Nermeen Galal

Clinical picture and treatment of 2212 patients with common variable immunodeficiency

BACKGROUND Common variable immunodeficiency (CVID) is an antibody deficiency with an equal sex distribution and a high variability in clinical presentation. The main features include respiratory tract infections and their associated complications, enteropathy, autoimmunity, and lymphoproliferative disorders. OBJECTIVE This study analyzes the clinical presentation, association between clinical features, and differences and effects of immunoglobulin treatment in Europe. METHODS Data on 2212 patients with CVID from 28 medical centers contributing to the European Society for Immunodeficiencies Database were analyzed retrospectively. RESULTS Early disease onset (<10 years) was very frequent in our cohort (33.7%), especially in male subjects (39.8%). Male subjects with early-onset CVID were more prone to pneumonia and less prone to other complications suggesting a distinct disease entity. The diagnostic delay of CVID ranges between 4 and 5 years in many countries and is particularly high in subjects with early-onset CVID. Enteropathy, autoimmunity, granulomas, and splenomegaly formed a set of interrelated features, whereas bronchiectasis was not associated with any other clinical feature. Patient survival in this cohort was associated with age at onset and age at diagnosis only. There were different treatment strategies in Europe, with considerable differences in immunoglobulin dosing, ranging from 130 up to 750 mg/kg/mo. Patients with very low trough levels of less than 4 g/L had poor clinical outcomes, whereas higher trough levels were associated with a reduced frequency of serious bacterial infections. CONCLUSION Patients with CVID are being managed differently throughout Europe, affecting various outcome measures. Clinically, CVID is a truly variable antibody deficiency syndrome.

Primary immunodeficiencies in highly consanguineous North African populations

The study of inbred populations has contributed remarkably to the description of new autosomal recessive primary immunodeficiencies (PIDs). Here, we examine the pattern of PIDs in North African populations and assess the impact of highly prevalent consanguinity. This review reports on the current status of pediatricians’ awareness of PIDs in Egypt, Morocco, and Tunisia, where awareness of PIDs is relatively recent. The phenotypic distribution of PIDs is reported and compared among the three countries and with other populations. Data analysis reveals a prevalence of autosomal recessive forms and a peculiar distribution of major PID categories, particularly more combined immunodeficiencies than antibody disorders. In these endogamous communities, molecular diagnosis is critical to developing a genetic‐based preventive approach. The organization of diagnosis and care services in these resource‐limited settings faces many obstacles. Autosomal recessive PIDs are overrepresented; thus, it is critical to continue investigation of these diseases in order to better understand the underlying mechanisms and to improve patient care.

Chronic granulomatous disease : Review of a cohort of Egyptian patients

BACKGROUND Chronic granulomatous disease (CGD) is an inherited disease that results from a defect in the phagocytic cells of the immune system. It is caused by defects in one of the major subunits of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. The clinical presentations of CGD patients are heterogeneous. OBJECTIVES This is the first report from Egypt discussing clinical and laboratory data of twenty-nine patients (from 26 families) with CGD from a single tertiary referral centre. RESULTS There were twenty male and nine female patients. The consanguinity rate was 76% (19/25). Their age of diagnosis ranged from 2 to 168 months with a mean of 52.8 months ± 49.6 SD. The most common manifestations were abscesses in 79.3% (deep organ abscesses in 37.9% of patients), followed by pneumonia in 75.8% and gastrointestinal symptoms in 27.5%. Rare but fatal complications were also reported among patients as one patient developed haemophagocytic lymphohistiocytosis (HLH) syndrome. Although X linked-CGD universally constitutes the most common pattern of inheritance; only 6 of our patients 6/25 (24%) belonged to this group with a Stimulation Index (SI) of 1-5, and confirmed by carrier pattern of their mothers. Mothers were not available for testing in four male children. Nineteen patients (76%) had autosomal recessive patterns; ten males and nine females patients based on having abnormal SI, positive history of consanguinity and their mothers showing normal SI. CONCLUSION Increasing the awareness of physicians about symptoms of CGD may lead to earlier diagnosis of the disease, thus enhancing proper management and better quality of life.

Hyperammonemia in the pediatric emergency care setting.

Hyperammonemia is encountered frequently in acutely ill children presenting for emergency care with altered levels of consciousness (ALOC). Ammonia production, metabolism, and excretion are affected by different variables. Hyperammonemia may be a transient state or may signify more grave etiologies as inborn errors of metabolism. Levels of ammonia are also affected by proper sampling technique, transport, and analysis. Objectives: To determine the level of ammonia in acutely ill children with ALOC, identify causes of hyperammonemia, and correlate levels with illness severity and morbidity. Design: Observational study. Setting: Emergency department at Cairo University Specialized Paediatric Hospital. Methods: Fifty cases of acutely ill pediatric patients with ALOC who presented to the emergency department were included in the study from 2008 through 2009. Emergency department patients (n = 20) with known diseases that may induce hyperammonemia were excluded. Patients were subjected to detailed history taking with emphasis on factors affecting ammonia levels and thorough clinical examination. A cohort group of age- and sex-matched children acted as a control group. Results: The measured blood ammonia level ranged between 13 and 265 &mgr;mol/L, with a mean level of 95 &mgr;mol/L. Sixty percent of the children with ALOC had ammonia levels of greater than 75 &mgr;mol/L, with levels greater than 200 &mgr;mol/L seen in 6% of the studied sample. The study demonstrated a highly significant statistical difference between children with ALOC and control groups. There was no correlation between blood ammonia level and age. Correlations of ammonia levels were also conducted in comparison with etiological diagnoses and laboratory parameters with no statistical significance.There was no statistical significance between ammonia level and duration of illness, Sequential Organ Failure Assessment score, or Glasgow Coma Scale score/Morray Scale score. Conclusions: Clinicians should consider testing children with ALOC for hyperammonemia, provided that a clear understanding of its metabolism and factors controlling it are understood. Proper sampling must be ensured. Mild elevations of ammonia levels are fairly common, but exceedingly high levels should raise concern and may require further evaluation.

Mutations in Recombination Activating Gene 1 and 2 in patients with severe combined immunodeficiency disorders in Egypt

The Recombination Activating Genes (RAG) 1/2 are important for the development and function of T and B cells. Loss of RAG1/2 function results in severe combined immunodeficiency (SCID), which could lead to early death. We studied the prevalence of RAG1/2 mutations in ten SCID patients in Egypt. We identified two novel homozygous nonsense mutations in RAG1, a novel homozygous deletion, and a previously reported homozygous missense mutation from four patients, as well as two homozygous mutations in RAG2 from the same patient. Prenatal diagnosis performed in the mother of a patient with RAG1 deficiency determined that the fetus was heterozygous for the same mutation. This represents the first report on RAG1/2 mutations in SCID patients in Egypt. The early diagnosis dramatically affects the outcome of the disease by allowing bone marrow transplantation at an early age, and providing prenatal diagnosis and genetic counseling for families with a history of SCID.

Isolation of poliovirus shedding following vaccination in children with antibody deficiency disorders.

INTRODUCTION Prolonged excretion of oral poliovirus may occur in primary antibody deficiency states. Those patients who persistently excrete the virus may pose the risk of aiding viral propagation in the environment. This study therefore aimed to identify the potential for prolonged poliovirus shedding by patients diagnosed with congenital antibody deficiency disorders. METHODOLOGY A cohort of children later diagnosed with antibody deficiency disorders was included in the study. Patient history was taken for each participant, with emphasis on vaccination data. Laboratory investigations included immunoglobulin profiles and stool sample collection at one month intervals from each patient, with follow-up for six months. The virus isolates were detected using enzyme-linked immunosorbent assay (ELISA) and molecular reverse transcription polymerase chain reaction (RT-PCR) techniques. RESULTS On the initial sample screens, one patient revealed excretion one for Sabin-like strain 1 (SL1) and one patient revealed excretion for Sabin like strain 2 (SL2). Only one patient continued to shed the virus (SL1) on three successive samples and on follow-up. There was no correlation between the level of immunoglobulins and duration of virus shedding. CONCLUSION The study demonstrates the low occurrence of prolonged vaccine polioviruses shedding in a group of children exposed to a live vaccine.

Poliovirus Excretion among Persons with Primary Immune DeficiencyDisorders: Summary of Data from Enhanced Poliovirus Surveillance in Egypt,2011-2014

Background: If exposed to oral poliovirus vaccine (OPV), persons with primary immune deficiency disorders (PID) are at increased risk of paralytic poliomyelitis; and can chronically excrete poliovirus. However, the risk of excretion of vaccine derived poliovirus among immunodeficient persons (iVDPV) is not well characterized. We present summary of data from poliovirus surveillance project among PID patients collected between 2011 and 2014 from 11 Egyptian Governorates. Methods: Stool was tested for polioviruses in suspected or confirmed PID children regardless of whether Acute Flaccid Paralysis (AFP) was present or not. Those excreting poliovirus were followed until three consecutive negative stool samples were obtained. Results: There were 122 patients with suspected or confirmed PID identified; 13/122 (11%) excreted poliovirus; of these, 6 excreted iVDPVs, the remaining 7 excreted Sabin virus. The duration of iVDPV excretion ranged from 1 to 21 months. AFP was detected in 3/6 (50%) of those excreting iVDPVs. All iVDPV excretors had history of receiving OPV. Conclusions: Chronic poliovirus excretion in PID patients is rare, however, poliovirus eradication requires removal of all polioviruses from circulation; and because PID individuals are not necessarily paralyzed they might be missed by current poliovirus surveillance based on detection of AFP. To achieve poliovirus eradication, surveillance for polioviruses among PID patients should be routinely conducted in all countries, and poliovirus antiviral therapy must be made available for those with chronic excretion.

CD4+ CD25+ cells in type 1 diabetic patients with other autoimmune manifestations

The existence of multiple autoimmune disorders in diabetics may indicate underlying primary defects of immune regulation. The study aims at estimation of defects of CD4+ CD25+high cells among diabetic children with multiple autoimmune manifestations, and identification of disease characteristics in those children. Twenty-two cases with type 1 diabetes associated with other autoimmune diseases were recruited from the Diabetic Endocrine and Metabolic Pediatric Unit (DEMPU), Cairo University along with twenty-one normal subjects matched for age and sex as a control group. Their anthropometric measurements, diabetic profiles and glycemic control were recorded. Laboratory investigations included complete blood picture, glycosylated hemoglobin, antithyroid antibodies, celiac antibody panel and inflammatory bowel disease markers when indicated. Flow cytometric analysis of T-cell subpopulation was performed using anti-CD3, anti-CD4, anti-CD8, anti-CD25 monoclonal antibodies. Three cases revealed a proportion of CD4+ CD25+high below 0.1% and one case had zero counts. However, this observation did not mount to a significant statistical difference between the case and control groups neither in percentage nor absolute numbers. Significant statistical differences were observed between the case and the control groups regarding their height, weight centiles, as well as hemoglobin percentage, white cell counts and the absolute lymphocytic counts. We concluded that, derangements of CD4+ CD25+high cells may exist among diabetic children with multiple autoimmune manifestations indicating defects of immune controllers.

Identification of T-Lymphocyte Function in Healthy vs. Septic Preterms and its Relation to Candidal Infections in the Hospital Setting

ObjectivesTo compare T-cell function in healthy/septic preterms in relation to healthy term babies. Also to determine correlation of sepsis severity with T-cell function and risk to candidal infection.MethodsPatients were recruited to one of three groups. Group (I) included 30 healthy growing preterms, group (II) included preterms with neonatal sepsis whereas group (III) included 30 healthy full term neonates. Patients underwent history taking and comprehensive examination plus laboratory tests including T-Lymphocyte function by blastoid transformation method using phytohaemagglutinin (PHA).ResultsA significant difference exists between healthy preterm vs. septic newborn T cell counts and functions especially those with multiorgan system failure. No correlation was found between candidal infection and T cell functions.ConclusionsT cell functions are remarkably lower in septic newborns. Septic preterms may have low T cell functions despite absence of lymphopenia. Early detection is advised to improve outcome.

Targeted Gene Panel Sequencing for Early-onset Inflammatory Bowel Disease and Chronic Diarrhea

Background: In contrast to adult-onset inflammatory bowel disease (IBD), where many genetic loci have been shown to be involved in complex disease etiology, early-onset IBD (eoIBD) and associated syndromes can sometimes present as monogenic conditions. As a result, the clinical phenotype and ideal disease management in these patients often differ from those in adult-onset IBD. However, due to high costs and the complexity of data analysis, high-throughput screening for genetic causes has not yet become a standard part of the diagnostic work-up of eoIBD patients. Methods: We selected 28 genes of interest associated with monogenic IBD and performed targeted panel sequencing in 71 patients diagnosed with eoIBD or early-onset chronic diarrhea to detect causative variants. We compared these results to whole-exome sequencing (WES) data available for 25 of these patients. Results: Target coverage was significantly higher in the targeted gene panel approach compared with WES, whereas the cost of the panel was considerably lower (approximately 25% of WES). Disease-causing variants affecting protein function were identified in 5 patients (7%), located in genes of the IL10 signaling pathway (3), WAS (1), and DKC1 (1). The functional effects of 8 candidate variants in 5 additional patients (7%) are under further investigation. WES did not identify additional causative mutations in 25 patients. Conclusions: Targeted gene panel sequencing is a fast and effective screening method for monogenic causes of eoIBD that should be routinely established in national referral centers.