DNMT3B Mutation in a Patient with Immunodeficiency, Centromeric Instability, and Facial Anomalies (ICF) Syndrome and a Bronchopulmonary Collateral Artery.

BACKGROUND: Immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is a rare autosomal recessive disorder. ICF1 is caused by bi-allelic mutations in the gene encoding deoxyribonucleic acid methyltransferase-3B (DNMT3B). Herein, we report a novel homozygous DNMT3B mutation in a patient with ICF1. CASE PRESENTATION: An eight-month-old Iranian Caucasian infant of consanguineous 1st-degree cousins presented to our clinic for evaluation of neutropenia. Physical examination was unremarkable except for low-set ears and a systolic cardiac murmur. He had a history of recurrent respiratory infections and oral thrush. Moreover, a collateral artery between the bronchial and pulmonary arteries was observed on the angiogram, mimicking a patent ductus arteriosus on the echocardiogram. Growth percentiles were normal; however, he had a neurodevelopmental delay. Family history was significant for a sibling who deceased at nine months of age after recurrent respiratory infections. Laboratory evaluation revealed a normal white blood cell count with neutropenia and normal bone marrow studies. He had hypogammaglobinemia with normal flow cytometric studies and was treated with prophylactic trimethoprim-sulfamethoxazole and itraconazole. After that, he was re-admitted three times due to recurrent episodes of pneumonia and an episode of pseudomonas aeruginosa meningitis. Currently, he is five years old and doing well on monthly intravenous immunoglobulin. Due to recurrent infections, hypogammaglobulinemia, and neutropenia, as well as a family history of consanguinity and a sibling who deceased during infancy, a primary immune deficiency was suspected. Genetic studies utilizing whole-exome sequencing demonstrated a homozygous missense mutation in DNMT3B (LRG_56t1:c.2008C>T; p.Arg670Trp) in the patient studied. The mutation has not been previously reported. CONCLUSION: We describe a novel homozygous DNMT3B mutation in an Iranian boy with ICF1. It is associated with recurrent infections, hypogammaglobinemia, neutropenia, mild facial anomalies, and a bronchopulmonary collateral artery.

Knowledge, awareness, and perception on genetic testing for primary immunodeficiency disease among parents in Malaysia: a qualitative study.

Background: Primary Immunodeficiency Disease (PID), also known as Inborn Errors of Immunity (IEI), comprises a group of rare genetic disorders that impair the body's immune responses. These conditions result from monogenic germline mutations that affect the function of genes governing the innate and adaptive immune system. Therefore, individuals with PID are more susceptible to infectious diseases, allergies, and autoimmune and autoinflammatory conditions. The prevalence of PID has been on the rise, with the number of classified diseases reaching 404, and 430 genetic defects reported to cause these conditions. However, in Malaysia, genetic testing for PID is currently limited and needs to be outsourced to overseas laboratories, posing financial challenges for families. Moreover, limited research has focused on the knowledge and awareness of genetic testing among parents of children with PID in Malaysia. This study aims to address this gap and provide valuable insights into the knowledge, awareness, and perception of genetic testing among this specific population. Method: This qualitative cross-sectional study utilised online open-ended, semi-structured focus group interviews to explore the perceptions and experiences of parents of children with Primary Immunodeficiency (PID). Participants were recruited through convenience sampling from the Malaysian Patient Organisation for Primary Immunodeficiencies (MyPOPI), a non-governmental organisation dedicated to providing support and raising awareness about PID. The study spanned from May 2023 to July 2023 and included participants from diverse regions of Malaysia who had undergone different diagnostic journeys in various hospitals. Result: The focus group discussions yielded 11 sub-themes that highlighted the experiences, understanding and challenges of the participants regarding genetic testing based on the semi-structured questions. These sub-themes were then grouped into four main themes that are awareness and understanding of genetic testing, the journey towards diagnosis and treatment, emotional impact and psychological factors, and the importance of medical experts in diagnosing and managing PID, as well as public perception and awareness. Conclusion: In conclusion, this study highlights the diverse knowledge, awareness, and perception surrounding genetic testing for PID. Factors such as access to services, family history, and personal circumstances shape individuals' understanding of genetic testing. The importance of healthcare professionals, along with the need for improved accessibility and targeted communication strategies, is underscored to enhance understanding and reduce stigma surrounding genetic testing for rare diseases like PID.

Primary immunodeficiencies in Bulgaria - achievements and challenges of the PID National Expert Center.

Tremendous progress has been made in the recognition of primary immune deficiencies (PIDs) in Bulgaria since in 2005 we have joined the J Project Central-Eastern European collaborative program. Ten years later an Expert Centre (ExpC) for Rare Diseases - Primary Immune Deficiencies at the University Hospital "Alexandrovska"- Sofia was established. In May 2017 The National Register of Patients with Rare Diseases also became operational as a database containing clinical and genetic information for Bulgarian patients with PID. The transfer of data and information on Bulgarian PID patients to the European Primary Immunodeficiency Database, managed by the European Society for Primary Immunodeficiency (ESID) has started in 2020. The total number of registered patients now is 191 (100 men and 91 women), with more than half of them being children (106; 55.5%). Regular updating of the information in the register showed that 5.2% of patients are deceased and the majority (94.8%) is a subject to continuous monitoring as it has been reported for other European countries as well. With the establishment of the ExpC, the dynamics in the diagnosis and registration of patients with PID significantly intensified. For a period of 5 years (2016-2021) 101 patients were evaluated and registered in comparison with previous period - before ExpC establishment when only 89 patients were diagnosed. The most common pathology was humoral immune deficiency (85 patients; 44.5%). Ninety-six (50.3%) of the patients underwent genetic testing, and 66. 7% had genetically confirmed diagnosis. Three of the variants have not been reported in population databases. Following genetic investigation confirmation of the initial phenotypic diagnosis was achieved in 82.8% of cases and change in the diagnosis - in 17%. Sixty-two patients were on regular replacement or specific therapy, and the rest received symptomatic and supportive treatment. In summary, we present the first epidemiological report of PIDs in Bulgaria, based on the National PID register. Data on the clinical, phenotypic and genetic characteristics of PID patients provided important information about the nature of primary immunodeficiency diseases in our country.

[Progress on the diagnosis and therapy about atopic diseases and primary immunodeficiency diseases].

Primary immunodeficiency diseases (PID) is a congenital disease caused by single gene germline mutation related to the immune system. PID patients have immune dysregulation, and are susceptible to infectious diseases, autoimmune diseases, autoimmune diseases, allergic diseases, and malignant tumors. The first symptom of some PID patients is atopic disease, therefore they go to the department of allergy, department of pediatrics and other relevant departments. How to identify and diagnose PID in allergic patients, to reduce diagnosis delay and prevent disease aggravation are the abilities that allergists, pediatricians, and doctors in other relevant departments need to master. This article summarizes the warning signs of PID in allergic patients and the mechanism of allergy combined with PID, and then summarizes the common types of PID in allergic patients, the evaluation, treatment and prevention in patients with PID and allergy.