Ahmed Aziz Bousfiha

Human genetics of tuberculosis: a long and winding road

Only a small fraction of individuals exposed to Mycobacterium tuberculosis develop clinical tuberculosis (TB). Over the past century, epidemiological studies have shown that human genetic factors contribute significantly to this interindividual variability, and molecular progress has been made over the past decade for at least two of the three key TB-related phenotypes: (i) a major locus controlling resistance to infection with M. tuberculosis has been identified, and (ii) proof of principle that severe TB of childhood can result from single-gene inborn errors of interferon-γ immunity has been provided; genetic association studies with pulmonary TB in adulthood have met with more limited success. Future genetic studies of these three phenotypes could consider subgroups of subjects defined on the basis of individual (e.g. age at TB onset) or environmental (e.g. pathogen strain) factors. Progress may also be facilitated by further methodological advances in human genetics. Identification of the human genetic variants controlling the various stages and forms of TB is critical for understanding TB pathogenesis. These findings should have major implications for TB control, in the definition of improved prevention strategies, the optimization of vaccines and clinical trials and the development of novel treatments aiming to restore deficient immune responses.

A Phenotypic Approach for IUIS PID Classification and Diagnosis: Guidelines for Clinicians at the Bedside

The number of genetically defined Primary Immunodeficiency Diseases (PID) has increased exponentially, especially in the past decade. The biennial classification published by the IUIS PID expert committee is therefore quickly expanding, providing valuable information regarding the disease-causing genotypes, the immunological anomalies, and the associated clinical features of PIDs. These are grouped in eight, somewhat overlapping, categories of immune dysfunction. However, based on this immunological classification, the diagnosis of a specific PID from the clinician’s observation of an individual clinical and/or immunological phenotype remains difficult, especially for non-PID specialists. The purpose of this work is to suggest a phenotypic classification that forms the basis for diagnostic trees, leading the physician to particular groups of PIDs, starting from clinical features and combining routine immunological investigations along the way. We present 8 colored diagnostic figures that correspond to the 8 PID groups in the IUIS Classification, including all the PIDs cited in the 2011 update of the IUIS classification and most of those reported since.

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.

Mycobacterial disease in patients with chronic granulomatous disease: A retrospective analysis of 71 cases

BACKGROUND Chronic granulomatous disease (CGD) is a rare primary immunodeficiency caused by inborn errors of the phagocyte nicotinamide adenine dinucleotide phosphate oxidase complex. From the first year of life onward, most affected patients display multiple, severe, and recurrent infections caused by bacteria and fungi. Mycobacterial infections have also been reported in some patients. OBJECTIVE Our objective was to assess the effect of mycobacterial disease in patients with CGD. METHODS We analyzed retrospectively the clinical features of mycobacterial disease in 71 patients with CGD. Tuberculosis and BCG disease were diagnosed on the basis of microbiological, pathological, and/or clinical criteria. RESULTS Thirty-one (44%) patients had tuberculosis, and 53 (75%) presented with adverse effects of BCG vaccination; 13 (18%) had both tuberculosis and BCG infections. None of these patients displayed clinical disease caused by environmental mycobacteria, Mycobacterium leprae, or Mycobacterium ulcerans. Most patients (76%) also had other pyogenic and fungal infections, but 24% presented solely with mycobacterial disease. Most patients presented a single localized episode of mycobacterial disease (37%), but recurrence (18%), disseminated disease (27%), and even death (18%) were also observed. One common feature in these patients was an early age at presentation for BCG disease. Mycobacterial disease was the first clinical manifestation of CGD in 60% of these patients. CONCLUSION Mycobacterial disease is relatively common in patients with CGD living in countries in which tuberculosis is endemic, BCG vaccine is mandatory, or both. Adverse reactions to BCG and severe forms of tuberculosis should lead to a suspicion of CGD. BCG vaccine is contraindicated in patients with CGD.

The 752delG26 mutation in the RFXANK gene associated with major histocompatibility complex class II deficiency: evidence for a founder effect in the Moroccan population

Major histocompatibility complex class II plays a key role in the immune response, by presenting processed antigens to CD4+ lymphocytes. Major histocompatibility complex class II expression is controlled at the transcriptional level by at least four trans-acting genes: CIITA, RFXANK, RFX5 and RFXAP. Defects in these regulatory genes cause MHC class II immunodeficiency, which is frequent in North Africa. The aim of this study was to describe the immunological and molecular characteristics of ten unrelated Moroccan patients with MHC class II deficiency. Immunological examinations revealed a lack of expression of MHC class II molecules at the surface of peripheral blood mononuclear cells, low CD4+ T lymphocyte counts and variable serum immunoglobulin (IgG, IgM and IgA) levels. In addition, no MHC class II (HLA DR) expression was observed on lymphoblasts. The molecular analysis identified the same homozygous 752delG26 mutation in the RFXANK genes of all patients. This finding confirms the association between the high frequency of the combined immunodeficiency and the defect in MHC class II expression and provides strong evidence for a founder effect of the 752delG26 mutation in the North African population. These findings should facilitate the establishment of molecular diagnosis and improve genetic counselling for affected Moroccan families.

Three New BLM Gene Mutations Associated with Bloom Syndrome

Blooms syndrome (BS) is a rare autosomal recessive disease predisposing patients to all types of cancers affecting the general population. BS cells display a high level of genetic instability, including a 10-fold increase in the rate of sister chromatid exchanges, currently the only objective criterion for BS diagnosis. We have developed a method for screening the BLM gene for mutations based on direct genomic DNA sequencing. A questionnaire based on clinical information, cytogenetic features, and family history was addressed to physicians prescribing BS genetic screening, with the aim of confirming or guiding diagnosis. We report here four BLM gene mutations, three of which have not been described before. Three of the mutations are frameshift mutations, and the fourth is a nonsense mutation. All these mutations introduce a stop codon, and may therefore be considered to have deleterious biological effect. This approach should make it possible to identify new mutations and to correlate them with clinical information.

Chronic Granulomatous Disease in Morocco: Genetic, Immunological, and Clinical Features of 12 Patients from 10 Kindreds

PurposeChronic granulomatous disease (CGD) is characterized by an inability of phagocytes to produce reactive oxygen species (ROS), which are required to kill some microorganisms. CGD patients are known to suffer from recurrent bacterial and/or fungal infections from the first year of life onwards. From 2009 to 2013, 12 cases of CGD were diagnosed in Morocco. We describe here these Moroccan cases of CGD.MethodsWe investigated the genetic, immunological and clinical features of 12 Moroccan patients with CGD from 10 unrelated kindreds.ResultsAll patients were children suffering from recurrent bacterial and/or fungal infections. All cases displayed impaired NADPH oxidase activity in nitroblue tetrazolium (NBT), dihydrorhodamine (DHR) or 2′,7′ dichlorofluorescein diacetate (DCFH-DA) assays. Mutation analysis revealed the presence of four different mutations of CYBB in four kindreds, a recurrent mutation of NCF1 in three kindreds, and a new mutation of NCF2 in three patients from a single kindred. A large deletion of CYBB gene has detected in a patient. The causal mutation in the remaining one kindred was not identified.ConclusionThe clinical features and infectious agents found in these patients were similar to those in CGD patients from elsewhere. The results of mutation analysis differed between kindreds, revealing a high level of genetic and allelic heterogeneity among Moroccan CGD patients. The small number of patients in our cohort probably reflects a lack of awareness of physicians. Further studies on a large cohort are required to determine the incidence and prevalence of the disease, and to improve the description of the genetic and clinical features of CGD patients in Morocco.

Collaborating to Improve Quality of Life in Primary Immunodeficiencies: World PI Week, 2013

World Primary Immunodeficiency Week (WPIW) 2013 ran from 22 to 29th April (www.worldpiweek.org), providing an opportunity to reflect on progress made and the challenges that remain for the primary immunodeficiency diseases (PID) community. In this article, representatives from leading PID societies evaluate the situation and plans for further progress in their respective areas of the world. It is hoped that this situation analysis will prompt further focus and enhanced collaboration on the gaps that remain in the pursuit of promoting early diagnosis and treatment of PIDs.

Primary Immunodeficiency Classification on Smartphone

Primary immunodeficiencies comprise at least 300 genetically defined single-gene inborn errors of immunity, presenting a broad spectrum of manifestations from susceptibility to infections to autoimmunity and inflammation. The International Union of Immunological Societ ies (IUIS) Expert Committee on Primary Immunodeficiency meets every other year to update the classification of human primary immunodeficiencies (PIDs). In recent years, two forms of classification have been published by the IUIS PID expert committee: a complete catalog of known PIDs subdivised in nine tables sharing a given pathogenesis, and a more userfriendly classification based on phenotype and laboratory results [1, 2]. This last classification has been welcomed by the PID community, as it proved to be useful at the bedside. Based on that classification, we developed an application for smartphones (Android and iOS) to help clinicians in their diagnosis. This application is subdivised in seven sections (Fig. 1). The first section presents the nine figures from the 2015 IUIS phenotypic classification [2], so that you can get your PID diagnosis literally at the bedside. The second section is a search function by disease name. It allows you to pinpoint the right table for the suspected disease and show the related diseases or genes. The third section is also a search function, by manifestation this time. You can select clinical and laboratory features, and the application will present corresponding diseases with a link to the related table. The fourth section, BHow to explore PID,^ is a guideline in 10 recommendations for a diagnosis approach of PID with basic laboratory tests. A link to the corresponding table is provided. Another section provides you the age-related reference values for laboratory tests such as CBC, lymphocyte subpopulation, immunoglobulin assay, and IgG subclass levels. The BCase studies^ section is based on the A-project workshop [3] and presents three PID clinical cases to be solved with the 10 recommendations from ASID. The last section is a translator based on the UnifiedMedical Dictionary and translates terms used in immunology from English to French and/or Arabic and vice versa. This application makes the IUIS classification available for anyone, anywhere, and at anytime. * Leïla Jeddane ljeddane@gmail.com

Erratum to: Emerging Infections and Pertinent Infections Related to Travel for Patients with Primary Immunodeficiencies

In today’s global economy and affordable vacation travel, it is increasingly important that visitors to another country and their physician be familiar with emerging infections, infections unique to a specific geographic region, and risks related to the process of travel. This is never more important than for patients with primary immunodeficiency disorders (PIDD). A recent review addressing common causes of fever in travelers provides important information for the general population Thwaites and Day (N Engl J Med 376:548-560, 2017). This review covers critical infectious and management concerns specifically related to travel for patients with PIDD. This review will discuss the context of the changing landscape of infections, highlight specific infections of concern, and profile distinct infection phenotypes in patients who are immune compromised. The organization of this review will address the environment driving emerging infections and several concerns unique to patients with PIDD. The first section addresses general considerations, the second section profiles specific infections organized according to mechanism of transmission, and the third section focuses on unique phenotypes and unique susceptibilities in patients with PIDDs. This review does not address most parasitic diseases. Reference tables provide easily accessible information on a broader range of infections than is described in the text.