Genetic Diagnosis of Inborn Errors of Immunity in an Emerging Country: a Retrospective Study of 216 Moroccan Patients.

PURPOSE: Genetic testing provides great support to validate the clinical diagnosis of inborn errors of immunity (IEI). However, the high cost and advanced technology make these tests inaccessible to a large proportion of patients in low-income countries. In the present study, we aim to evaluate the Moroccan experience in genetic testing and to report the main molecular features and difficulties encountered in genetic diagnosis. METHODS: We performed a multi-center retrospective analysis of all patients with a molecular diagnosis and registered in the national registry between 2010 and 2022. To estimate the impact of the newly identified mutations, we calculated the Combined Annotation Dependent Depletion (CADD) score and the mutation significance cutoff (MSC) for each variant. RESULTS: A total of 216 (29%) patients received a genetic diagnosis out of 742 patients with IEI included in the registry. All genetic tests were performed in the context of thesis projects (40%) or international collaborations (60%). A set of 55 genetic defects were identified, including 7 newly reported: SNORA31, TBX21, SPPL2A, TYK2, RLTPR, ZNF341, and STAT2 GOF. Genetic diagnoses were more frequent in the defects of innate and intrinsic immunity with a percentage of 78%, while antibody deficiencies had a lower frequency with a percentage of 17.5%. Only one genetic diagnosis has been made in the complement deficiency group. The most commonly used molecular techniques were Sanger sequencing (37%) followed by targeted gene sequencing (31%). CONCLUSION: The thesis projects and collaborations were beneficial as they allowed us to provide a definitive genetic diagnosis to 29% of the patients and to contribute to the identification of new genetic defects and mutations. These results offer insight into the progress made in genetic diagnoses of IEI in Morocco, which would provide a baseline for improving the clinical management of patients with IEI.

Rhinovirus C is associated with wheezing and rhinovirus A is associated with pneumonia in hospitalized children in Morocco.

Human rhinovirus (RV) is commonly associated with severe acute lower respiratory infections (ALRI) in children. We aimed to describe the distribution of RV species and associations between RV species and clinical features in children hospitalized with clinically severe pneumonia (CSP) in Morocco. Nasopharyngeal aspirates (NPAs) were collected from 700 children, 2-59 months of age, admitted with CSP to the Hôpital d'Enfants de Rabat in Morocco. At least one respiratory virus was identified in 92% of children, of which RV was the most common (53%). PCR assays, sequencing, and phylogenetic tree analyses were carried out on 183 RV-positive NPAs to determine RV species and genotypes. Of 157 successfully genotyped NPAs, 60 (38.2%) were RV-A, 8 (5.1%) were RV-B, and 89 (56.7%) were RV-C. Wheezing and cyanosis were more common in RV-C-positive than RV-A-positive children (80.9% vs. 56.7%; P = 0.001 for wheezing and 10.1% vs. 0%; P = 0.011 for cyanosis). Physician's discharge diagnosis of pneumonia was more frequent among RV-A-positive (40.0%) than RV-C-positive children (20.2%; P = 0.009). RV-A and RV-C showed distinct seasonal patterns. Our findings suggest that RV-C is associated with wheezing illness while RV-A is associated with pneumonia. J. Med. Virol. 89:582-588, 2017. © 2016 Wiley Periodicals, Inc.

Chronic granulomatous disease in Morocco: genetic, immunological, and clinical features of 12 patients from 10 kindreds.

PURPOSE: Chronic 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. METHODS: We investigated the genetic, immunological and clinical features of 12 Moroccan patients with CGD from 10 unrelated kindreds. RESULTS: All 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. CONCLUSION: The 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.

The epidemiology and aetiology of infections in children admitted with clinical severe pneumonia to a university hospital in Rabat, Morocco.

OBJECTIVES: Scarce and limited epidemiological, clinical and microbiological data are available regarding paediatric respiratory tract infections in the Kingdom of Morocco, a middle-income country in northwestern Africa. The results of hospital-based surveillance aiming at describing the aetiology and epidemiology of respiratory distress among children <5 years of age are presented. METHODS: Children admitted to the Hôpital d'Enfants de Rabat, Morocco, and meeting the World Health Organization clinical criteria for severe pneumonia were recruited over a period of 14 months and were thoroughly investigated to ascertain a definitive diagnosis. RESULTS: In total, 700 children were recruited for the study. Most frequent clinical diagnoses included wheezing-related conditions (bronchitis/asthma, 46%; bronchiolitis, 15%), while typical bacterial pneumonia was infrequent (only 19% of the cases). Invasive bacterial disease detected by classical microbiology or molecular methods was also uncommon, affecting only 3.5% of the patients, and with an overall low detection of pneumococcal or Haemophilus influenzae type b disease. Conversely, coverage of respiratory viral detection in the nasopharynx was almost universal among cases (92%), with the three most frequent viruses detected being rhinovirus (53%), respiratory syncytial virus (18%) and adenovirus (17%). The overall case fatality rate (CFR) among recruited patients with a known outcome was 4.1% (28/690). CONCLUSIONS: In Morocco, the epidemiological profile of paediatric acute respiratory infections is markedly shifted towards wheezing-related diseases and thus resembles that of high-income countries. However, the high associated CFRs found in this study call for an improvement in preventive and clinical management strategies.

Dataset of acute respiratory infections: Epidemiological and etiological data from a cohort of 801 Moroccan children.

Acute respiratory infections remain a leading cause of death among young children in low- and middle-income countries. The etiological diagnosis of these infections is challenging due to the similarity in clinical presentations and overlapping symptoms caused by various pathogens. This database provides comprehensive epidemiological, clinical, paraclinical, and biological data on 801 Moroccan children admitted to the Children's Hospital of Rabat for the management of Clinical Severe Pneumonia. Identification of the pathogens responsible of respiratory infections was carried out using blood samples for hemoculture, standard bacterial culture and multiplex RT-PCR using the TrueScience RespiFinder Pathogen Identification Panel (Applied Biosystems).

Multifocal tuberculosis in children: A case of spinal tuberculosis.

Multifocal tuberculosis (TB) accounts for up to one-third of all cases of TB and children are at higher risk for extrapulmonary TB than adults. Spinal TB is the regular form of skeletal TB. Spondylodiscitis TB represents 47%-94% of spinal TB. Cervical localization is rare but remains dangerous because of diagnostic difficulties and severe complications. We report a case of a 10-year-old Moroccan girl, bacille Calmette-Guerin vaccinated, with no medical history or trauma, parents and siblings are healthy and no contact with TB. The patient was complaining of neck pain, asthenia, and loss of weight for 1 year. During this period, she had been treated with analgesics and anti-inflammatory drugs, with no clinical evolution. The parents consulted the pediatric emergency room when they noticed a tumefaction in the middle thoracic region. Physical examination found a pectus carinatum deformity, palpable axillary, and submandibular lymph node, and a fixed palpable median thoracic mass fistulized to the skin. The GeneXpert MTB/RIF and QuantiFERON-TB Gold assay were positive. Chest computed tomography showed cervicodorsal spondylodiscitis staged at C5-D10, with abscessed perivertebral and peristernal collections, with epidural extension at C5-C6 and pleural level. The presence of an axillary lymph node with necrotic center. The skin biopsy showed a morphological appearance of epithelial and gigantocellular granulomatous inflammation. The patient had pharmacological treatment anti-TB drug with fixed-dose combination regimen and supportive therapy for pain management.

An Exploration of Features Impacting Respiratory Diseases in Urban Areas.

Air pollution exposure has become ubiquitous and is increasingly detrimental to human health. Small Particulate matter (PM) is one of the most harmful forms of air pollution. It can easily infiltrate the lungs and trigger several respiratory diseases, especially in vulnerable populations such as children and elderly people. In this work, we start by leveraging a retrospective study of 416 children suffering from respiratory diseases. The study revealed that asthma prevalence was the most common among several respiratory diseases, and that most patients suffering from those diseases live in areas of high traffic, noise, and greenness. This paved the way to the construction of the MOREAIR dataset by combining feature abstraction and micro-level scale data collection. Unlike existing data sets, MOREAIR is rich in context-specific components, as it includes 52 temporal or geographical features, in addition to air-quality measurements. The use of Random Forest uncovered the most important features for the understanding of air-quality distribution in Moroccan urban areas. By linking the medical data and the MOREAIR dataset, we observed that the patients included in the medical study come mostly from neighborhoods that are characterized by either high average or high variations of pollution levels.

Influenza-associated severe acute respiratory infections among children under five years old in Morocco, September 2017 to March 2019.

The main aim of this research is to investigate the trend of influenza infection among children under 5 years with severe acute respiratory infections (SARI) as well as those who suffer from a high burden of disease. This research is based on a survey conducted from September 2017 to March 2019. During this period nasopharyngeal swabs were collected in a group of 942 children under 5 years with SARI, admitted in pediatric services of 8 sentinel hospitals. The virological surveillance of influenza was carried out at the National influenza Center, located in the National Institute of Hygiene, using a Reverse transcription polymerase chain reaction (qRt-PCR) monoplex assay developed by the Centers for Disease Control and Prevention (CDC; Atlanta, GA). The median age of participants was 11 months, and 40% of them were female. A total of 112 samples were reported positive yielding a frequency of 11.88% (112/942). Among all the influenza confirmed cases, 68.75% (77/112), 15.17% (17/112), 16.04% (18/112) were subtyped as influenza AH1N1pdm09, AH3N2 and influenza B respectively. Meanwhile, the proportion of patients admitted at the intensive care unit was 5,35% (6/112). Out of which 83.33% (5/6) were AH1N1pdm09 and it was reported that just 1.78% (2/112) of the positive cases were vaccinated. The study confirms that influenza affects greatly children with SARI. Thus, the need for influenza vaccines is highly recommended for children under 5 years. Moreover, our findings highlight that influenza virus is not the only cause of SARI among this group of children. Accordingly, special attention should be paid to the non-flu respiratory viruses.

Machine Learning for Predicting the Risk for Childhood Asthma Using Prenatal, Perinatal, Postnatal and Environmental Factors.

The prevalence rate for childhood asthma and its associated risk factors vary significantly across countries and regions. In the case of Morocco, the scarcity of available medical data makes scientific research on diseases such as asthma very challenging. In this paper, we build machine learning models to predict the occurrence of childhood asthma using data from a prospective study of 202 children with and without asthma. The association between different factors and asthma diagnosis is first assessed using a Chi-squared test. Then, predictive models such as logistic regression analysis, decision trees, random forest and support vector machine are used to explore the relationship between childhood asthma and the various risk factors. First, data were pre-processed using a Chi-squared feature selection, 19 out of the 36 factors were found to be significantly associated (p-value < 0.05) with childhood asthma; these include: history of atopic diseases in the family, presence of mites, cold air, strong odors and mold in the child's environment, mode of birth, breastfeeding and early life habits and exposures. For asthma prediction, random forest yielded the best predictive performance (accuracy = 84.9%), followed by logistic regression (accuracy = 82.57%), support vector machine (accuracy = 82.5%) and decision trees (accuracy = 75.19%). The decision tree model has the advantage of being easily interpreted. This study identified important maternal and prenatal risk factors for childhood asthma, the majority of which are avoidable. Appropriate steps are needed to raise awareness about the prenatal risk factors.

Medicines Acceptability in Hospitalized Children: An Ongoing Need for Age-Appropriate Formulations.

Although knowledge on medicine acceptability remains fragmented, this multi-faceted concept has emerged as a key factor for compliance in pediatrics. In order to investigate the acceptability of medicines used in the University Medical Centre Ibn Sina (CHIS) of Rabat, Morocco, an observational study was conducted. Using a multivariate approach integrating the many aspects of acceptability, standardized observer reports were collected for 570 medicine intakes in patients up to the age of 16, then analyzed on a reference framework. Tablets appeared to be well accepted in children greater than 6 years old, but were crushed/dissolved for 90% of the 40 children aged from 3 to 5, and 100% of the 38 patients younger than 3. Moreover, the prescribed dose was fully taken for only 52% and 16% of these younger children, respectively. Despite this, tablets represented 24% of evaluations in children from 3 to 5 and 20% in infants and toddlers. Oral liquid preparations appeared to be better accepted than tablets in preschoolers, but not for those under 3. Overall, these findings highlight the lack of suitable alternatives for the younger children, especially for formulations of antiepileptics, antithrombotic, and psycholeptic agents in the local context.

The pharmacist's role in managing and ameliorating childhood's asthma care: a descriptive and transversal study about 104 pharmacists in the city of Rabat in Morocco.

This work aims at enhancing the management of childhood asthma, with a focus on pharmacists in particular, by evaluating their knowledge of childhood asthma and assessing their attitude while they are providing asthma medicines. Consequently, it will look at the necessity of introducing training days about childhood asthma for pharmacists. This is a transversal and descriptive study which lingered from August to October 2015. Data has been collected using a questionnaire that was self-administered to every surveyed pharmacist in the city of Rabat. The 104 pharmacists who replied to the questionnaire have an average general understanding about asthma and its treatment. Only a quarter of them managed an asthma crisis in their pharmacy before directing the child to the emergency. 50% of them do not know the difference between the basic asthma therapy and the asthma attack therapy. However, all of them recommended the parents to see a physician regarding their child's asthma. 75% advise the systematic use of an asthma spacer with the inhaler. 87.5% of them give advice to parents regarding the good measures for environmental control, and 98% estimate that the therapeutic education is important in childhood asthma management. 88.5% among them are interested in training days about childhood asthma.This study shows the necessity of further pharmacists' education about asthma and its management.

[Epidemiological profile of respiratory diseases in children hospitalized at the Rabat Children's Hospital, Morocco]. / Profil épidémiologique des pathologies respiratoires chez l'enfant à l'Hôpital d'Enfants de Rabat, Maroc.

INTRODUCTION: Respiratory diseases are a common cause of pediatric hospitalization. This study aimed to evaluate the epidemiological profile of respiratory diseases among children at the Rabat Children's Hospital, Morocco. METHODS: We conducted an observational-cross sectional study of all children aged 3 months to 15 years hospitalized for respiratory disease at the Department of Pneumoallergology and Pediatric Infectious Diseases at the Rabat Children's Hospital, Morocco over a one-year period, from 1 January 2014 to 31 December 2014. RESULTS: Out of 3537 hospitalized patients, 2493 (70.5%) had respiratory disease. Hospitalizations due to asthmatic exacerbation (p < 0.001), acute bronchiolitis (p < 0.001) and laryngeal dyspnoea (p = 0.004) were more frequent among boys, while hospitalizations due to acute pneumonia (p = 0.005), inhalation of a foreign body (p = 0.007) and pertussis (p = 0.020) were frequent among girls. Hospitalizations due to acute pneumonia (p < 0.001), exacerbation of serious viral disease sequelae (p < 0.001) and pertussis (p < 0.001) were more frequent among infants. Hospitalizations due to acute pneumonia (p < 0.001) and pertussis (p = 0.015) were more frequent during the autumn-winter period. CONCLUSION: The causes of hospitalization were dominated by asthmatic exacerbations and acute bronchiolitis, which were more frequent among boys. Respiratory infections, such as acute pneumonitis and pertussis, were more frequent during the autumn-winter period and mainly affected the infants.

Grisel's syndrome: a rare complication following traditional uvulectomy.

A case is reported of an eight-month-old female patient who had traditional uvulectomy for sore throat complicated by Grisel's syndrome. She was admitted into the hospital one week after uvulectomy with Torticolis. Grisel's syndrome is a nontraumatic atlantoaxial subluxation, usually secondary of an infection or an inflammation at the head and neck area, or after surgery in the same area. Patients typically suffer from painful torticollis. Diagnosis of Grisel's syndrome is largely based on suspicion of the patient who has recently undergone surgery or has a history of an infection in head and neck area. Physical examination and imaging techniques assist in diagnosis. Thus, clinicians should be aware of acute nontraumatic torticollis if patient had a recent surgery in the head or neck area or undergone an upper respiratory tract infection. In this paper, a case of an eight-month-old female patient who had Grisel's syndrome after uvulectomy is discussed. This case is reported to highlight this neurogical threatening complication following traditional uvulectomy as well as highlighting the unnecessary morbidity and mortality associated with this persisting mode of treatment in Africa.

Knowledge gaps on paediatric respiratory infections in Morocco, Northern Africa.

BACKGROUND: The burden of acute respiratory infections (ARI) among Moroccan children remains significant. However, scarce information is available regarding trends in its epidemiology and etiology, or regarding its associated prognostic factors. The purpose of this work was to review available data on the burden of ARI among children under five years of age in Morocco. METHODS: A systematic review was conducted for the period 1997-2014 using the PRISMA proposed methodology. Various online databases were screened, in addition to physical libraries of Moroccan medical schools, and official reports of the Moroccan Ministry of Health. Search queries in English and French languages included: Respiratory Tract Infections, pneumonia, epidemiology, etiology, microbiology, mortality and Morocco. The documents were included for analysis when they reported original data on the incidence, distribution, or a clinical description of the diseases or their etiology or described clinical management or national preventive strategies. RESULTS: Thirty-two documents were included in the final analysis. 21 of which had been published. In 2012, ARI caused 13% of paediatric deaths, half of the consultations at health facilities and third of the paediatric admissions. The microorganisms more frequently identified among hospitalized children were Streptococcus pneumoniae (38%) and Haemophilus influenza type b (Hib) (15%). The MOH introduced Hib vaccines into the national immunization program (PNI) in 2007and the 13-valent vaccine against pneumococcus in 2010. The national first line antibiotics recommended for non-severe ambulatory treatment is Amoxicillin. Studies of antibiotic resistance showed from 1998 to 2008 a 22% increase in the rate of penicillin non-susceptibility among Streptococcus pneumoniae isolates. Viral respiratory infections and the role attributed to air pollution in the incidence of ARI have been poorly characterized. CONCLUSIONS: Further efforts should be made towards the development of adequate surveillance programs to better clarify the epidemiology, etiology, antimicrobial susceptibility patterns and the effectiveness of the preventives and curatives strategies in place against paediatric ARIs in Morocco. Additionally, a holistical approach should be used to identify the heath determinants of ARIs among children.

Risk factors for a poor outcome among children admitted with clinically severe pneumonia to a university hospital in Rabat, Morocco.

OBJECTIVES: Data on prognostic factors among children with severe pneumonia are scarce in middle-income countries. We investigated prognostic factors for an adverse outcome among children admitted to the Hôpital d'Enfants de Rabat, Morocco with World Health Organization-defined clinically severe pneumonia (CSP). METHODS: Children aged 2-59 months admitted to the hospital and fulfilling the CSP definition were recruited into this 13-month prospective study. A poor prognosis was defined as death, a need for intensive care, or a Respiratory Index of Severity in Children (RISC) score ≥3. Multivariate logistic regression was performed to ascertain independent predictive factors for a poor prognosis. RESULTS: Of the 689 children included in this analysis, 55 (8.0%) required intensive care and 28 died (4.0%). Five hundred and two (72.8%) children were classified as having a good prognosis and 187 (27.2%) as having a poor prognosis. A history of prematurity (odds ratio (OR) 2.50, 95% confidence interval (CI) 1.24-5.04), of fever (OR 2.25, 95% CI 1.32-3.83), living in a house with smokers (OR 1.79, 95% CI 1.18-2.72), impaired consciousness (OR 10.96, 95% CI 2.88-41.73), cyanosis (OR 2.09, 95% CI 1.05-4.15), pallor (OR 2.27, 95% CI 1.34-3.84), having rhonchi on auscultation (OR 2.45, 95% CI 1.58-3.79), and human metapneumovirus infection (OR 2.13, 95% CI 1.13-4.02) were all independent risk factors for an adverse outcome, whereas a history of asthma (OR 0.46, 95% CI 0.25-0.84) was the only independent risk factor for a positive outcome. CONCLUSIONS: The early identification of factors associated with a poor prognosis could improve management strategies and the likelihood of survival of Moroccan children with severe pneumonia.

Antibiotic Usage Prior and During Hospitalization for Clinical Severe Pneumonia in Children under Five Years of Age in Rabat, Morocco.

Scarce and limited epidemiological, clinical and microbiological data are available regarding pediatric respiratory tract infections in the Kingdom of Morocco, a middle-income country in Northwestern Africa. Data on antibiotic usage for such infections are also scarce. A good understanding of pre-admission and intra-hospital usage of antibiotics in children with respiratory infections linked with an adequate surveillance of the antibiotic susceptibility from circulating pathogens could help policy makers improve their recommendations on management of respiratory infections. We hereby present data on antibiotic usage prior and during admission and antibiotic susceptibility of major circulating respiratory pathogens in children under five years of age admitted to the Hôpital d'Enfants de Rabat, Morocco, with a diagnosis of clinical severe pneumonia (using World Health Organization (WHO) standardized case definitions) during a period of 14 months (November 2010-December 2011), as part of a larger hospital-based surveillance study designed to understand the etiology and epidemiology of severe pneumonia cases among children.

Clinical features of the initial cases of 2009 pandemic influenza A (H1N1) virus infection in an university hospital of Morocco.

BACKGROUND: The first case of 2009 pandemic influenza A (H1N1) virus infection in our center was documented on June 15. Subsequently, persons with suspected cases of infection and contacts of those with suspected infection were tested. Persons in whom infection was confirmed were hospitalized and quarantined, and some of them were closely observed for the purpose of investigating the nature and duration of the disease. The aim of the present study was to describe baseline characteristics, treatment, outcomes, hospital length of stay and mortality of the first 186 cases of influenza A (H1N1) virus infection, with special interest in those developing severe respiratory failure with intensive care unit (ICU) care requirement. METHODS: observational study of 186 consecutive cases of influenza A (H1N1) virus infection admitted in 3 departments that were reference centers for the care of patients with influenza A and 4 ICU in Ibn Sina university hospital (Rabat, Morocco) between June and December 2009. Real time reverse-transcriptase-polymerase-chain-reaction (RT-PCR) testing was used to confirm infection. Demographic data, symptoms, comorbid conditions, illness progression, laboratory and chest radiologic findings, treatments, clinical outcomes and ICU care requirement were closely monitored. RESULTS: The mean age of the 186 patients was 17.6 ± 14.8 years, 47.8% had less than 14 years and 57% were male. The median duration of symptoms before hospital admission was 3 days (interquartile range (IQR): 2-5). The most common symptoms were fever (in 91.5% of the patients), cough in 92.5%, and nasal congestion in 62.4%. Twenty four percent of patients had comorbid respiratory disorders and 7.5% were pregnant. Abnormalities in chest radiography were detected in 26.3% of 186 patients on admission or after hospitalization. Twenty patients have required ICU care and 10 have required mechanical ventilation. The hospital length of stay was 5 days (IQR: 4-5). The following were risk factors of ICU admission: older age (p = 0.03), long duration of symptoms (p = 0.07), asthma (p = 0.01), obesity (P < 0.001), abnormalities of chest radiography (P < 0.001), leukocytosis (p = 0.005), and higher C-reactive protein (CRP) (P < 0.001). The ICU length of stay was 4 days (IQR: 3-6.7). The mortality rate was 3.5% among all patients and 30% among ICU patients. CONCLUSIONS: Close observation of patients infected with the 2009 pandemic influenza A (H1N1) virus infection provided us with several information. The influenza A (H1N1) virus infection affected young people particularly, with comorbid respiratory disorders. Risk factors of ICU admission were older age, long duration of symptoms, asthma, obesity, abnormalities of chest radiography, leukocytosis and higher CRP. Clinicians should be aware of complications of influenza A (H1N1) virus infection, particulary in patients with risk factors.