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AIMS: To understand the characteristics of combined immunodeficiency disorders that affect cellular and humoral immunity (CID) in the Arabian Peninsula. METHODS: Retrospective study of 236 patients with CID from the region were enrolled from 2004 to 2022. RESULTS: 236 patients were included with a majority being profound CID. Among patients with a family history of CID, the ages at onset and diagnosis, and the delay in diagnosis were lower compared to those with no family history of CID, but this did not affect time to transplant. HSCT was performed for 51.27% of the patients with median time from diagnosis to HSCT of 6.36 months. On multivariate analysis, patients who underwent early transplant had increased odds of having CD3 count ≤1000 cell/µl, diagnosed by screening or erythroderma. CONCLUSION: There is a delay in diagnosis and treatment of CID in our region. Establishing newborn screening programs and HSCT units in our region are the urgent need.
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Transplante de Células-Tronco Hematopoéticas , Doenças da Imunodeficiência Primária , Recém-Nascido , Humanos , Estudos Retrospectivos , Imunidade Humoral , Triagem NeonatalRESUMO
Monogenic immune dysregulation diseases (MIDD) are caused by defective immunotolerance. This study was designed to increase knowledge on the prevalence and spectrum of MIDDs, genetic patterns, and outcomes in Middle East and North Africa (MENA). MIDD patients from 11 MENA countries (Iran, Turkey, Kuwait, Oman, Algeria, Egypt, United Arab Emirates, Tunisia, Jordan, Qatar, and Azerbaijan) were retrospectively evaluated. 343 MIDD patients (58% males and 42% female) at a median (IQR) age of 101 (42-192) months were enrolled. The most common defective genes were LRBA (23.9%), LYST (8.2%), and RAB27A (7.9%). The most prevalent initial and overall manifestations were infections (32.2% and 75.1%), autoimmunity (18.6% and 41%), and organomegaly (13.3% and 53.8%), respectively. Treatments included immunoglobulin replacement therapy (53%), hematopoietic stem cell transplantation (HSCT) (14.3%), immunosuppressives (36.7%), and surgery (3.5%). Twenty-nine (59.2%) patients survived HSCT. Along with infectious complications, autoimmunity and organomegaly may be the initial or predominant manifestations of MIDD.
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Doenças da Imunodeficiência Primária , Proteínas Adaptadoras de Transdução de Sinal/genética , Adolescente , Criança , Pré-Escolar , Egito , Feminino , Humanos , Masculino , Doenças da Imunodeficiência Primária/genética , Sistema de Registros , Estudos Retrospectivos , Tunísia , Turquia , Proteínas de Transporte Vesicular/genética , Proteínas rab27 de Ligação ao GTP/genéticaRESUMO
BACKGROUND: There is an increased demand for hematopoietic stem cell transplant (HSCT) to treat various diseases including combined immunodeficiencies (CID), with limited worldwide availability. Variables affecting the decision regarding CID patients' prioritization for HSCT are not known. We aimed to determine general, clinical, and immunologic factors associated with the higher risk of early death (≤6 months after diagnosis) in untransplanted CID patients. METHODS: Data collection was done retrospectively from five centers and included general patients' information, and clinical and laboratory variables. Inclusion criteria were untransplanted patients who are either dead or alive with a follow-up period ≥6 months after diagnosis. RESULTS: Two hundred and thirty-six CID patients were reported by participating centers, of whom 111 were included in the study with a cumulative follow-up period of 278.6 years. Seventy-two patients died with the median age of death of 10.5 months. 35.1% of the patients succumbed within 6 months after the diagnosis. Having a history of Candida infections, sepsis or hepatomegaly was associated with an increased risk of early death. None of the other general or clinical variables was associated with such risk. Bivariate analysis of lymphocyte subsets showed that patients with the following counts: CD3+ < 100, CD4+ < 200, CD8+ < 50, or CD16+ CD56+ <200 cells/µl had increased risk of early death. In adjusted analysis, increased risk of early death was observed among patients with CD3+ count <100 cells/µl. CONCLUSION: Combined immunodeficiencies patients with a history of Candida infections, sepsis, hepatomegaly, or severe T-lymphopenia should be given priority for HSCT to avoid early death.
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Candidíase , Transplante de Células-Tronco Hematopoéticas , Doenças da Imunodeficiência Primária , Sepse , Humanos , Lactente , Imunidade Humoral , Estudos Retrospectivos , Hepatomegalia/etiologia , Doenças da Imunodeficiência Primária/etiologia , Sepse/etiologia , Candidíase/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversosRESUMO
BACKGROUND: Little is known about the etiology of childhood diarrhea in the United Arab Emirates (UAE) especially after the introduction of rotavirus vaccines. This study aimed to identify gastrointestinal pathogens in children with diarrhea (cases) and the carriage rate of these pathogens in asymptomatic children (controls). METHODS: Stool samples were collected from 203 cases and 73 controls who presented to two major hospitals in Al Ain city, UAE. Samples were analyzed with Allplex™ Gastrointestinal Full Panel Assay for common entero-pathogens. The association between diarrhea and the isolated pathogens was calculated in a multivariate logistic regression model. The adjusted attributable fractions (aAFs) were calculated for all pathogens significantly associated with cases. RESULTS: At least one pathogen was identified in 87 samples (42.8%) from cases and 17 (23.3%) from controls (P < 0.001). Rotavirus, norovirus GII and adenovirus were significantly more prevalent in cases. Their aAFs with 95% ci are 0.95 (0.64, 1.00) for rotavirus, 0.86 (0.38, 0.97) for norovirus GII and 0.84 (0.29, 0.96) for adenovirus. None of the 13 bacteria tested for were more commonly found in the cases than in controls. Cryptosporidium spp. were more significantly detected in cases than in controls. Co-infections occurred in 27.9% of the children. Viruses and parasites were significantly more likely to occur together only in the cases. CONCLUSIONS: Multiplex PCR revealed high positivity rates in both cases and controls which demand a cautious interpretation. Rotavirus remains the main childhood diarrhea pathogen in UAE. Effective strategies are needed to better control rotavirus and other causative pathogens.
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Infecções por Adenovirus Humanos/epidemiologia , Adenovírus Humanos/genética , Infecções por Caliciviridae/epidemiologia , Coinfecção/epidemiologia , Criptosporidiose/epidemiologia , Cryptosporidium/genética , Diarreia/epidemiologia , Norovirus/genética , Infecções por Rotavirus/epidemiologia , Rotavirus/genética , Infecções por Adenovirus Humanos/virologia , Adenovírus Humanos/isolamento & purificação , Animais , Infecções por Caliciviridae/virologia , Estudos de Casos e Controles , Pré-Escolar , Coinfecção/parasitologia , Coinfecção/virologia , Criptosporidiose/parasitologia , Cryptosporidium/isolamento & purificação , Diarreia/parasitologia , Diarreia/virologia , Fezes/parasitologia , Fezes/virologia , Feminino , Humanos , Lactente , Masculino , Reação em Cadeia da Polimerase Multiplex/métodos , Norovirus/isolamento & purificação , Rotavirus/isolamento & purificação , Infecções por Rotavirus/virologia , Vacinas contra Rotavirus , Emirados Árabes Unidos/epidemiologiaRESUMO
Phosphorescence O2 analyzer was used to measure calvarial bone cellular respiration (cellular mitochondrial O2 consumption) in Taylor Outbred mice in the presence and absence of zoledronic acid. This potent bisphosphonate inhibits osteoclast-mediated calcium resorption, and its effects on bone respiration have not been previously investigated. The change of O2 concentration with time was measured in closed vials containing phosphate-buffered saline (PBS), 5 mM glucose and 5-25 mg calvarial bone fragments, and it was complex for t = 0-30 h. Cyanide (specific inhibitor of cytochrome oxidase) halted O2 consumption, confirming the oxidation occurred in the respiratory chain. Initial rate of respiration was estimated from the zero-order plots d[O2]/dt for t = 0-4 h. For untreated specimens, the rate (mean ± SD) was 2.0 ± 1.2 µM O2 h-1 mg-1 (n = 6). This value was 7-10 times lower than that of other murine organs, but similar to that reported for rat and Guinea pig calvaria (averaging, 2.7 nmol O2 h-1 mg-1). The corresponding rate in the presence of 10-100 µM zoledronic acid was 2.7 ± 0.7 µM O2 h-1 mg-1 (n = 11), p = 0.216. The first-order plots ln ([O2] t ÷ [O2] t=0) versus time for t = 0-30 h were also used to compare treated and untreated specimens. The rate (h-1 mg-1 103) for specimens incubated in PBS without glucose was 1.3 ± 0.6 (n = 3, p = 0.007), in PBS + glucose it was 10.7 ± 6.9 (n = 10), in PBS + glucose + 10 µM zoledronic acid it was 12.1 ± 6.7 (n = 10, p = 0.579), in PBS + glucose + 20 µM zoledronic acid it was 12.9 ± 3.3 (n = 9, p = 0.356), and in PBS + glucose + 100 µM zoledronic acid it was 13.7 ± 7.7 (n = 9, p = 0.447). Thus, exposure to high-doses of zoledronic acid over several hours imposed a statistically insignificant increase in calvarial bone cellular respiration.
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Difosfonatos/farmacologia , Imidazóis/farmacologia , Crânio/citologia , Animais , Respiração Celular/efeitos dos fármacos , Glucose/farmacologia , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Consumo de Oxigênio/efeitos dos fármacos , Crânio/efeitos dos fármacos , Ácido ZoledrônicoRESUMO
OBJECTIVES: Anaphylactic shock is associated with severe hypotension. Potassium channel blockers, such as 4-aminopyridine, induce vasoconstriction. The objective of this study was to test the ability of 4-aminopyridine to restore blood pressure and increase survival in anaphylactic shock. DESIGN: Experimental study. SETTING: Physiology laboratory. SUBJECTS: Adult male Wistar rats. INTERVENTIONS: Rats were sensitized with ovalbumin (1 mg SC), and anaphylactic shock was induced by IV injection of ovalbumin (1 mg). Experimental groups included non-allergic rats (NA) (n = 6); allergic rats (Controls) (n = 6); allergic rats treated with 4-aminopyridine (4-aminopyridine) (1 mg/kg) (n = 6); and allergic rats treated with epinephrine (EPI) (10 µg/kg) (n = 6). Treatments were administered 1 minute after induction of anaphylactic shock. MEASUREMENTS AND MAIN RESULTS: Mean arterial blood pressure, heart rate, and survival were measured for 60 minutes. Plasma levels of histamine, leukotriene B4, prostaglandin E2, prostaglandin F2, pH, and HCO3 were measured. Mean arterial blood pressure was normal in the NA group; severe hypotension and high mortality were observed in controls; normalization of mean arterial blood pressure, heart rate, and increased survival were observed in 4-aminopyridine and EPI groups. All allergic 4-aminopyridine-treated rats survived after the induction of anaphylactic shock. Histamine level was higher in controls and the 4-aminopyridine group but reduced in the EPI group. Prostaglandin E2 increased in controls and EPI group and decreased in 4-aminopyridine group; prostaglandin F2 increased in controls but decreased in 4-aminopyridine and EPI groups. Leukotriene B4 decreased in 4-aminopyridine and EPI groups. Metabolic acidosis was prevented in the 4-aminopyridine group. CONCLUSIONS: Our data suggest that voltage-dependent K+ channel inhibition with 4-aminopyridine treatment restores blood pressure and increases survival in the Wistar rat model of anaphylactic shock. 4-aminopyridine or related voltage-dependent K channel blockers could be a useful additional therapeutic approach to treatment of refractory anaphylactic shock.
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4-Aminopiridina/farmacologia , Anafilaxia/tratamento farmacológico , Pressão Sanguínea/efeitos dos fármacos , Bloqueadores dos Canais de Potássio/farmacologia , Acidose/prevenção & controle , Animais , Dinoprosta/sangue , Dinoprostona/sangue , Modelos Animais de Doenças , Epinefrina/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Histamina/sangue , Leucotrieno B4/sangue , Masculino , Ratos Wistar , Vasoconstritores/farmacologiaAssuntos
Transplante de Células-Tronco Hematopoéticas , Síndromes de Imunodeficiência/imunologia , Linfonodos/imunologia , Proteínas Serina-Treonina Quinases/deficiência , Linhagem Celular , Criança , Pré-Escolar , Humanos , Síndromes de Imunodeficiência/genética , Lactente , Masculino , Proteínas Serina-Treonina Quinases/genética , Quinase Induzida por NF-kappaBRESUMO
Primary immunodeficiencies are disorders of the immune system often caused by mutations of genes required for lymphocyte development. Phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1) gene mutations are associated with SHORT syndrome, a rare multisystem disease. The name stands for Short stature, Hyperextensibility, Ocular depression, Rieger anomaly and Teething delay. Our case describes a child who presented with agammaglobulinemia with phenotypical features of SHORT syndrome. Upon further investigation, he was found to have a rare variant of the PIK3R1 gene mutation. This new mutation combines two distinct diseases with the same gene defect, which otherwise has been reported as two separate entities. The objective of this report is to identify a new gene mutation associated with SHORT syndrome along with agammaglobulinemia and to highlight the importance of recognizing the features of SHORT syndrome. We describe a nine-year-old male who presented with developmental delay and recurrent infections at the age of 12 months. Immunological evaluation revealed agammaglobulinemia and he has been scheduled for regular intravenous immunoglobulin replacement therapy. In view of characteristic syndromic physical features, speech and teething delay, we investigated further for the underlying genetic reason for agammaglobulinemia. The molecular analysis demonstrated a rare homozygous variant, c.244dup, in the PIK3R1 gene. This case reveals the association of the PIK3R1 gene mutation with agammaglobulinemia and SHORT syndrome. It further demonstrates the discovery of a new pathological variant of the gene. A detailed history and examination along with an immunological and genetic workup should be carried out for children with certain distinct phenotypical features. SHORT syndrome has specific characteristics that call for awareness and early recognition for prompt diagnosis and intervention. Emphasis is placed on genetic counseling as the disease is inherited in an autosomal recessive pattern, as demonstrated by molecular genetic studies.
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Background: Chronic granulomatous disease (CGD) is a genetic disorder caused by defective oxidative burst within phagocytes, manifesting as recurrent, severe infections as well as hyperinflammation. Objective: This is the first report from the United Arab Emirates (UAE) to describe the demographic, clinical, laboratory, radiological, and genetic characteristics of patients with CGD. Methods: This is a retrospective study that was conducted at Tawam Hospital in the UAE on patients with confirmed CGD between 2017 and 2022. Results: A total of 14 patients were diagnosed with CGD, of whom 13 patients had autosomal recessive (AR) CGD due to NCF1 deficiency. Consanguinity was noted in all patients with AR CGD, whereas positive family history was identified in 50% of cases. The median age of onset of symptoms was 24 months, while the median age at diagnosis was 72 months. Lymphadenitis was the most common clinical feature identified in 71% of patients. Other common infectious manifestations included abscess formation (57%), pneumonia (50%), invasive aspergillosis (21%), oral thrush (14%), and sepsis (14%). Disseminated trichosporonosis was reported in one patient. Autoimmune and inflammatory manifestations included celiac disease in two patients, diabetes mellitus and asymptomatic colitis in one patient each. Genetic analysis was performed in all patients; NCF1 deficiency was diagnosed in 13 (93%) patients, with c.579G>A being the most prevalent pathogenic variant identified. The treatment modalities, as well as treatment of acute infections, treatment modalities included antimicrobial prophylaxis in 12 (86%) patients and hematopoietic stem cell transplant in six patients (42%). Conclusion: This is the first report from the UAE describing the clinical and molecular characteristics of patients with CGD. The homozygous variant c.579G>A causing NCF1 deficiency can be considered as a founder mutation for AR CGD in the UAE.
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Doença Granulomatosa Crônica , Humanos , Pré-Escolar , Criança , Doença Granulomatosa Crônica/diagnóstico , Doença Granulomatosa Crônica/epidemiologia , Doença Granulomatosa Crônica/genética , Emirados Árabes Unidos/epidemiologia , Estudos Retrospectivos , NADPH Oxidases/genéticaRESUMO
BACKGROUND: No population study has explored the population distribution of adult asthma in the United Arab Emirates (UAE). The objective is to estimate asthma prevalence in general population in UAE. METHODS: Using standard European Community Respiratory Health Survey (ECRHS) questionnaires and tools, this is a cross-sectional assessment of a random sample of the population in established quotas of the seven Emirates in the UAE. We surveyed 1,220 participants, of which 63.2% were male, and 20.1% were UAE Nationals, with a mean (SD) age of 32.9 (14.1) years. RESULTS: Prevalence of individual respiratory symptoms from the ECRHS screening questionnaire in all participants were generally ranging 8 - 10%, while participants 20-44 years presented lower prevalence in all symptoms (p < 0.05). The expected male:female ratio of reported wheezing and asthma attacks and its treatment by age was not observed. Participating women reported more individual symptoms than men. Overall, there were 15.4% (95% C.I. 13.5 - 17.5) participants who fulfilled our screening criteria for asthma, while for consistency with ECRHS, there were 12.1% (95% C.I. 10.4 - 14.1) participants who fulfilled the ECRHS asthma definition, being 9.8% (95% C.I. 7.8 - 12.2) of those 20-44 years, that is 8.6% of male and 11.8% of female young adults participating. CONCLUSION: We conclude that asthma is common in the UAE, and gender differences are not observed in reported asthma symptoms in young adults. This being the first population based study exploring the prevalence of asthma and its determinants in the United Arab Emirates based on the ECRHS.
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Asma/epidemiologia , Adulto , Tosse/epidemiologia , Estudos Transversais , Dispneia/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Sons Respiratórios , Rinite Alérgica Sazonal/epidemiologia , Inquéritos e Questionários , Emirados Árabes Unidos/epidemiologiaRESUMO
Purpose: Inborn Errors of Immunity (IEI) are heterogeneous disorders of immunity with variable clinical presentation and outcome. This is the first comprehensive report from the United Arab Emirates aiming to describe the demographics, clinical characteristics, categories, treatment modalities and outcome of patients with IEI. Methods: This retrospective study was conducted on patients who attended Tawam Hospital between 2016-2020. Results: We identified 162 patients with IEI, of whom 152 were children. The age of onset of symptoms ranged between birth to 38 years. About two-thirds of patients were Emirati nationals, 64.2% had consanguineous parents and 38.3% of cases were familial. Patients were classified as; immunodeficiencies affecting cellular and humoral immunity (20.4%), combined immunodeficiencies with associated or syndromic features (38.3%), predominantly antibody deficiencies (16%), immune dysregulation (4.3%), congenital defects of phagocytes number or function (8.6%), defects in intrinsic and innate immunity (1.9%) autoinflammatory disorders (1.9%), complement deficiency (6.2%), bone marrow failure (1.9%) and phenocopies of inborn errors of immunity (0.6%). Genetic testing was performed in 85.2% of patients with a diagnostic yield of 92.7%. Complications included bronchiectasis, neoplasia, and vaccine-related infections. Immunoglobulin therapy and antimicrobial prophylaxis were both used in (51.9%) of patients while (20.4%) underwent hematopoietic stem cell transplantation (HSCT). The overall mortality rate was 10.5%. Conclusion: This report highlights the burden of IEI in the UAE. Ongoing education of physicians, establishment of a national registry and considering changes to early BCG vaccination are measures recommended to improve outcomes.
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Doenças Genéticas Inatas/epidemiologia , Síndromes de Imunodeficiência/epidemiologia , Doenças da Imunodeficiência Primária/epidemiologia , Adolescente , Adulto , Antibioticoprofilaxia , Criança , Pré-Escolar , Feminino , Testes Genéticos , Transplante de Células-Tronco Hematopoéticas , Humanos , Imunização Passiva , Lactente , Recém-Nascido , Masculino , Estudos Retrospectivos , Emirados Árabes Unidos/epidemiologia , Adulto JovemRESUMO
The mechanism of anaphylactic shock (AS) remains incompletely understood. The potassium channel blocker 4-aminopyridine (4-AP), the inhibitors of cystathionine γ-lyase (ICSE), dl-propargylglycine (DPG) or ß-cyanoalanine (BCA), and the nitric oxide (NO) synthase produce vasoconstriction and could be an alternative for the treatment of AS. The aim of this study was to demonstrate the ability of L-NAME, ICSE alone or in combination with 4-AP to restore blood pressure (BP) and improve survival in ovalbumin (OVA) rats AS. Experimental groups included non-sensitized Wistar rats (n = 6); AS (n = 6); AS (n = 10 per group) treated i.v. with 4-AP (AS+4-AP), epinephrine (AS+EPI), AS+DPG, AS+BCA, or with L-NAME (AS+L-NAME); or AS treated with drug combinations 4-AP+DPG, 4-AP+BCA, 4-AP+L-NAME, or 4-AP+EPI. AS was induced by i.v. OVA (1 mg). Treatments were administered i.v. one minute after AS induction. Mean arterial BP (MAP), heart rate (HR), and survival were monitored for 60 min. Plasma levels of histamine, prostaglandin E2 (PGE2) and F2 (PGF2α), leukotriene B4 and C4, angiotensin II, vasopressin, oxidative stress markers, pH, HCO3, PaO2, PaCO2, and K+ were measured. OVA induced severe hypotension and all AS rats died. Moreover, 4-AP, 4-AP+EPI, or 4-AP+BCA normalized both MAP and HR and increased survival. All sensitized rats treated with 4-AP alone or with 4-AP+BCA survived. The time-integrated MAP "area under the curve" was significantly higher after combined 4-AP treatment with ICSE. Metabolic acidosis was not rescued and NO, ICSE, and Kv inhibitors differentially alter oxidative stress and plasma levels of anaphylactic mediators. The AS-induced reduction of serum angiotensin II levels was prevented by 4-AP treatment alone or in combination with other drugs. Further, 4-AP treatment combined with EPI or with BCA also increased serum PGF2α, whereas only the 4-AP+EPI combination increased serum LTB4. Serum vasopressin and angiotensin II levels were increased by 4-AP treatment alone or in combination with other drugs. Moreover, 4-AP alone and in combination with inhibition of cystathionine γ-lyase or EPI normalizes BP, increases serum vasoconstrictor levels, and improves survival in the Wistar rat model of AS. These findings suggest possible investigative treatment pathways for research into epinephrine-refractory anaphylactic shock in patients.
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AIMS: To present the details of Bacillus Calmette-Guérin (BCG)-vaccine associated complications (VACs) in combined immunodeficiencies (CID) patients. METHODS: Five centers participated in this retrospective study and completed a data form, which included general patients' information, clinical and laboratory data. RESULTS: Among 236 CID patients, 127 were BCG vaccinated. 41.9% of patients with family history of CID and 17.1% who were diagnosed by screening were BCG vaccinated. Twenty-three patients (18.1%) developed BCG-VACs. The median age of VACs was 6 months and the median time from vaccination to complications was 6 months. The highest rate of BCG-VACs was recorded in patients receiving the Russian BCG strain compared to the Tokyo and Danish strains. Univariate analysis of T-lymphocyte subsets showed increased odds of BCG complications in patients with CD3+, CD4+, and CD8+ counts of ≤250 cells/µL. Only CD8 + count ≤250 cells/µL had increased such odds on multivariate analysis. VACs were disseminated in 13 and localized in 10 patients. Localized complication occurred earlier after vaccination (median: 4 months) compared with disseminated ones (median: 7 months). There were no significant associations between sex, administered vaccine strain, serum immunoglobulins levels, lymphocyte subsets counts, and the chance of having either localized or disseminated BCG-related complications. COCLUSIONS: Although contraindicated, many patients with CID continue to be vaccinated with BCG. Low CD8 + count is a risk factor for BCG-related complications and localized complications occurred earlier than disseminated ones. Considerations should be undertaken by health care authorities especially in countries with high incidence of CID to implement newborn screening, delay the time of BCG vaccine administration beyond 6 months of age and to use the relatively safer strains like the Danish and Tokyo ones.
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Vacina BCG , Mycobacterium bovis , Doenças da Imunodeficiência Primária , Criança , Humanos , Lactente , Recém-Nascido , Vacina BCG/efeitos adversos , Imunidade Humoral , Imunoglobulinas , Doenças da Imunodeficiência Primária/complicações , Estudos Retrospectivos , Vacinação/efeitos adversosRESUMO
Importance: Clinical, genetic, and laboratory characteristics of Middle Eastern patients with multisystem inflammatory syndrome in children (MIS-C) have not yet been documented. Objective: To assess the genetic and clinical characteristics of patients with MIS-C of primarily Arab and Asian origin. Design, Setting, and Participants: A prospective, multicenter cohort study was conducted from September 1, 2020, to August 31, 2021, in the United Arab Emirates and Jordan. Forty-five patients with MIS-C and a matched control group of 25 healthy children with a confirmed SARS-CoV-2 infection status were recruited. Whole exome sequencing in all 70 participants was performed to identify rare, likely deleterious variants in patients with MIS-C and to correlate genetic findings with the clinical course of illness. Exposures: SARS-CoV-2. Main Outcomes and Measures: Fever, organ system complications, laboratory biomarkers, whole exome sequencing findings, treatments, and clinical outcomes were measured. The Mann-Whitney U test was used to assess the association between genetic variants and MIS-C attributes. The Fisher exact test was used to compute the genetic burden in MIS-C relative to controls. Results: A total of 45 patients with MIS-C (23 [51.1%] male; 30 [66.7%] of Middle Eastern origin; mean [SD] age, 6.7 [3.6] years) and 25 controls (17 [68.0%] male; 24 [96.0%] of Middle Eastern origin; mean [SD] age 7.4 [4.0] years) participated in the study. Key inflammatory markers were significantly dysregulated in all patients with MIS-C. Mucocutaneous and gastrointestinal manifestations were each reported in 36 patients (80.0%; 95% CI, 66.1%-89.1%), cardiac findings were reported in 22 (48.9%; 95% CI, 35.0%-63.0%), and neurologic findings were reported in 14 (31.1%; 95% CI, 19.5%-45.6%). Rare, likely deleterious heterozygous variants in immune-related genes, including TLR3, TLR6, IL22RA2, IFNB1, and IFNA6, were identified in 19 patients (42.2%; 95% CI, 29.0%-56.7%), of whom 7 had multiple variants. There was higher enrichment of genetic variants in patients relative to controls (29 vs 3, P < .001). Patients with those variants tended to have earlier disease onset (7 patients [36.8%; 95% CI, 19.1%-58.9%] with genetic findings vs 2 [7.7%; 95% CI, 2.1%-24.1%] without genetic findings were younger than 3 years at onset) and resistance to treatment (8 patients [42.1%; 95% CI, 23.1%-63.7%] with genetic findings vs 3 patients [11.5%; 95% CI, 4.0%-29.0%] without genetic findings received 2 doses of intravenous immunoglobulin). Conclusions and Relevance: The results of this cohort study suggest that rare, likely deleterious genetic variants may contribute to MIS-C disease. This finding paves the way for additional studies with larger, diverse populations to fully characterize the genetic contribution to this new disease entity.
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COVID-19 , Síndrome de Resposta Inflamatória Sistêmica , COVID-19/complicações , COVID-19/genética , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Masculino , Oriente Médio , Estudos Prospectivos , SARS-CoV-2 , Síndrome de Resposta Inflamatória Sistêmica/genéticaAssuntos
Canais de Cálcio/imunologia , Fibroblastos/imunologia , Síndromes de Imunodeficiência/genética , Mutação , Linfócitos T/imunologia , Adulto , Canais de Cálcio/genética , Proliferação de Células/efeitos dos fármacos , Criança , Consanguinidade , Feminino , Fibroblastos/patologia , Expressão Gênica , Células HEK293 , Humanos , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/patologia , Transporte de Íons , Masculino , Proteína ORAI1 , Linhagem , Cultura Primária de Células , Linfócitos T/efeitos dos fármacos , Linfócitos T/patologia , Acetato de Tetradecanoilforbol/farmacologia , TransfecçãoRESUMO
BACKGROUND: Food allergy is common in children, and its occurrence is strongly associated with other allergies including anaphylaxis. Both genetic (e.g., CD14, STAT6, IL-10, SPINK5, and FOXP3 genes) and environmental (e.g., early exposure to highly allergic food) factors appear to contribute to food allergy. METHOD: Cross-sectional study involved children in public primary schools in Al-Ain city (United Arab Emirates). 660 students from the chosen classes were provided with 35 questions to be answered by their parents with a response rate 60.2%. The objective of the study was to determine predictors for food allergy in children. RESULT: Significant associations were found between childhood food allergy and a history of personal allergy (atopic dermatitis, asthma or allergic rhino-conjunctivitis) or immediate family members with food allergy or other allergic diseases. The best predictors for childhood food allergy were a personal history of asthma (p < 0.001), a personal history of atopic dermatitis (p < 0.001), a paternal history of atopic dermatitis (p = 0.005) and a paternal history of allergic rhino-conjunctivitis (p = 0.012). DISCUSSION: These results are consistent with the notion that "various forms of allergy, including childhood food allergy are hereditarily coupled". Thus, predicting childhood food allergy provides an opportunity to prevent or ameliorate the symptoms.
Assuntos
Hipersensibilidade Alimentar/epidemiologia , Hipersensibilidade Alimentar/imunologia , Predisposição Genética para Doença , Asma/complicações , Asma/epidemiologia , Asma/imunologia , Criança , Conjuntivite Alérgica/complicações , Conjuntivite Alérgica/epidemiologia , Conjuntivite Alérgica/imunologia , Estudos Transversais , Dermatite Atópica/complicações , Dermatite Atópica/epidemiologia , Dermatite Atópica/imunologia , Hipersensibilidade Alimentar/complicações , Humanos , Pais , Rinite Alérgica Perene/complicações , Rinite Alérgica Perene/epidemiologia , Rinite Alérgica Perene/imunologia , Fatores de RiscoRESUMO
OBJECTIVES: Inborn errors of immunity (IEI) are prevalent in tribal cultures due to frequent consanguineous marriages. Many of these disorders are autosomal recessive, resulting from founder mutations; hence they are amenable to prevention. The primary objective of this study was to evaluate the pathogenicity of novel variants of IEI found among Emiratis. METHODS: This retrospective data collection study reports novel variants of IEI detected by diagnostic exome sequencing. Pathogenicity prediction was based on scoring tools, amino acid alignment, and Jensen-Shannon divergence values. RESULTS: Twenty-one novel variants were identified; nine were frameshift, three nonsense, four intronic (one pathogenic), and five missense (two pathogenic). Fifteen variants were likely pathogenic, of which 13 were autosomal recessive and two uncertain inheritance. Their clinical spectra included combined immunodeficiency, antibody deficiency, immune dysregulation, defects in intrinsic/innate immunity, and bone marrow failure. CONCLUSION: The described novel pathogenic variants are core to a planned national screening program that aims toward IEI prevention. Future studies, however, are needed to confirm their natural history in individual patients and estimate their prevalence in the community.
Assuntos
Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/imunologia , Variação Genética , Animais , Transtornos da Insuficiência da Medula Óssea/genética , Biologia Computacional , Herpesvirus Humano 4/fisiologia , Humanos , Imunidade Inata/genética , Linfo-Histiocitose Hemofagocítica/genética , Estudos RetrospectivosRESUMO
In the United Arab Emirates, BCG (Bacillus Calmette-Guérin) is administered to all newborns. We present here a young infant with an inborn error of immunity (IEI) who developed fatal adverse events to this live-attenuated vaccine. This male infant received BCG (Serum Institute of India Pvt., Ltd., India) on Day 11 of life. On Day 25, he developed fever, followed by cervical lymphadenitis and bilateral otitis media with fluid drainage. On Day 118, he was admitted with severe hemophagocytic lymphohistiocytosis (HLH), and passed away on Day 145. The diagnostic exome sequencing test identified a hemizygous nonsense variant, NM_000397.3(CYBB):c.676C>T, p.Arg226* (rs137854592). Pathogenic variants of CYBB [cytochrome b(-245), beta subunit; Mendelian Inheritance in Man [MIM] accession code, 300481] are known to cause "immunodeficiency 34, mycobacteriosis, X-linked" (IMD34, MIM#300645) and "chronic granulomatous disease, X-linked" (CGDX, MIM#306400). The natural history of his illness is consistent with "X-linked recessive Mendelian susceptibility to mycobacterial disease (MSMD)." This entity is responsible for his BCG disease and is a likely trigger of his HLH. This disastrous event underlines the importance of developing worldwide policies that target BCG disease prevention, especially in communities with high prevalence of IEI. Moreover, screening for genetic causes of MSMD in the community could pave the way, at least partially, for scale-up of tuberculosis (TB) prevention.
RESUMO
Fermitin family homolog 3 (FERMT3), alternatively kindlin-3 (KIND3), is an integrin binding protein (of 667 residues) encoded by the FERMT3 gene. The molecule is essential for activating integrin αIIbß3 (the fibrinogen receptor) on platelets and for the integrin-mediated hematopoietic cell (including platelets, T lymphocytes, B lymphocytes, and granulocytes) adhesion. Its defects are associated with impaired primary hemostasis, described as "Glanzmann's thrombasthenia (MIM#273800)-like bleeding problem." The defects are also associated with infections, designated as "LAD1 (leukocyte adhesion deficiency, type I; MIM#116920)-like immune deficiency." The entity that joins the impaired primary hemostasis with the leukocyte malfunction has been termed "leukocyte adhesion deficiency, type III" (LAD3, autosomal recessive, MIM#612840), representing a defective activation of the integrins ß1, ß2, and ß3 on leukocytes and platelets. Here, we report a male toddler with novel compound heterozygous variants, NM_178443.2(FERMT3):c.1800G>A, p.Trp600* (a non-sense variant) and NM_178443.2(FERMT3):c.2001del p.*668Glufs*106 (a non-stop variant). His umbilical cord separated at about 3 weeks of age. A skin rash (mainly petechiae and purpura) and recurrent episodes of severe epistaxis required blood transfusions in early infancy. His hemostatic work-up was remarkable for a normal platelet count, but abnormal platelet function screen with markedly prolonged collagen-epinephrine and collagen-ADP closure times. The impaired platelet function was associated with reduced platelet aggregation with all agonists. The expression of platelet receptors was normal. Other remarkable findings were persistent lymphocytosis and granulocytosis, representing defects in diapedesis due to the integrin dysfunction. The natural history of his condition, structure and sequence analysis of the variations, and comparison with other LAD3 cases reported in the literature are presented.
RESUMO
We present here a male young infant with X-linked severe combined immunodeficiency (MIM#300400) due to the novel nonsense variant of IL2RG (interleukin 2 receptor, gamma; MIM#308380), NM_000206.2(IL2RG):c.820_823dup p.Ser275Asnfs*29. He developed aggressive reactive lymphohistiocytic proliferation after receiving the live-attenuated Bacillus Calmette-Guérin (BCG) vaccine at birth. This report advocates for modifying the current practice of early use of BCG. The natural history of his disease also suggests considering IL2RG variants as a potential cause of "X-linked recessive Mendelian susceptibility to mycobacterial disease" (MSMD). His reactive lymphohistiocytic proliferation and massive hepatosplenomegaly simulated hemophagocytic lymphohistiocytosis (HLH, likely triggered by the BCG disease). This entity was masked by the absence of fever and markedly elevated inflammatory biomarkers. Thus, his findings stimulate discussion on the need to modify the diagnostic criteria of HLH, in order to accommodate conditions, such IL2RG variants that block systemic inflammation.