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- Background: Severe Combined Immunodeficiency (SCID) is a category of inborn errors of immunity where there is impaired T and B cell development and/or function. Artemis SCID (Art-SCID) is characterized by dysfunctional Artemis protein, which is crucial for V(D)J recombination in T and B cell maturation. Art-SCID is fatal without management, and current definitive treatment involves hematopoietic stem cell transplantation (HSCT) or gene therapy. As the prognosis and survival of SCID patients improves, current research has begun unveiling long-term complications and morbidities. Previous literature has reported neurodevelopmental abnormalities in SCID patients, such as developmental delay and Autism Spectrum Disorder (ASD). However, it remains unknown whether these neurodevelopmental differences are linked to the SCID mutation, an adverse outcome of treatment and hospitalization, or comorbid social isolation and psychosocial challenges.Aims: In this case series, we discuss two cases of Art-SCID which presented with neurodevelopmental deficits following successful HSCT.Results: In both cases, SCID was detected on Newborn Screening (NBS), and Art-SCID was confirmed with genetic testing. Both patients were successfully treated with HSCT at 80 days of life, and followed up clinically well, with robust cell counts. Both patients later presented in toddlerhood with developmental, speech and language delay, however only one patient met diagnostic criteria for ASD.Conclusion: The definitive relationship between SCID, HSCT, and neurodevelopmental outcomes remain unclear, and warrants further study to allow for early intervention. We are currently working with colleagues across the country to further investigate and define this complex relationship.Statement of Novelty: We are investigating the complex relationship between SCID, HSCT, and potential neurodevelopmental outcomes. We present two cases of patients with Artemis SCID who were successfully treated with HSCT, and later presented in toddlerhood with developmental, speech, and language delay.
- Azhar Al Shaqaq,
- Marina Sham,
- Laura Abrego Fuentes,
- Jenny Garkaby,
- Jessica Willett Pachul,
- Linda Vong,
- Julia Upton,
- Vy Kim, and
- Chaim M. Roifman
Background: The global impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been profound, with over 760 million confirmed infections and almost 7 million deaths from coronavirus disease 2019 (COVID-19). The pandemic, officially declared in March 2020, has caused significant and irreversible changes in society. COVID-19 continues to pose a serious threat, ranging from asymptomatic cases to severe outcomes such as acute respiratory distress syndrome and organ failure, putting immense pressure on healthcare systems worldwide. The effects of SARS-CoV-2 infection on individuals with primary immunodeficiency (PID) are not yet fully understood. To date, the available research remains scarce, and the results do not yet provide conclusive evidence of a definitive link between PID and severe SARS-CoV-2 infection. In this study we present the clinical course and outcome of COVID-19 in individuals with PID.Methods: This study is a retrospective analysis involving 65 patients, comprising both pediatric and adult individuals diagnosed with PID, who exhibited symptoms of SARS-CoV-2 infection and tested positive at The Hospital for Sick Children in Toronto, Ontario, Canada. The data was collected from October 2020 to December 2022.Results: Sixty-five patients (36 children and 29 adults) were enrolled in our study. Our patients were diagnosed with primary immunodeficiency, and categorized as combined immunodeficiency, antibody deficiency, immune dysregulation disorder, phagocyte defect, intrinsic and innate immunity, or autoinflammatory disorder. Each of our patients had their COVID-19 infection confirmed through serology, rapid antigen test, and/or PCR. Among the study participants, 24 individuals had pre-existing lung conditions. At the time of contracting the infection, 42 patients had been vaccinated against SARS-CoV-2. The majority of patients in the study experienced mild to moderate symptoms of COVID-19.Conclusion: Our patients with PID exhibited mild to moderate symptoms of COVID-19, and all made a full recovery without any complications.Statement of Novelty: This study sheds light on impact of COVID-19 in individuals with primary immunodeficiency, revealing a noteworthy observation that patients exhibited mild to moderate symptoms, and remarkably, all experienced a complete recovery devoid of complications.- Background: Signal Transducers and Activators of Transcription (STAT) proteins are fundamental for multiple cellular processes, including immunity. STAT5B serves as a signal transducer downstream of cytokine and growth factor-mediated activation. Aberrations in STAT5B are associated with the development of atopy, immunodeficiencies, autoimmunity, cancers, hematological disease, growth disorders, and lung disease. Biallelic STAT5B variants are associated with loss-of-function of the gene, and cause a recessive disorder characterized by growth hormone insensitivity and immune dysregulation. Clinically significant heterozygous variants result in either dominant negative or gain-of-function effects; these latter variants are rare and their impact on the immune system is less clearly delineated than those responsible for the recessive form of the condition.Aim: We describe the presentation, immune workup, and genetic findings in a pediatric patient with a novel STAT5B heterozygous variant.Methods: A thorough retrospective review of the patient’s chart was performed.Results: A four-year-old male presented with history of lymphadenopathy, eczema, asthma, food allergy, short stature, and recurrent upper and lower respiratory tract infections. Clinical trio whole exome sequencing identified a novel heterozygous variant (c.1A>G; p. Met1?) in STAT5B. His mother harbours the same heterozygous variant and has a history remarkable for atopy. Immune investigations on the child revealed persistent elevated IgE. The patient’s variant targets the STAT5B N-terminal domain, and represents the first case with a heterozygous variant affecting this region.Conclusion: We present a novel STAT5B variant associated with a dominantly-inherited growth and immune phenotype. This is the first report of a heterozygous variant affecting the N-terminal domain in association with a clinical phenotype, expanding the genotypic landscape of this disorder. Further investigations and follow up responses to growth hormone replacement are needed to better delineate the functional effect of the variant identified in this family.Statement of Novelty: We report a novel germline heterozygous STAT5B variant in a paediatric patient with lymphadenopathy, atopy, and short stature.
- Background: Neurodevelopment is closely entwined with immune maturation and function during embryogenesis. While haematopoietic-derived microglia have recognized roles in a number of neurodevelopmental processes, the contribution of molecules classically involved in the immune system (including complement, toll-like receptors, and cytokines) are also emerging. To date, approximately 11% of genes known to cause primary immunodeficiency also confer varying degrees of neurological abnormalities. These can range from intellectual disability, cognitive and behavioural disorders, through to seizures, spasticity, and motor development delay. However, very rarely are sensory processing defects associated with aberrations of the immune system.Aims: To define the clinical presentation and immune phenotype of a novel syndrome encompassing immunodeficiency, neurodevelopmental abnormalities, and altered pain sensitivity in two siblings.Methods: Comprehensive retrospective review of the patient’s charts were performed, in accordance with local research ethics board approval.Results: We describe two teenage sisters who presented with recurrent sinopulmonary infections, lymphopenia affecting both B and T cells, developmental delay, learning and processing disorder, seizures, and reduced sensitivity to pain. Other features include bronchogenic cyst, microscopic hematuria, oral ulcers, papular urticaria, and keratosis pilaris.Conclusion: An underlying defect in genes known to cause primary immunodeficiency was not identified, suggesting the role of an as-yet undefined molecule at the crossroads of immunity, neurodevelopment, and sensory processing.Statement of novelty: We report on two patients, siblings, with a novel phenotype of combined immunodeficiency, neurodevelopmental delay, and reduced sensitivity to painful stimuli.
- FREE ACCESSBackground: The cell cytoskeleton is regulated by the ezrin-radixin-moesin (ERM) family of proteins, forming links between transmembrane proteins and the underlying actin cytoskeleton. Phosphorylation and activation of these proteins enable interactions with partners critically involved in shape regulation, such as actin filaments, transmembrane proteins, and scaffolding proteins. The MSN gene encodes moesin, which is ubiquitously expressed in lungs, spleen, kidney, endothelial cells of vessels, lymphocytes, and neutrophils. Deficiency or dysregulation of moesin, called X-linked moesin-associated immunodeficiency (X-MAID), is characterized by severe leukopenia affecting T cells, B cells, and neutrophils. To date, the clinical picture of patients with X-MAID is variable.Aim: We describe the presentation, immune-workup, and lung histopathology findings of a young male patient with X-MAID and multi-organ involvement, whose severe pulmonary vein stenosis necessitated a double lung transplant.Methods: A thorough review of the patient’s chart was performed.Results: The patient presented with a history of recurrent respiratory tract infections, oral thrush, and 3 major bacterial infections requiring admission and antibiotic therapy. His immune evaluation was remarkable for low T cells, and normal numbers of B and NK cells. At age 4 years he underwent a double lung transplant due to severe pulmonary vein stenosis and pulmonary hypertension. He further developed chronic kidney injury post-transplant. Clinical trio whole exome sequencing revealed a novel hemizygous variant in the MSN gene (c.278dupT; p.L93FfsX21), predicted to cause loss-of-function in moesin. Histologic evaluation of the lung tissue before transplantation identified profound abnormalities in alveoli formation.Conclusion: Patients with moesin deficiency may present during infancy or childhood with a severe form of the disease, including combined immunodeficiency with lymphopenia and neutropenia, while adults may have a milder clinical picture. The novel MSN mutation described here adds to the known spectrum of disease and highlights the non-redundant functions of moesin, particularly in the lung.Statement of Novelty: We report the first lung histopathological description of an X-MAID case, in a pediatric patient with recurrent infections, cytopenia, and autoimmunity who underwent a double lung transplant.
- FREE ACCESSBackground: Autoinflammatory diseases are a genetically heterogeneous group of conditions characterized by excessive activation of the innate immune system. They frequently present with overlapping features, particularly in cases of digenic or polygenic inheritance. The most common cause of autoinflammation arises from causative variants in the MEFV gene, responsible for familial Mediterranean fever. Clinical features include recurrent episodes of fever with serositis and amyloidosis. Individuals with variants in MEFV that present atypically with heterogeneous autoinflammatory features have also been described. Notably, gene modifiers of MEFV, such as NOD2 encoding an intracellular bacterial sensor, can result in more severe disease. NOD2 underlies a number of autoinflammatory and immunodeficiency conditions, including Blau syndrome. To date, Blau syndrome has not been described in the context of MEFV.Aim: To expand the presentation and phenotype of autoinflammatory disease associated with defects in the NOD2 and MEFV genes.Methods: A retrospective review of the patient’s chart was performed, including family history, medical history, immune laboratory evaluation, and genetics.Results: We describe here a 68-year-old male with a remarkable medical history since childhood of skin rash, erythroderma, recurrent infections, autoinflammation, arthritis, uveitis, and malignancy. A significant family history of cancer and autoinflammation was noted. Genetic work-up involving a 17-gene autoinflammatory panel revealed 3 heterozygous variants of uncertain significance, 2 of which were present in the MEFV gene and one in the NOD2 gene. His features were consistent with an overlapping phenotype of Blau syndrome and atypical FMF.Conclusion: Heterozygous variants in NOD2 and MEFV can result in a spectrum of autoinflammatory disorders with a heterogeneous phenotype. The NOD2 variant identified in our patient has not previously been associated with Blau syndrome.Statement of Novelty: We describe a patient harbouring heterozygous mutations in the MEFV and NOD2 genes marked by recurrent childhood infections.
- FREE ACCESSBackground: Hemophagocytic lymphohistiocytosis (HLH) is a rare and life-threatening disease in which cells of the immune system are overactivated, leading to uncontrolled inflammation and tissue destruction. Inherited or familial forms of HLH (FHL) are further classified into FHL1 to 5, based on the underlying genetic etiology. The most common form, FHL2, is associated with mutations in the PRF1 gene encoding perforin, a pore-forming glycoprotein required for natural killer and cytotoxic T cell-mediated apoptosis. Importantly, diagnosis of FHL can be challenging, particularly in late-onset cases in which presentation is delayed beyond the first years of life.Aim: We report the essential role of whole exome sequencing in the diagnostic work-up of a patient with complex, late-onset FHL.Methods: A comprehensive retrospective chart review was performed.Results: Our patient presented at 11 years of age with recurrent fever, hepatosplenomegaly, and pancytopenia. In the following years, she was admitted to hospital on multiple occasions, including twice for febrile neutropenia, and once for febrile cytopenia. Serial immune evaluation revealed features of immune dysregulation. While HLH was suspected, she did not fulfil the diagnostic criteria. Initial genetic work-up involving a targeted primary immunodeficiency gene panel identified only a single novel variant of uncertain significance, c.T374C (p.I125T) in PRF1. Subsequently, research-based whole exome sequencing was performed which revealed a second variant, c.C272T (p.A91V), in the same gene. The expanded genetic findings, a set of compound heterozygous missense mutations in PRF1, strengthened the diagnosis of FHL. She later fulfilled the diagnostic criteria for HLH.Conclusion: Whole exome sequencing identified compound heterozygous mutations in the PRF1 gene in a patient with late-onset FHL.Statement of Novelty: We report the use of whole exome sequencing to identify compound heterozygous mutations in PRF1, including a novel p.I125T variant not previously identified in FHL.
- FREE ACCESSBackground: Polyclonal hypergammaglobulinemia (PHGG) is commonly associated with liver disorders and could signify an enhanced or defective immune system. This study was conducted to determine the distribution and significance of PHGG in phases of chronic hepatitis B infection (CHB).Methods: Serum protein electrophoresis and colorimetric protein were assayed in 80 inactive (IA), 45 immune-clearance (IC) and 17 immune-escape (IE) CHB participants. ANOVA and Student’s t-test were used for the comparison of data, while area under curve analysis was used to assess the performance.Results: A significant elevation in γ-globulin was observed in the 3 phases studied in relation to non-hepatitis B virus-infected controls. The incidence of PHGG in different phases of CHB are IA (61.3%), IC (33.3%), and IE (29.4%). The IA phase, considered the least severe, has the highest incidence of PHGG.Conclusion: Occurrence of PHGG seems to signify enhanced immune responses. It may also be used to some extent to predict the IA phase.Statement of novelty: This study utilized both qualitative and quantitative methods to evaluate the patterns of PHGG in untreated and categorized CHB infections.
- FREE ACCESS
- Jenny Garkaby,
- Ori Scott,
- Laura Abrego Fuentes,
- Linda Vong,
- Jessica Willett Pachul,
- Myra Pereira,
- Vy Hong-Diep Kim, and
- Chaim M. Roifman
Background: Since the onset of the COVID-19 pandemic, a main challenge for clinicians and public health decision-makers has revolved around risk stratification in vulnerable populations, in particular individuals with inborn errors of immunity (IEI). However, available reports of the clinical course of COVID-19 in patients with IEI show wide variability, from a complete lack of symptoms to severe and complicated disease.Objective: To present the clinical features and outcomes of SARS-CoV-2 infection in adult patients with IEI.Methods: We performed a retrospective chart review documenting patient characteristics and clinical course of SARS-CoV-2 infection between December 2021 and July 2022.Results: Ten adult patients with IEI followed in our center were diagnosed with COVID-19, as determined by RT-PCR or rapid antigen testing. IEI in this cohort included those with humoral and combined immunodeficiencies, as well as phagocytic defects. An underlying lung comorbidity was identified in 3 patients. Symptoms were mostly mild and self-limiting, and no severe outcomes, complications, or mortality were noted in this study.Conclusions: We suggest that patients affected by a wide range of both humoral and combined IEI may demonstrate resilience, while highlighting the possible protective effects of vaccination and immunoglobulin replacement in this population.Statement of Novelty: We report on the mild COVID-19 clinical course of 10 adults with IEI. - FREE ACCESSBackground: Yellow Nail Syndrome is defined as a triad of lymphedema, respiratory symptoms, and nail discolouration. The precise etiology remains unknown, however it has been reported alongside a broad spectrum of conditions including malignancies, autoinflammatory diseases, and immunodeficiencies.Aim: To highlight the association between defects in the intracellular bacterial sensor gene NOD2 and Yellow Nail Syndrome.Methods: A retrospective review of the patient’s chart was performed, including family history, characteristics, immune laboratory evaluation, and genetics.Results: A 65-year-old female was referred to our centre for lymphedema and bronchiectasis. She had recurrent episodes of pneumonia, cellulitis, and oral ulcers. Bilateral lymphedema on her lower limbs up to the hip and discoloured yellow nails were reported. Given her clinical picture, she was diagnosed with Yellow Nail Syndrome. The immunological evaluation was unremarkable overall, with normal T cell subsets and function and adequate antibody titers. Genetic testing identified a heterozygous mutation in the NOD2 gene, c.2107C>T (p.Arg703Cys), considered a variant of uncertain significance.Conclusion: Heterozygous variants in NOD2 can result in a spectrum of autoimmune and autoinflammatory disorders, including Yellow Nail Syndrome.Statement of novelty: We describe a patient with Yellow Nail Syndrome, presenting with the classic triad of clinical features. Genetic evaluation identified a heterozygous variant in NOD2, which has been extensively associated with several autoinflammatory diseases, but not Yellow Nail Syndrome.
- FREE ACCESS
- Jenny Garkaby,
- Laura Edith Abrego Fuentes,
- Jessica Willett Pachul,
- Abby Watts-Dickens, and
- Meghan Fraser
Introduction: DiGeorge syndrome is a heterogenous disorder with various clinical presentations. Common features include thymic hypoplasia, T cell lymphopenia, conotruncal heart defects, facial dysmorphism, cleft palate, developmental delay, and hypoparathyroidism. The severity of this condition varies, however typical presentation includes congenital heart defects and characteristic facial features. Isolated hypocalcemia in DiGeorge syndrome is rarely seen in neonates but rather as the sole manifestation in older teenagers or adults.Aim: To report a case of an atypical presentation of DiGeorge syndrome.Results: We report here a case of an infant who was diagnosed with DiGeorge syndrome, with seizures being the only clinical manifestation displayed by the patient. He was found to have low T cell receptor excision circle levels on a newborn screen (NBS) for severe combined immunodeficiency (SCID). He did not have facial dysmorphism nor cardiac defect.Conclusion: Our case shows that severe hypocalcemia can be the only presenting symptom in DiGeorge syndrome. Based on this case, we recommend physicians test for calcium levels and PTH at the first encounter with a patient who screened positive during NBS for SCID.Statement of Novelty: We describe an infant with DiGeorge syndrome who presented with severe hypocalcemia. - OPEN ACCESSIntroduction: The epidemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing coronavirus disease 2019 (COVID-19), continues to affect most of the world’s population. In children, the respiratory and systemic involvement appears to have a much more benign course in comparison to adults, with almost no fatalities reported. However, we are now encountering a post-infectious immune mediated condition, termed, multisystem inflammatory syndrome in children (MIS-C). In most cases the main features are prolonged fever and elevated inflammatory markers. Many of the patients present with abdominal pain and varying degrees of myocardial involvement, from mild reduction in cardiac output to the most alarming manifestation of cardiovascular shock.Results: We present two patients with unusual manifestations of MIS-C related to post COVID-19 infection: an infant born to a mother who was severely ill at the very end of pregnancy, presenting with prolonged fever, rash, pericardial effusion, and evidence of coronary arteries wall dilation thickening as a result of inflammation, and, a teenage girl with severe cardiac tamponade without the more common cardiac manifestations of myocardial involvement.Discussion: Post COVID-19 MIS-C can present with a wide variety of manifestations. The pathophysiologic mechanisms underlying these inflammatory responses in infants are yet to be elucidated. Physicians should be aware of such presentations since rapid diagnosis and treatment are key for a favourable outcome.Statement of novelty: We present two unique manifestations of post COVID-19 infection which, to date, are not discussed frequently in the literature.
- OPEN ACCESSIntroduction: Common Variable Immune Deficiency (CVID) is the most prevalent form of severe antibody deficiency in children and adults. Most patients suffer recurrent, mainly sinopulmonary, infections. Despite adequate IVIG replacement therapy, chronic lung disease continues to be a main cause of morbidity and mortality. The term granulomatous-lymphocytic interstitial lung disease (GLILD) is frequently used to describe interstitial lung disease associated with immune dysregulation in primary antibody deficiency, such as CVID.Aim: To describe the case of a 10-year-old male with CVID who developed GLILD and his response to treatment with Rituximab.Discussion: Our patient is a young male with CVID and no genetic diagnosis, whose lung functions and general condition continued to deteriorate despite adequate intravenous immunoglobulin replacement therapy and mycophenolate mofetil treatment. After the diagnosis of GLILD, we initiated treatment with a 4-dose weekly course of Rituximab with prompt resolution of his interstitial disease. Although GLILD is a well described condition that accompanies CVID as a manifestation of immune dysregulation, it is still under recognized, especially in the pediatric population. Among experts, there is little uniformity when it comes to diagnostic and treatment approaches. Recent studies showed improved outcomes when using combination therapy with Rituximab, such as in our patient.Statement of Novelty: We shed light on GLILD, an important condition that accompanies CVID, and demonstrate an excellent response to the steroid sparing agent Rituximab. This is a crucial aspect when considering therapeutic choices for the pediatric population.
- OPEN ACCESS
- Adebayo Lawrence Adedeji,
- Dauda Jimoh,
- Jelili Abiodun Badmus,
- Ibrahim Olabanji Bello,
- Ibrahim Eleha Suleiman, and
- Olubunmi Gloria Ayelagbe
Background: Serum protein abnormalities, particularly elevated gamma globulins (hypergammaglobulinemia, HGG), have been reported in apparently healthy Nigerians living in Ogbomoso and elsewhere. Since the mechanisms for this phenomenon have not been fully substantiated, we hypothesized that impaired neutrophil phagocytosis could contribute to this condition.Methods: Healthy humans exhibiting HGG were identified using serum protein electrophoresis performed on cellulose acetate gel in barbital buffer (pH 8.6). GelQuant image analysis and quantitation software were further employed to quantify the gamma globulin fraction. Neutrophils were isolated from K3EDTA anticoagulated peripheral blood using Histopaque neutrophil isolation reagent. Neutrophil phagocytic activity was analyzed using a non-subjective commercial colorimetric phagocytosis assay kit.Results: The purity and viability of isolated neutrophils were approximately 94% and 92%, respectively. Ex-vivo phagocytic activity of neutrophils isolated from apparently healthy subjects exhibiting HGG, expressed as a percentage of the average absorbance of the control group, was 48.1 ± 8.6% which was significantly lower (p < 0.05) compared to the controls (98.9 ± 14.3%).Conclusion: Since neutrophils play crucial roles in innate immune responses, impairment of neutrophil phagocytic activity may lead to persistent antigenic stimulations of the adaptive immune system. This could in turn orchestrate gamma globulins expression leading to HGG.Statement of novelty: We demonstrated reduced neutrophil phagocytic activity as a possible basis for hypergammaglobulinemia in healthy Nigerians, perhaps for the first time. - OPEN ACCESSIntroduction: The impact of SARS-CoV-2 infections in children has generally been described as relatively benign. However, since April 2020, there have been reports of a new multisystem inflammatory illness affecting children and related to COVID-19 termed multisystem inflammatory syndrome in children (MIS-C).Aim: To describe 3 cases of children diagnosed with MIS-C and discuss the disease spectrum.Methods: We collected and reviewed data from 3 cases diagnosed with MIS-C admitted to our pediatric ward between October 2020 and January 2021.Discussion: MIS-C is a newly described disease that spans a spectrum of phenotypes and severity, and while it shares clinical similarities with Kawasaki disease, it has a unique set of epidemiological, laboratory, and prognostic characteristics. In this review, we hope to add to the understanding of this new entity.Statement of Novelty: This report discusses 3 cases of MIS-C and elaborates on the spectrum and immunology of this entity. Our cases are unique in their relatively wide spectrum and variability. We hope our own experience with MIS-C adds to the accumulating knowledge and understanding of this emerging disease.
- OPEN ACCESSBackground: Coronavirus disease 2019 (Covid-19) remains a pandemic with multiple challenges to confirm patient infectivity: lack of sufficient tests, accurate results, validated quality, and timeliness of results. We hypothesize that a rapid 15-minute Point-Of-Care serological test to evaluate past infection complements diagnostic testing for Covid-19 and significantly enhances testing availability.Method: A three arm observational study at Sharp Healthcare, San Diego, California was conducted using the Clungene® lateral flow immunoassay (LFI) and compared with the Cobas® Roche real-time polymerase chain reaction (RT-PCR) results. Arm 1: Thirty-five (35) subjects with confirmed Covid-19 using RT-PCR were tested twice: prior to 14 days following symptom onset and once between 12 and 70 days. Arm 2: Thirty (30) subjects with confirmed Covid-19 using RT-PCR were tested 12-70 days post symptom onset. Arm 3: Thirty (30) subjects with a negative RT-PCR for Covid-19 were tested 1–10 days following the RT-PCR test date.Results: Specificity of confirmed negative Covid-19 by RT-PCR was 100% (95% CI, 88.4%–100.0%); meaning there was 100% negative positive agreement between the RT-PCR and the Clungene® serological test results. Covid-19 subjects tested prior to day 7 of symptom onset were antibody negative. In subjects 7–12 days following symptom onset with a confirmed positive Covid-19 by RT-PCR, the combined sensitivity of IgM and IgG was 58.6% (95% CI, 38.9%–76.5%). In subjects 13–70 days following symptom onset with a confirmed positive Covid-19 by RT-PCR, the combined sensitivity of IgM and IgG was 90.5% (95% CI, 80.4%–96.4%).Conclusion: The Clungene® lateral flow immunoassay (LFI) is a useful tool to confirm individuals with an adaptive immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) indicating past infection. Providing Point-Of-Care results within 15 minutes without any laboratory instrumentation or specialized software has an added value of increasing test availability to patients who have been symptomatic for more than 1 week to confirm past infection. Performance characteristics are optimal after 13 days with a sensitivity and specificity of 90% and 100%, respectively.Statement of novelty: Formal controlled clinical studies of Covid-19 antibody tests have been limited. This study demonstrates the utility of the 15 minute rapid Clungene® test and the potential for expanded use where Covid-19 RT-PCR testing and vaccination is limited.
- OPEN ACCESSBackground: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic. The application of point of care serological testing can help determine past infection and assist healthcare workers assess patient risk.Method: An observational study of 114 subjects in North Suburban Chicago, Illinois, was performed using the Clungene® lateral flow immunoassay (LFI). Patients’ PCR test results and clinical symptoms were used to compare the seroconversion rate of this patient population with the surrounding community.Results: Excluding 1 aberrant result, there was 100% positive agreement (10) between PCR and antibody (IgG or IgM) test results. There were 7 patients who did not have a prior PCR test who were positive for IgG; 5 of the 7 had clinical symptoms consistent with possible exposure and 2 were asymptomatic. There was 1 person with a suspected exposure to an infected person who was IgM positive. Ninety-five asymptomatic patients were seronegative. The overall rate of 15.9% seroconversion (IgG or IgM) is consistent with other community-based testing results in the North Suburban Chicago, Illinois area.Conclusion: Rapid screening tests to identify antibody positive patients recovered from coronavirus disease-2019 can be a useful tool for healthcare professionals to determine or confirm past infection.Statement of novelty: Limited data is available on the use of point of care serological testing to assist healthcare professionals with the assessment of their patient population regarding past SARS-CoV-2 infectivity and seroconversion. The present study successfully investigated the use of a point of care antibody test in a physician’s office to determine which patients have developed antibodies, indicating an immune response to SARS-CoV-2, and to assist with decisions on whether patients should pursue normal social and workplace activities.
- OPEN ACCESSObjectives: To assess the psychological effects of systemic lupus erythematosus (SLE), including perception of aging, in a cohort of participants who were either diagnosed with SLE or had an affected family member.Methods: Over a period of 1 year, we conducted once-monthly face-to-face interviews with 12 participants. The participants were from 4 related families and include 7 females and 5 males. Three participants had a confirmed diagnosis of SLE. Spouses were also included in this study to assess transitivity of the psychological signs of SLE. Responses to structured interview questions were analyzed to assess the perception of aging.Results: The major complaints in participants diagnosed with SLE were pain and psychological stress. Nephrotic syndrome, urinary tract infection, weight disorders and increased need for psychosocial support were common in the participants’ medical history. Qualitative analysis of questionnaires completed by participants with SLE revealed a correlation of “feeling old” with the non-resolution of health complaints. Family members who did not have SLE also reported “feeling old”. Complaints of stress, anxiety, nervousness and lack of enjoyment of life were common in those who were diagnosed with SLE, as well as those who were not. All spouses reported experiencing digestive disorders, hemorrhoids as well as various phobias, regardless of whether their partners had a confirmed SLE diagnosis.Conclusions: In this study, we found that participants with SLE or those who had a close family member with SLE displayed psychological signs of aging. All participants had a predisposition to anxiety, while spouses developed various phobias.Statement of novelty: We show that individuals with SLE and close family members have an increased self-perception of aging.
- OPEN ACCESS
- Mehdi Yeganeh,
- Tallal Basha,
- Lina Sobhi Abdrabo,
- Sophie Ran Wang,
- Joël Lafond-Lapalme,
- Jean-Baptiste Rivière,
- Duncan Lejtenyi,
- David S. Rosenblatt,
- Christine McCusker,
- Reza Alizadehfar, and
- Bruce D. Mazer
Background: Patients with chromosome 18 abnormalities can present with an immune phenotype that resembles common variable immunodeficiency. Knowledge of the genes underlying the immune defects related to chromosome 18 aberrations could improve our understanding of the molecular basis of primary antibody deficiencies. Here we present a patient with ring chromosome 18 affected by primary antibody deficiency and autoimmunity.Methods: Lymphocyte populations were determined by flow cytometry. Specific antibody response to protein vaccines and pneumococcal capsule antigen were measured by ELISA. Genome sequencing was performed using a PCR-free protocol.Case: The patient was diagnosed with ring chromosome 18 for delayed growth and dysmorphic features at the age of 1 month. Array comparative genomic hybridization showed deletions of 18p11.21-pter and 18q21.31-qter. At the age of 10 months, she started having recurrent episodes of otitis media and pneumonia, as well as autoimmune arthritis. Serum immunoglobulins and specific antibody levels were low. The CD19+CD27+ memory B cell and CD45RO+ T cell populations were decreased. Recurrent infections were controlled with parenteral immunoglobulin and autoimmune arthritis was treated with systemic and intra-articular therapies.Conclusions: Selective IgA deficiency is the most common form of immunodeficiency associated with chromosome 18 abnormalities, however patients with ring chromosome 18 may also be affected by specific antibody deficiency and require immunoglobulin replacement for optimal care. These patients might partially share the same genomic loss as in patients with non-syndromic primary antibody deficiency.Statement of novelty: This report highlights an important teaching point about immune deficiency in a chromosomal anomaly that is not infrequently encountered in pediatric hospitals. Furthermore, our investigations provide more insight into the pathogenesis of immunodeficiency among patients with chromosome 18 abnormalities. - OPEN ACCESSIntroduction: Serum sickness is a type III hypersensitivity reaction. Immune complex deposition activates complement pathways resulting in fever, vasculitic rash, arthritis and lymphadenopathy. Medications are known to trigger serum sickness-like reactions which clinically resemble serum sickness, however, are not thought to involve circulating immune complexes. The full pathophysiology is not clear. Risperidone is an atypical antipsychotic drug commonly used in the paediatric population.Aim: To describe the diagnosis, disease course and outcome of a patient who developed serum sickness-like reaction secondary to risperidone.Methods: Review of patient chart and medical interview in accordance with institutional research ethics board approval.Results: The patient, a 7 year old male with Attention Deficit Hyperactivity Disorder, was started on risperidone 0.25 mg once daily. Within a week the dose was increased to 0.5 mg once daily. During the third week after initiation of medication, the patient developed generalized purpuric, confluent, maculopapular rash. Although the patient did not have any signs and symptoms of a viral illness, he was diagnosed with viral-induced exanthema and continued on risperidone. On day 28, he developed significant, bilateral swelling of upper and lower extremities, facial angioedema, lymphadenopathy, arthralgia and arthritis in ankles, knees, hands and elbows without fever. Investigations showed normal complement C3 and C4 levels. C1 esterase inhibitor, anti-nuclear antibody and urinalysis were normal. Erythrocyte sedimentation rate, C-reactive protein and leukocyte levels were elevated. The diagnosis of serum sickness-like reaction to risperidone was made and the patient subsequently treated with cetirizine, hydrocortisone, and prednisone for 1 week with significant improvement. Skin biopsy was declined by the patients’ parents and therefore was not performed. Provocative oral challenge to risperidone was not considered because of clear suggestive history and ethical consideration.Conclusion: Psychotropic medications are known to cause cutaneous eruptions. Serum sickness-like reactions can happen upon exposure to risperidone. Clinicians should be aware of this potential adverse reaction that can develop weeks after therapy initiation, and be encouraged to discontinue risperidone when the suggestive symptoms emerges.Statement of novelty: We describe a case of serum sickness-like reaction to risperidone in a paediatric patient. To our knowledge, this is the first case of serum sickness-like reaction to risperidone.
- OPEN ACCESSObjective: The objectives of this study are to present a case series of immunodeficient children who underwent a transcervical thymic biopsy and to describe the transcervical approach to the thymus gland.Design: Case series.Setting: Pediatric otolaryngology practice in an academic setting.Patients: Consecutive sample of immunodeficient children (≤18 years old) who underwent thymic biopsies from 1996 to 2019 for the purpose of confirming or excluding profound T cell immunodeficiency.Intervention: Diagnostic transcervical thymic biopsy.Results: A total of 14 patients with atypical combined immunodeficiency underwent the procedure during the study period, with minimal post-operative complication. The thymus was found to be abnormal histologically in 9 children and normal in another 5 patients. In all cases, thymus morphology helped define the extent of the immunodeficiency, resulting in either supporting a decision to perform a bone marrow transplant (8 patients) or avoid this high risk procedure (3 patients).Conclusion: Thymus biopsy is helpful in the characterization of childhood immunodeficiency and provides critical information that affects the medical management. The transcervical approach to the thymus is feasible in children and can be accomplished with minimal morbidity.Statement of novelty: Biopsies of the thymus have assisted in the characterization of new entities of primary immunodeficiency.
- OPEN ACCESSIntroduction: Coronin 1A is part of a family of highly conserved actin regulatory proteins with key roles in T cell homeostasis and T cell receptor signaling. Null mutations in coronin 1A result in severe combined immunodeficiency, whereas hypomorphic mutations have been associated with a somewhat milder immunological phenotype. Nevertheless, all patients described so far have markedly reduced naïve peripheral T cells, impaired T cell responses to mitogens, and limited T cell receptor diversity. Interestingly, despite poor thymic output, thymus architecture appears normal. To date, only 2 cases of hematopoietic stem cell transplantation (HSCT) have been reported in coronin 1A deficiency.Aim: To describe the identification, transplantation course, and long term outcome of a Canadian Inuit patient diagnosed with coronin 1A deficiency.Methods: Patient chart review was performed in accordance with institutional research ethics approval. A combination of immunological investigations and molecular genetic analyses were utilized to identify a novel mutation in the tryptophan-aspartate repeat region of coronin 1A. Based on the patient’s profound T cell dysfunction, the decision was made to proceed with HSCT.Results: The patient presented with a history of recurrent urinary tract infections, otitis media, and developmental delay involving poor axial and peripheral muscle tone. Axillary lymphadenopathy was noted and subsequent thymus biopsy revealed aberrant CD7+ T cell deficiency. Lymphocyte responses to mitogens and T cell receptor excision circle levels were markedly reduced, consistent with the diagnosis of severe combined immunodeficiency. Whole exome sequencing and Sanger confirmation revealed a novel mutation in coronin 1A. HSCT using a HLA-matched unrelated donor resulted in long term engraftment and solid immune reconstitution.Conclusion: Very few patients with coronin 1A deficiency have been described to date, making it difficult to evaluate its natural history and management. Here, we describe the presentation, identification, transplantation, and outcome in our patient.Statement of novelty: We describe the successful hematopoietic stem cell transplantation course and outcome in a patient with a novel mutation in coronin 1A.
- OPEN ACCESSBackground: Patient–physician shared decision making (SDM) can result in better care as well as reduced treatment costs. A better understanding of the factors predicting when physicians implement SDM during the treatment of primary immunodeficiency (PID) could provide insight for making recommendations to improve outcomes and reduce healthcare costs in PID and other long-term chronic conditions.Method: This study made use of grounded theory and was based on the interview responses of 15 immunologists in the United States. It focused on their decision making in the diagnosis and treatment of PID, how they interact with patients, and the circumstances under which they encourage SDM with patients.Results: All invited immunologists took part in the interviews and were included in the study. All but one had 10 or more years of experience in treating PID. The study found that SDM is bounded/limited by “nudging” bias, power balance considerations, and consideration of patient health literacy alignment. Immunologists also reported that they were mainly responsible for coordinating care and for allowing sufficient time for consultations.Conclusion: SDM occurs between the physician and patient throughout the treatment of PID. The study also shows the ways physicians influence SDM by guiding patients through the process.Statement of novelty: Little is known about the factors that influence SDM in the long-term management of chronic diseases. The present study investigated the extent to which immunologists experienced in the treatment of patients with PID include SDM in clinical practice. Findings such of these may be of use when formulating treatment guidelines and improving the effectiveness of long-term management of PID.
- OPEN ACCESS
- Alexandra Langlois,
- Bahar Torabi,
- Marieme Dembele,
- Marylin Desjardins,
- Reza Alizadehfar,
- Moshe Ben-Shohan,
- Isabelle De Bie,
- Ana Santanna,
- Christine McCusker, and
- Bruce Mazer
Background: Gastrointestinal defects and immunodeficiency syndrome (GIDID) is a severe neonatal disorder usually fatal within the first months of life. We report a case presenting with intestinal atresia, combined immunodeficiency, and a novel association with hypothyroidism and cardiac malformations. The immune phenotype was remarkable for agammaglobulinemia, lymphopenia, and mildly decreased lymphocyte proliferation. We present here the unique phenotype as well as studies to determine if the agammaglobulinemia was due to an intrinsic B lymphocyte defect.Methods: Peripheral blood mononuclear cells from the patient and a healthy control were isolated by Ficoll-Hypaque centrifugation and stimulated with anti-CD40, IL-4 and IL-21 for 7 days. Total IgG production was measured by ELISA in the supernatant of the stimulated sample on day 7. Cells were stained for CD19, CD27, IgM, CD11b, CD11c, and CD14.Results: At day 7, supernatant from the patient stimulated cells contained levels of total IgG comparable to the control (755 ng/mL vs. 658 ng/mL, respectively). B cell maturation appeared impaired, as morphologically the patient sample demonstrated fewer B cell clones and cells with dendritic projections.Conclusions: Despite this typical severe clinical picture of GIDID with agammaglobulinemia, IgG production was detected under optimal stimulation for induction of plasma cells. This suggests that there may not be an inherent defect in class switching and antibody production in B cells in this disorder. It is possible that the in vivo physical or cytokine milieu may be defective for optimal B cell function. Further studies assessing the function of the immune cells as well as possible gastrointestinal loss of immunoglobulins are needed in this disease.Statement of novelty: Despite much improvement in understanding the effects of TTC7A mutations in GIDID, the root cause of hypogammaglobulinemia in these patients is still unclear. The work portrayed in this study furthers the current knowledge. It suggests that when appropriately stimulated in vitro, this patient’s B cells were capable of adequate immunoglobulin production. Moreover, to the best of our knowledge, this patient is the first with this genetic defect to be reported with hypothyroidism and cardiac malformations. - OPEN ACCESSBackground: Inherited defects in the function of the purine nucleoside phosphorylase (PNP) enzyme can cause severe T cell immune deficiency and early death from infection, autoimmunity, or malignancy. In addition, more than 50% of patients suffer diverse non-infectious neurological complications. However the cause for the neurological abnormalities are not known.Objectives: Differentiate induced pluripotent stem cells (iPSC) from PNP-deficient patients into neuronal cells to better understand the effects of impaired purine metabolism on neuronal development.Methods: Sendai virus was used to generate pluripotent stem cells from PNP-deficient and healthy control lymphoblastoid cells. Cells were differentiated into neuronal cells through the formation of embryoid bodies.Results: After demonstration of pluripotency, normal karyotype, and retention of the PNP deficiency state, iPSC were differentiated into neuronal cells. PNP-deficient neuronal cells had reduced soma and nuclei size in comparison to cells derived from healthy controls. Spontaneous apoptosis, determined by Caspase-3 expression, was increased in PNP-deficient cells.Conclusions: iPSC from PNP-deficient patients can be differentiated into neuronal cells, thereby providing an important tool to study the effects of impaired purine metabolism on neuronal development and potential treatments.Statement of novelty: We report here the first generation and use of neuronal cells derived from induced pluripotent stem cells to model human PNP deficiency, thereby providing an important tool for better understanding and management of this condition.
- OPEN ACCESS
- Arnon Broides,
- Ronit Gavrieli,
- Jacov Levy,
- Rachel Levy,
- Nurit Hadad,
- Dirk Roos,
- Baruch Wolach, and
- Amit Nahum
Chronic granulomatous disease is a primary immunodeficiency disease caused by a genetic mutation in any of the 5 genes encoding the different components of the Nicotinamide Adenine Dinucleotide Phosphate reduced (NADPH)-Oxidase enzyme complex. Since primary immunodeficiency diseases are considered to be rare diseases, the genetic diagnosis of a certain primary immunodeficiency leads to the reasonable assumption that all patients with the same disease within the same family will have the same genetic mutation. We report 2 patients with chronic granulomatous disease from the same extended consanguineous family who had different genetic causes of their disease. Therefore, it is crucial to obtain a definitive genetic diagnosis of primary immunodeficiency disease even in patients from the same family, where the same genetic diagnosis is presumed to be the cause of the disease.Statement of novelty: Genetic causes of chronic granulomatous disease may be different in patients from the same family. - OPEN ACCESS
Psychosocial issues of the adolescent PI patient and the development of the PI Teen Outreach Program
Background: The effects of disruptions in the lives of the adolescent Primary Immunodeficiency (PI) patient require psychosocial staff involved in their care to find unique approaches to treatment. The demands of living with PI in adolescence complicates this already turbulent life cycle transition. Absence from school due to infections and treatment can lead to social isolation and in turn issues of self-esteem, creating challenges for teenagers with chronic diseases. The importance of maintaining social support with peers and developing a new network of social supports with teens with similar diagnoses is highlighted in the literature as an important factor in helping teens successfully cope with the demands of chronic illness.Methods: To best meet the complex needs of this population, the PI Teen Outreach Program was created in 2010. The goal was to connect teens with PI to one another in an environment that engages them in “normal” activities while providing an opportunity to discuss diagnosis, coping, and the impact of living with PI. The program consists of group teen events that involve an activity for peers to connect followed by a meal for sharing of life experiences. Community peers are invited to assist teens in demystifying their PI disease to their community friends.Results: At the conclusion of each outreach event, teens were given an anonymous evaluation utilizing both Likert scales and qualitative narrative comments. The positive feedback highlights the importance of providing creative and unique programs for this population.Conclusion: A diagnosis of PI can be difficult for teenagers as they cope with the developmental tasks of adolescence alongside a chronic illness. The Teen Outreach Program has been successful in enhancing the psychosocial support and normalizing the experience of teenagers with PI.Statement of novelty: There is a paucity of literature addressing the psychosocial issues that the PI teen population face and any novel programming to address their unique needs. - OPEN ACCESSBackground: Cartilage-hair hypoplasia (CHH), caused by mutations in the ribonuclease mitochondrial RNA-processing (RMRP) gene, is associated with diverse immune abnormalities including combined immune deficiency (CID). Most patients with CHH are managed with supportive measurements, while few have received allogeneic hematopoietic stem cell transplantations (HSCT). The progression of the immune abnormalities and the impact of HSCT in patients with CHH and CID have not been well characterized.Methods: The clinical and laboratory findings of 2 siblings diagnosed in infancy with CHH and CID due to the common 70A>G mutation in RMRP, including the effects of HSCT performed in 1 of them, were compared.Results: Both patients suffered from recurrent respiratory infections at early age with reduced T cells numbers and responses. Patient 1 immune function continued to deteriorate leading to HSCT from an HLA-matched sibling at 4.5 years of age. The patient suffered acute and chronic graft versus host disease of the skin with residual mild joint contractures and scleroderma-like skin changes. Seven years after HSCT patient 1 has normal immune function. Immune evaluations of patient 2 in the first years of life indicated mild improvement. The patient did not have a suitable related HSCT donor and the family elected to continue with supportive care. At 7 years of age, patient 2 is clinically well and thriving with persistent T cell abnormalities.Conclusions: Close monitoring of immune function in early life for patients with CHH and CID as well as the availability of suitable donors assists in determining management, including HSCT.Statement of novelty: The manuscript demonstrates the importance of close monitoring and personalized approach in the management of patients affected by CHH.
- OPEN ACCESSIndividuals with 22q11.2 deletion syndrome (22q11.2DS) have an embryological midline fusion defect, which can result in a syndrome including congenital heart disease, cleft palate, hypoparathyroidism, thymic hypoplasia, immunologic abnormalities, and developmental delay. The majority of patients have a 3 megabase deletion, which contains multiple genes, including the T-box transcription factor (TBX1) gene. Definitive diagnosis is made through fluorescent in situ hybridization (FISH) or chromosomal microarray (CMA). Newborn screening (NBS) for severe combined immune deficiency (SCID) via low T-cell receptor excision circles (TRECs) can also identify this population if thymic output is low. Samples from infants who screen positive undergo further testing, which includes a purine profile and TBX1 deletion analysis. Diagnostic follow-up testing is centre-dependent and may not include more definitive testing for 22q11.2DS by FISH or CMA. We report a case of a newborn with 22q11.2DS, detected by low TRECs on the SCID NBS, with a normal screening TBX1 result, who was subsequently found to have a TBX1 gene deletion on follow-up 22q11.2 FISH and CMA. This case highlights the limitations of the TBX1 screening assay and the importance of performing diagnostic testing with FISH and (or) CMA regardless of the initial TBX1 result. It also emphasizes the need for a standardized follow-up testing algorithm across institutions for newborns who screen positive for SCID.Statement of novelty: To our knowledge, this is the first case to be described in the literature where a newborn with 22q11.2DS with a typical deletion encompassing the TBX1 gene was not identified by initial TBX1 screening, highlighting the limitations of this test as a standalone screening assay.
- OPEN ACCESSHemophagocytic lymphohistiocytosis (HLH) is a life-threatening inflammatory condition believed to be caused by uncontrolled activation of macrophages and histiocytes. HLH may be triggered by infections or associated with malignancy, metabolic disorders and drug toxicity, or alternatively, by a variety of genetic defects. While this disorder has been reported to be associated with a growing number of primary immunodeficiencies, especially those with significant T cell and (or) NK cell dysfunction, it has never been reported in ataxia telangiectasia (AT). AT is characterized by truncal ataxia, dilatation of blood vessels, immunodeficiency and a high predisposition to cancer. Almost all cases of AT have at least 1 or a combination of more than 1 of the following features: low immunoglobulin levels, inability to produce specific antibodies in response to vaccination, T cell lymphopenia and (or) T cell dysfunction. In this report, we describe the first case of a fatal episode of HLH in a patient with AT. The overlapping laboratory anomalies of HLH and lymphoid malignancy poses a challenge for accurate diagnosis, and awareness of the phenomenon by clinicians may result in earlier treatment and resolution of inflammation.Statement of novelty: HLH can affect various types of immunodeficiency but has never been reported in patients with AT. Here, we report the first case of a fatal episode of HLH in a patient with AT.
- OPEN ACCESSBackground: Interleukin-12 Receptor β1 (IL-12Rβ1) deficiency causes susceptibility to weakly virulent atypical mycobacteria and Salmonella. Genotype–phenotype correlations are weak and penetrance is not complete. Most of the culture-recovered Salmonella are with the non typhi types.Case report: We describe an 11 year old male patient with IL-12Rβ1 deficiency. He had an erythematous rash resembling Henoch Schonlein Purpura, and initially presented with slightly elevated CRP. Skin biopsy revealed leukocytoclastic vasculitis. Due to lack of evidence of an active infection, positive ANA, and positive direct Coombs test, an autoimmune lupus-like disease was suspected. In conjunction with rash flares, he showed progressively elevated inflammatory markers, chronic anemia, and hypoalbuminemia. Extensive investigations for an infectious etiology were negative, and without isolation of any pathogens. However, the last of a series of abdominal ultrasound examinations revealed enlarged peritoneal and retroperitoneal lymph-nodes, and biopsy yielded slow-growing bacteria, identified as Salmonella typhi. Prolonged treatment with 2 antimicrobial agents resulted in resolution of skin rash and normalization of laboratory results.Conclusions: We describe an IL-12Rβ1 deficient patient with a progressive inflammatory process with a unique immune dermatological manifestation which was probably triggered by an unexpected pathogen, Salmonella typhi. This patient’s case demonstrates the need for invasive procedures to identify an infectious etiology when routine cultures and serology tests are negative.Statement of novelty: In this case report, we describe a unique presentation of infection with Salmonella typhi in a patient with IL-12Rβ1 deficiency, manifesting with bouts of leucocytoclastic vasculitis. We also report in the same patient, recurrent infection with an unusual pathogen, Kocuria kristinae. Both phenomena have not been reported in such constellation, and we believe this to be a useful and important description that could alert physicians, immunologists, and pediatricians alike to such manifestations. Further, it may help in a rapid and successful diagnosis, therefore benefiting such patients.
- OPEN ACCESSRoifman syndrome is an association of humoral immunodeficiency, growth retardation, spondyloepiphyseal dysplasia, developmental delay, retinal dystrophy, and unique dysmorphism. Compound heterozygote mutations in the RNU4ATAC gene, an essential component of the minor spliceosome, were found to be the culprit for this disorder. Here we report a novel mutation in the RNU4ATAC gene, involving position 116. This mutation redefines the Sm protein binding site of this gene.Statement of novelty: We report here a patient with a novel mutation in the Sm protein-binding site that redefined its boundaries to include position 116.
- OPEN ACCESSNuclear factor kappa B (NFκB) pathway defects are associated with immunodeficiency; however, multiple phenotypes for mutations in genes encoding for NFκB proteins have been reported. We sought to create a database of published mutations in the genes encoding for IKKα and IKKβ and the regulatory subunit IKKγ, also referred to as NFκB essential modulator (NEMO). All published mutations were reviewed. The clinical and laboratory phenotypes were recorded and yearly updates of new mutations and phenotypes will be performed. Multiple immunodeficiency and infectious phenotypes were recorded particularly for patients with NEMO gene mutations. Even patients with the same NEMO mutation tended to have somewhat different phenotypes. In patients with primary immunodeficiency, the clinical phenotype may not direct the clinician to the genetic cause of the disease. Therefore, a comprehensive database will expand our knowledge and enhance the clinician’s ability to predict which gene mutation is the cause of the immunodeficiency. This database can assist clinicians in the diagnoses of patients with specific features of immunodeficiency.Statement of novelty: A comprehensive database of published mutations in the genes encoding for IKKα, IKKβ, and IKKγ was created. This database may aid the clinician in recognizing specific immunodeficiency phenotypes.
- OPEN ACCESS
- Mark Stein,
- Agnes Nemet,
- Santhosh Kumar,
- William Lumry,
- Hartwig Gajek,
- Roberta Macchia,
- Vladislava Zamfirova,
- Garrett Bergman,
- Donald McNeil,
- John Hooper,
- James Moy,
- Robert Pesek,
- Julia Upton,
- Ralph Shapiro,
- Gordon Sussman, and
- Chaim M. Roifman
Background: Primary immunodeficiency involving defective antibody formation requires antibody replacement therapy with immunoglobulin products to prevent and reduce infections. Immunoglobulin for intravenous use (IVIG) is a processed blood product with limited availability, and the various marketed IVIG products may have different tolerability among patients. New IVIG products are therefore necessary to offer options to patients and to reduce the risk of a product shortage.Methods: Forty-five adult and pediatric patients with primary immunodeficiency, documented agammaglobulinemia or hypogammaglobulinemia, and antibody deficiency were enrolled in a prospective, multi-centre, open-label, single-arm historically controlled Phase III study to evaluate the safety, efficacy, and pharmacokinetics of a new 10% IVIG produced by Kedrion.Results: Forty-four patients completed the study while one withdrew consent. Over the 12-month study period, only 2 episodes of acute serious bacterial infections (both bacterial pneumonias) were recorded, for a mean annual event rate of 0.04 per subject, with an upper one-sided 99% confidence limit of 0.11. Values for all secondary efficacy endpoints were comparable with those in similar studies. The primary safety endpoint was met as the rate of infusions temporally associated (i.e., within 72 hours) with ≥1 adverse event was 16% (upper 95% confidence limit 20.4%). Pharmacokinetics were assessed in 31 patients and found to be comparable with those published for other IVIG products.Conclusion: Kedrion IVIG 10% is safe, efficacious, and well tolerated by patients with primary immunodeficiency.Statement of novelty: This report describes the safety, efficacy, and pharmacokinetics of a new IVIG preparation. - OPEN ACCESS
- Cornelia Thoeni,
- Ellen A. Hamilton,
- Abdul Elkadri,
- Ryan Murchie,
- Karoline Fiedler,
- Adi Ovadia,
- Nigel Sharfe,
- Bo Ngan,
- Ernest Cutz,
- Amit Nahum,
- Aleixo M. Muise, and
- Chaim M. Roifman
Introduction: Mutations in the signal transducer and activator of transcription1 (STAT1) have been associated with a variety of clinical patterns. Interestingly patients with heterozygous mutations in the DNA binding domain (DBD) of STAT1 suffer acute and chronic colitis.Methods: To further analyze the role of STAT1 deficiency in intestinal inflammation, we employed protein expression analysis of total and activated STAT1 in intestinal biopsy samples from 2 patients with heterozygous mutations in the DBD of the STAT1 gene.Results: Both patients showed clinical and histological features of colitis. Total and activated STAT1 were decreased in duodenal and colonic enterocytes, and total STAT1 was found to be mislocalized in aggregates subapically. In addition, intestinal biopsy samples showed decreased numbers of lymphocytes. Patient-derived lymphoblasts demonstrated lack of viability and high susceptibility for cell death.Conclusion: STAT1 expression and distribution in the gut of patients with mutations in the DBD are abnormal, suggesting a primary role of STAT1 dysfunction in enterocytes in addition to the secondary effect of aberrant inflammation.Statement of novelty: Colitis associated with STAT1 mutations appears to have unique features distinct from typical inflammatory bowel disease. - OPEN ACCESS
- Mohammad Alsalamah,
- Amrita Sarpal,
- Victoria Mok Siu,
- Paul Gibson,
- CA Rupar,
- Michelle Barton,
- Marina I Salvadori, and
- Sharan Goobie
Introduction: Primary hemophagocytic lymphohistiocytosis (HLH) is a life-threatening inflammatory process that has been linked to abnormal cytotoxic T-cell and natural killer (NK) cell function. We report on the first case of severe combined immunodeficiency (SCID) caused by a CD3δ mutation presenting with HLH in a female of Mennonite descent.Case Description: A Low-German-speaking Mennonite female with past medical history of eczema, mouth sores, and refractory oral and diaper candidiasis presented at the age of 6 months with vomiting, diarrhea, and lethargy. The patient developed HLH that was refractory to treatment and led to multi-organ failure. Immunological evaluation was diagnostic for SCID and post-mortem genetic testing confirmed a homozygous mutation in CD3δ that was previously described in Mennonites.Method: Targeted molecular testing for CD3δ deficiency confirmed a homozygous C-to-T transition at nucleotide position 202, predicting a premature stop codon, with a truncation at residue 68 (R68X) in the extracellular domain of the protein.Discussion: Many primary immunodeficiency diseases (PID) that affect cytotoxic T cells and NK cells have presented with HLH. However, a growing number of PID with no obvious NK-cell defect have also been found to predispose patients to HLH, suggesting that failure of NK activity is not the only mechanism leading to this unusual form of inflammation.Conclusion: CD3δ is known to be critical for T-cell but not NK-cell development, which may suggest an alternate mechanism for overwhelming inflammation leading to HLH.Statement of novelty: This is the first case report of CD3δ deficiency presenting with HLH. - OPEN ACCESS
- Benyamin Rosental,
- Avishai Shemesh,
- Michal Yaron-Mendelson,
- Lauren C. Klein,
- Yona Kodman,
- Jacov Levy,
- Angel Porgador, and
- Arnon Broides
Background: Familial hemophagocytic lymphohistiocytosis (FHL) is a rare, genetic, immune dysregulation disorder of aberrant hyperactivation of lymphocytes causing inflammation and hemophagocytosis. We report on a 3-month old male who was evaluated for the possibility of FHL because of a positive family history. The patient was asymptomatic; however, levels of the soluble interleukin 2 (IL-2) receptor were elevated and the quantity and function of the natural killer (NK) cells were severely decreased.Methods: Purification of NK cells and evaluation of the cytotoxicity and IFNγ/TNFα secretion of NK cells after IL-2 activation relative to the patient's family members.Results: The patient's NK specific lysis was enhanced compared with his mother, and it was slightly higher than his sister. The IFNγ and TNFα secretion by the patient's NK cells after challenge with target 721 cells or anti-natural cytotoxicity receptors (NKp30 and NKp44) antibodies showed levels that are close to the mother's and sister's NK secretion levels. Owing to a low yield of NK cells from the patient's father the results for his NK cells are incomplete. The patient did not undergo HSCT and continued to be followed. He is now 7 years old and thriving without signs of FHL. His last examination was in August 2012 for functionality of isolated NK cells. The results showed normal cytotoxicity, cytokine secretion, and CD107a up-regulation to the NK cell surface.Conclusion: We propose that NK function assessment in patients with presumed FHL should be performed on isolated NK cell populations. This practice may reduce the number of false-negative results in NK function assays.Statement of novelty: In this case report we show that functional assessment of unpurified NK cells could lead to a false-negative assessment in 1 of the parameters in FHL. Assessment of NK function without NK purification may lead to an erroneous diagnosis of poor NK function. - OPEN ACCESS
- Anne Pham-Huy,
- Vy Hong-Diep Kim,
- Elizabeth Nizalik,
- Gabrielle Weiler,
- Jennifer Vethamuthu, and
- Eyal Grunebaum
Inherited defects in the ubiquitous adenosine deaminase (ADA) enzyme disrupt the function of the immune system as well as many other organs and tissues. Some patients may also suffer from kidney damage. Here we report on an ADA-deficient patient who was treated with ADA replacement therapy from infancy and at 6 years of age developed acute kidney failure, thrombocytopenia, and severe anemia. A kidney biopsy demonstrated mesangiolysis and occlusion of kidney loops by erythrocytes and platelet aggregates, which is consistent with hemolytic-uremic syndrome (HUS). There was no evidence of exposure to Shiga toxins, nor were any complement abnormalities detected. The kidney function improved following hemodialysis. Our report demonstrates the increased susceptibility of ADA-deficient patients to develop HUS and expands the nonimmune abnormalities associated with ADA deficiency. This further emphasizes the vigilance required when caring for such patients.Statement of novelty: Here we provide the first detailed clinical and histological characterization of hemolytic-uremic syndrome developing in an ADA-deficient patient. - OPEN ACCESSBackground: Combined immunodeficiency (CID) presents in infancy with severe microbial infections due to either the depletion or dysfunction of lymphocytes. Several mutated genes have been implicated in causing this condition. These encoded proteins are involved in gene recombination, signal transduction from receptors to transcription factors, or they are critical for lymphocyte development. There remain 20%–30% of patients with similar phenotypes but with no known genetic aberration. The objective of this study was to define the molecular basis of CID in a group of patients.Genotyping was performed using linkage panel chips, and the results were analyzed for parametric linkage. Whole genome sequencing was also performed. In vitro mitogen stimulation, flow cytometry, real time PCR, Western blotting, and cytokine ELISA were used to assess immunological status and signal transduction pathways.We identified a homozygous mutation in the gene for the NFκB transcription factor RelB in 3 patients who suffered repeated infection despite the presence of circulating T and B cells. This mutation introduces a premature stop, resulting in an ablation of RelB expression. Evaluation of patient immune systems revealed reduced response to mitogens and an inability to maintain an adequate antibody response to immunizations.Lack of RelB expression results in a clinical presentation of CID.Statement of novelty: We describe RelB deficiency for the first time.
- OPEN ACCESS
- Osama Y. Al-Dirbashi,
- Svetlana Ogrel,
- Nathan McIntosh,
- Lauren Higgins,
- Christine McRoberts,
- Larry Fisher,
- Dennis E. Bulman,
- Michael T. Geraghty, and
- Pranesh Chakraborty
Background: Screening newborns for severe combined immunodeficiency (SCID) aims for early identification and treatment of the affected newborns. Adenosine deaminase (ADA) deficiency, a defect in the purine metabolic pathway, is a major cause of SCID and is characterized by the accumulation of adenosine (Ado) and deoxyadenosine (dAdo) in dried blood spots (DBSs). If left untreated, infants with this disorder are at risk of life-threatening infections. Analysis of T-cell receptor excision circles (TRECs) in DBS samples is the gold-standard screening method. However, TREC analysis is insufficient to determine SCID etiology, and a fraction of ADA–SCID may not be detected.Methods: We used the original DBS screening sample to measure Ado, dAdo, and ADA activity. Erythro-9-(2-hydroxy-3-nonyl) adenine was used as an ADA inhibitor to imitate ADA deficiency, making it possible to create quality control material with pathological enzyme activity and metabolite levels. Quantification was achieved by tandem mass spectrometric analysis with a run time of 2.5 min.Results: The 95th percentile reference intervals (n = 588) of Ado and dAdo were 0.9–3.0 and 0.1–0.4 µmol/L, respectively. The 95th percentile reference interval (n = 200) of ADA activity using 13C10, 15N5 Ado and 15N5 dAdo as substrates were 0.8–1.6 and 0.4–0.7 pmol/DBS, respectively. In confirmed ADA patients (n = 4), Ado and dAdo were significantly elevated, whereas ADA activity was almost absent.Conclusion: These novel methods are applied, in our lab, to samples with low TRECs, with no false negative or false positives encountered to date. The potential of using these methods as a primary screening approach for ADA–SCID is in the process of validation.Statement of novelty: New mass spectrometric methods to simultaneously measure adenosine, deoxyadenosine, guanosine, and deoxguanosine, as well as ADA activity in neonatal DBS samples have been developed. This methodology highlights the metabolic nature of ADA–SCID and complements TREC analysis by providing additional biochemical information. - OPEN ACCESS
- Amit Nahum,
- David Manson, and
- Bo Ngan
X-linked agammaglobulinemia (XLA) is a rare immunodeficiency caused by defects in the Bruton tyrosine kinase (BTK) gene, characterized by impaired B-cell development, reduced immunoglobulin production, and increased susceptibility to bacterial infections at an early age. Some XLA patients show atypical presentations, with most reports concentrating on the diagnosis at a relatively old age. They presented with infections at late age or with unusual pathogens; however, other atypical manifestations have only rarely been reported.Methods: Description of patients with XLA and novel mutations in BTK who presented with atypical manifestations or developed noninfectious complications.Results: Four patients presented unique manifestations unusual for XLA. The first with Granulomatous Dermatitis, the second with acute demyelinating encephalomyelitis, the third with “Crohn's disease like” localized protein-losing enteropathy, and the last patient with idiopathic thrombocytopenic purpura, which is an unexpected finding in a patient devoid of endogenous immunoglobulins. Mutations in BTK were found in all domains of the gene; 1 resulted in a stop codon and 3 were missense mutations.Conclusions: Early recognition of atypical presentations and manifestations of patients with XLA is crucial for timely initiation of life-saving therapy, which may include anti-bacterial and anti-inflammatory treatments in addition to immunoglobulin.Statement of novelty: In this study we present unique inflammatory and autoimmune phenomenons in XLA patients that were not described previously and are somewhat unexpected. These should alert the immunologist for the possibility of XLA diagnosis. - OPEN ACCESS
- Vy H.D. Kim,
- Rae Brager,
- Julia Upton,
- Bo Ngan,
- Andrea Newell,
- Maian Roifman,
- Aleixo M. Muise,
- Susanne M. Benseler,
- Eyal Grunebaum, and
- Chaim M. Roifman
Mutations in IL-10R1, IL-10R2, and IL-10 have been identified in infants with severe colitis. The only possible hope for cure in these conditions is a hematopoietic stem cell transplantation (HSCT). We report here on a patient with IL-10R1 deficiency who suffered severe colitis and arthritis. She received a HSCT from a matched unrelated donor and her post-transplant course was uneventful. She has fully engrafted and her immune reconstitution was complete and robust. Although signs of colitis were completely resolved, arthritis was not reversed by HSCT. She continues to have joint swelling in the knees and inflammatory changes in the wrists. In conclusion, HSCT seems to have reversed colitis, but was insufficient to improve arthritis and possibly other autoimmune manifestations.Statement of novelty: This report describes a successful HSCT in severe infantile colitis caused by mutations in IL-10R1. Yet, the arthritis remains active, suggesting that conditions such as severe rheumatic disorders in childhood may not be reversed by replacement of the hematopoietic system. - OPEN ACCESS
- Bo Ngan,
- Daniele Merico,
- Nufar Marcus,
- Vy H.D. Kim,
- Julia Upton,
- Andrea Bates,
- Joanne Herbrick,
- Thomas Nalpathamkalam,
- Bhooma Thiruvahindrapuram,
- Peter Cox, and
- Chaim M. Roifman
Introduction: Genetic aberrations associated with combined immunodeficiency have been increasingly identified in the past two decades. Yet, there are still 30% of these patients with unidentified genetic cause.Methods: We employed whole genome sequencing to identify the genetic defect leading to combined immunodeficiency. Thymus, gut, and lung tissues were studied using hematoxylin and eosin staining as well as immunohistochemistry.Results: We identified 2 deleterious mutations in the TTC7A gene. Surprisingly, the patient did not have intestinal atresia but suffered repeated infections as well fatal pneumonitis. Dendriform lung ossification developed, which was unique to this case. The patient had typical presentation of combined immunodeficiency including profound lymphopenia, markedly reduced in-vitro response to mitogens, as well as low TRECS. Serum immunoglobulins were also markedly reduced.Conclusion: Mutations in the TTC7A gene can cause combined immunodeficiency with no intestinal atresia and predispose to lung ossification.Statement of novelty: TTC7A mutations can cause profound immunodeficiency without multiple intestinal atresia. We report here for the first time that this defect is associated with dendriform lung ossification. - OPEN ACCESSIntroduction: The transcription factor Signal Transducer and Activator of Transcription 1 (STAT1) is a key element in many of the signalling cascades involved in immune system function. Different mutations in STAT1 are associated with heterogeneous clinical phenotypes that range from early fatality due to overwhelming infection to limited involvement of the mucus membrane with recurrent Candida infections. Multiple genes related to immune function have been associated with the development of hemophagocytic lymphohistiocytosis (HLH), but the association between STAT1 mutation and HLH has not been described in detail.Methods: We report the genetic background of a patient with chronic mucocutaneous candidiasis (CMC) as well as an unusual clinical course.Results: In this study we describe a patient with a mutation in the STAT1 DNA-binding domain and a history of CMC who developed a refractory and fatal case of HLH despite having bone marrow transplantation.Conclusion: We describe a patient with refractory and fatal HLH who was found to have a mutation in the DNA-binding domain of STAT1.Statement of novelty: The association of chronic mucocutaneous candidiasis with HLH.
- OPEN ACCESSIntroduction: For close to half a century immunoglobulin replacement therapy has been the main therapy for patients unable to produce functioning antibodies. To date, both subcutaneous (SC) and intravenous delivery methods have been successful at effectively and safely replacing immunoglobulin. Home intravenous and SC therapy programs have been established and have gained attention, but the true motivation and frequency of switching from traditional hospital-based treatment to these alternatives remains unknown. This study aims to determine the willingness of patients in Canada to switch to a home-based gammaglobulin treatment program by quantifying related experiences and preferences.Methods: A cohort of 169 patients in Ontario currently on hospital-based intravenous immunoglobulin (IVIG) replacement therapy (referral centers or community hospitals) were sent a 2.5 page survey consisting of 25 questions. Data were collected and statistically analyzed using Fisher, χ2, and McNemar tests, where P < 0.05 was considered statistically significant.Results: Ninety-one patients responded and most agreed to consider home therapy regardless of the administration route, based on recommendations from an immunologist (IVIG, P = 0.006; SC, P < 0.001). Patients preferred switching to home IVIG rather than to SC (P = 0.01), but their concerns regarding home healthcare costs were more prominent with IVIG (P = 0.01). The main concern with current intravenous therapy was the overall loss of time (P = 0.0001), whereas for home therapy it was the loss of supervision (P = 0.0009) and possible associated costs. Patients considered home treatment more convenient, as it is less time consuming (P = 0.01), and this was perceived as an improvement in quality of life (P = 0.001). It was considered less convenient because it may be unsafe and (or) more expensive.Conclusion: This survey demonstrates that home intravenous therapy maybe the preferred option for patients with antibody deficiency in Ontario, provided this decision was supported by a specialist in the field, secured supervision was available, and it was not associated with personal expenses.Statement of novelty: The first study to examine patient willingness to try a new route of gammaglobulin administration at home.