Introduction Cystic fibrosis (CF) is a life-shortening genetic disorder traditionally mischaracterised as affecting only populations of European descent. This framing has contributed to under-recognition of CF in African populations, despite emerging evidence of both common and region-specific cystic fibrosis transmembrane conductance regulator mutations across the continent. Diagnostic barriers, structural inequities and lack of surveillance further exacerbate disparities in care and visibility.Methods and analysis This scoping review aims to characterise CF in African populations by synthesising evidence on clinical presentation, diagnostic practices, genotypic diversity, prevalence and structural barriers to care. We will include case reports, cohort studies, registry analyses and other primary data sources involving individuals of African descent with suspected or confirmed CF. Key outcomes include clinical phenotype, age at diagnosis, mutation profile, diagnostic testing access and mortality. Data sources include Ovid Medline, Embase, Ebsco Global Health, CAB Abstracts and Web of Science Core Collection. Multiple-reviewer screening and extraction will be conducted. We will use narrative synthesis, thematic analysis and meta-analysis for prevalence where feasible.Ethics and dissemination No ethical approval is required as the review uses published data. Results will be shared with clinicians, researchers and CF networks in Africa and globally to inform diagnostic strategies and policy.

Background Severe acute bronchiolitis (SAB) can be life-threatening for infants and may be responsible for the congestion of intensive care units (ICU) during epidemics. We aimed to study the clinical and paraclinical characteristics of patients with SAB requiring a transfer to the ICU in order to examine their outcomes and to identify the predictors of a stay of ≥7 days and/or death. Methods This was a cross-sectional retrospective study including infants aged ≤12 months transferred to the ICU for their first episode of SAB between 1 January 2010 and 31 December 2019. Results We collected data on 380 patients with a median age of 1.75 months. They had a history of prematurity (20.53 %), low birth weight (18.68 %), parental atopy (12.89 %), and comorbidity (7.37 %, mainly congenital heart disease [5 %]). The leading cause of transfer was hypoxemia and increased oxygen requirements (49.73 %). The patients required mechanical ventilation (MV) in 63.42 % of the cases and noninvasive ventilation (NIV) in 67.63 %. NIV has supplanted MV over the years. Its use has increased from 40.4 % in 2010 to 96 % in 2019 compared with 83.84 % and 42 % for MV. A total of 14 (3.68 %) patients died. The independent predictors of a stay of ≥7 days and/or death were young age ≤2 months (p = 0.002), failure to thrive (p = 0.006), apnea (p = 0.045), dehydration (p = 0.018), the presence of biological inflammatory reaction (p = 0.002), isolation of respiratory syncytial virus (p < 0.001), and bacterial coinfection (p = 0.013).NIV was a protective factor (p < 0.001). A severity score ranging from 0 to 17 was established with an optimal cut-off value of 5 points. Conclusion Specific caution is needed in patients with these severity predictors. The generalization ofNIV in general pediatrics departments would improve SAB management and reduce transfers to the ICU.

This is the final of four papers updating standards for the care of people with CF. That this paper “Planning a longer life” was considered necessary, highlights how much CF care has progressed over the past decade. Several factors underpin this progress, notably increased numbers of people with CF with access to CFTR modulator therapy.As the landscape for CF changes, so do the hopes and aspirations of people with CF and their families. This paper reflects the need to consider people with CF not as a “problem” to be solved, but as a success, a potential and a voice to be heard. People with CF and the wider CF community have driven this approach, reflecting many of the topics in this paper. This exercise involved wide stakeholder engagement. People with CF are keen to contribute to research priorities and be involved in all stages of research. People with CF want healthcare professionals to respect them as individuals and consider the impact of our actions on the world around us.Navigating life presents challenges to all, but for people with CF these challenges are heightened and complex. In this paper we highlight the concerns and life moments that impact people with CF, and events that the CF team should aim to support, including the challenges around having a family.People with CF and their care teams must embrace the updated standards outlined in these four papers to enjoy the full potential for a healthier life.

Candida albicans chronically colonizes the respiratory tract of patients with Cystic Fibrosis (CF). It competes with CF-associated pathogens (e.g. Pseudomonas aeruginosa) and contributes to disease severity. We hypothesize that C. albicans undergoes specific adaptation mechanisms that explain its persistence in the CF lung environment. To identify the underlying genetic and phenotypic determinants, we serially recovered 146 C. albicans clinical isolates over a period of 30 months from the sputum of 25 antifungal-naive CF patients. Multilocus sequence typing analyses revealed that most patients were individually colonized with genetically close strains, facilitating comparative analyses between serial isolates. We strikingly observed differential ability to filament and form monospecies and dual-species biofilms with P. aeruginosa among 18 serial isolates sharing the same diploid sequence type, recovered within one year from a pediatric patient. Whole genome sequencing revealed that their genomes were highly heterozygous and similar to each other, displaying a highly clonal subpopulation structure. Data mining identified 34 non-synonymous heterozygous SNPs in 19 open reading frames differentiating the hyperfilamentous and strong biofilm-former strains from the remaining isolates. Among these, we detected a glycine-to-glutamate substitution at position 299 (G299E) in the deduced amino acid sequence of the zinc cluster transcription factor ROB1 (ROB1G299E), encoding a major regulator of filamentous growth and biofilm formation. Introduction of the G299E heterozygous mutation in a co-isolated weak biofilm-former CF strain was sufficient to confer hyperfilamentous growth, increased expression of hyphal-specific genes, increased monospecies biofilm formation and increased survival in dual-species biofilms formed with P. aeruginosa, indicating that ROB1G299E is a gain-of-function mutation. Disruption of ROB1 in a hyperfilamentous isolate carrying the ROB1G299E allele abolished hyperfilamentation and biofilm formation. Our study links a single heterozygous mutation to the ability of C. albicans to better survive during the interaction with other CF-associated microbes and illuminates how adaptive traits emerge in microbial pathogens to persistently colonize and/or infect the CF-patient airways.

The incapacity to synthesize certain components of pulmonary surfactant causes a heterogeneous group of rare respiratory diseases called genetic disorders of surfactant dysfunction. We report a female full-term infant with neonatal respiratory distress of early onset due to inherited SP-B deficiency. The infant failed oxygen weaning at multiple trials. Chest computed tomography was performed on the 29th day of life revealing ground-glass opacities, regular interlobular septal thickening and fine interlobular reticulations. Analysis of genomic DNA showed homozygosity for an extremely rare SFTPB gene variant (c.620A>G, p.Tyr207Cys). Both parents were heterozygotes for the mutation. The diagnosis of congenital SP-B deficiency should be suspected whenever an early and acute respiratory failure in a term or near-term infant does not resolve after five days of age: diagnostic confirmation can be easily and rapidly obtained with the analysis of genomic DNA.

Pediatric PulmonologyVolume 57, Issue 10 p. 2540-2541 LETTER Up-to-date incidence and initial characteristics of cystic fibrosis in Tunisia Samia Hamouda, Corresponding Author Samia Hamouda [email protected] orcid.org/0000-0003-2006-9390 Children's Department B, Bechir Hamza Children's Hospital of Tunis, Faculty of Medicine of Tunis, University Al Manar, Tunis, Tunisia Correspondence Samia Hamouda, Children's Department B, Bechir Hamza Children's Hospital of Tunis, Faculty of Medicine of Tunis, University El Manar, 1007 Tunis, Tunisia. Email: [email protected]Search for more papers by this authorSondess Hadj Fredj, Sondess Hadj Fredj Referral Biochemistry Laboratory, Bechir Hamza Children's Hospital of Tunis, Faculty of Medicine of Tunis, University Al Manar, Tunis, TunisiaSearch for more papers by this authorTaieb Messaoud, Taieb Messaoud Referral Biochemistry Laboratory, Bechir Hamza Children's Hospital of Tunis, Faculty of Medicine of Tunis, University Al Manar, Tunis, TunisiaSearch for more papers by this authorVirginie Scotet, Virginie Scotet UMR 1078, Inserm, Univ Brest, EFS, GGB, Brest, FranceSearch for more papers by this authorKhadija Boussetta, Khadija Boussetta Children's Department B, Bechir Hamza Children's Hospital of Tunis, Faculty of Medicine of Tunis, University Al Manar, Tunis, TunisiaSearch for more papers by this authorAnne Munck, Anne Munck orcid.org/0000-0003-2331-278X CF Centre, Hopital Necker Enfants Malades, Paris, France Société Française du Dépistage Neonatal (SFDN), Paris, FranceSearch for more papers by this author Samia Hamouda, Corresponding Author Samia Hamouda [email protected] orcid.org/0000-0003-2006-9390 Children's Department B, Bechir Hamza Children's Hospital of Tunis, Faculty of Medicine of Tunis, University Al Manar, Tunis, Tunisia Correspondence Samia Hamouda, Children's Department B, Bechir Hamza Children's Hospital of Tunis, Faculty of Medicine of Tunis, University El Manar, 1007 Tunis, Tunisia. Email: [email protected]Search for more papers by this authorSondess Hadj Fredj, Sondess Hadj Fredj Referral Biochemistry Laboratory, Bechir Hamza Children's Hospital of Tunis, Faculty of Medicine of Tunis, University Al Manar, Tunis, TunisiaSearch for more papers by this authorTaieb Messaoud, Taieb Messaoud Referral Biochemistry Laboratory, Bechir Hamza Children's Hospital of Tunis, Faculty of Medicine of Tunis, University Al Manar, Tunis, TunisiaSearch for more papers by this authorVirginie Scotet, Virginie Scotet UMR 1078, Inserm, Univ Brest, EFS, GGB, Brest, FranceSearch for more papers by this authorKhadija Boussetta, Khadija Boussetta Children's Department B, Bechir Hamza Children's Hospital of Tunis, Faculty of Medicine of Tunis, University Al Manar, Tunis, TunisiaSearch for more papers by this authorAnne Munck, Anne Munck orcid.org/0000-0003-2331-278X CF Centre, Hopital Necker Enfants Malades, Paris, France Société Française du Dépistage Neonatal (SFDN), Paris, FranceSearch for more papers by this author First published: 06 June 2022 https://doi.org/10.1002/ppul.26032Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat No abstract is available for this article. REFERENCES 1Scotet V, Gutierrez H, Farrell PM. Newborn screening for CF across the globe -where is it worthwhile? Int J Neonatal Screen. 2020; 6:18. doi:10.3390/ijns6010018 10.3390/ijns6010018 PubMedWeb of Science®Google Scholar 2Castellani C, Duff A, Bell SC, et al. ECFS best practice guidelines: the 2018 revision. J Cyst Fibros. 2018; 17: 153-178. doi:10.1016/j.jcf.2018.02.006 10.1016/j.jcf.2018.02.006 PubMedWeb of Science®Google Scholar 3Hider AM. Cystic fibrosis in the Middle East: an awareness analysis. J Cyst Fibros. 2019; 18: e40-e41. doi:10.1016/j.jcf.2018.12.002 10.1016/j.jcf.2018.12.002 PubMedGoogle Scholar 4Guo J, Garratt A, Hill A. Worldwide rates of diagnosis and effective treatment for cystic fibrosis. J Cyst Fibros. 2022; S1569-1993(22): 00031-00035. doi:10.1016/j.jcf.2022.01.009 Google Scholar 5Hamouda S, Fredj SH, Hilioui S, et al. Preliminary national report on cystic fibrosis epidemiology in Tunisia: the actual state of affairs. Afr Health Sci. 2020; 20: 444-452. doi:10.4314/ahs.v20i1.51 10.4314/ahs.v20i1.51 PubMedWeb of Science®Google Scholar Volume57, Issue10October 2022Pages 2540-2541 ReferencesRelatedInformation

INTRODUCTION:Children's Interstitial Lung Diseases (cHILD) are a heterogeneous group of rare respiratory diseases. Their common characteristics are gas exchange abnormalities and diffuse pulmonary infiltrates on chest imaging. This group includes inherited surfactant protein deficiency (ISPD), a little-known etiology in Tunisia.CASE PRESENTATION:A 22-month-old boy was referred to investigate recurrent respiratory infections. He had polypnea, cyanosis, finger clubbing, pectus carinatum, intercostal retraction, and bilateral crackles on pulmonary auscultation. The chest imaging revealed a diffuse ground-glass appearance consistent with cHILD. Lung biopsy was suggestive of ISPD. The infant was mainly treated with intravenous corticosteroids. At the age of nine, he was still dependent on oxygen but had better exercise tolerance.CONCLUSION:This case showed that recurrent respiratory infections can hide cHILD which may be related to ISPD, particularly in infants. A better knowledge of this disease was necessary to start specific treatment. Early management would lead to better prognosis.

Langerhans cell histiocytosis (LCH) is a rare disorder of clonal proliferation of dendritic cell mostly seen in children. It consists in various clinical manifestations from a single lytic bone lesion to multisystemic lesions with organ dysfunction. Atlantoaxial involvement by LCH is very rare, especially in a young child. We report a rare case of the cervical spine LCH resulting in dragging torticollis as the first symptom lasting for 4 weeks in a 6-year-old boy. Histological features were consistent with the diagnosis. The patient received chemotherapy with steroids and he underwent a laminectomy with arthrodesis. He remained well with no evidence of recurrence during the follow-up period. The rarity of this disease as well as the site of bone involvement draws attention for early diagnosis to prevent neurological lesions and other late complications.

Background: Mutations in the ATP-binding cassette transporter A3 (ABCA3) gene are one of the most common surfactant disorders leading to interstitial lung diseases (ILD). The clinical spectrum and severity of lung disease caused by ABCA3 deficiency due to missense variants is variable. Case Presentations: A novel ABCA3 c.3135G>C (p.Gln1045His) mutation was identified at the homozygous state in 3 subjects from 2 unrelated families: one 19-month-old boy with severe ILD and his homozygous pauci-symptomatic mother, and one 10-year-old girl with moderate late-onset ILD. Corticosteroid pulses associated with hydroxychloroquine were beneficial for both children. Conclusion: We illustrate here the huge intra- and interfamilial phenotypic variability associated with the same homozygous missense ABCA3 mutation, and the benefit of identifying the disease for treatment, follow-up, and appropriate genetic counseling.

"Instability of Mature ABCA3 Protein: Toward a New Classification of ABCA3 Mutations?." American Journal of Respiratory Cell and Molecular Biology, 67(5), pp. 602–605

A female-term neonate showed a severe respiratory distress syndrome (RDS) at hour 3 of life requiring her transfer to intensive care. She was intubated and started on assist-control mechanical ventilation associated with inhaled nitric oxide then high-frequency oscillation ventilation at day 12. Chest X-ray was gradually deteriorating. Chest computed tomography (CT) scan revealed diffuse interstitial lung disease. Flexible bronchoscopy excluded pulmonary alveolar proteinosis. The genetics study confirmed surfactant protein-B (SP-B) deficiency caused by the novel homozygous c.770T>C, p.Leu257Pro mutation in the SFTPB gene (NM_000542.5). Methylprednisolone pulse therapy was administered from day 20. As the infant worsened, azithromycin, sildenafil, and inhaled steroids were added at the age of 6 months and azathioprine at the age of 10 months. At the age of 12 months, chest CT showed diffuse "crazy-paving." The infant died of respiratory failure at the age of 13 months. Unexplained neonatal RDS should raise the suspicion of SP-B disease. This novel mutation could be part of the mutations allowing partial SP-B production result in prolonged survival. Lung transplant in infants, unavailable in numerous countries, remains the unique way to reverse the fatal outcome.

Candida albicans colonizes the respiratory tract of patients with Cystic Fibrosis (CF). It competes with CF-associated pathogens, such as Pseudomonas aeruginosa and Staphylococcus aureus , and contributes to disease severity. We serially recovered 160 C. albicans clinical isolates over a period of 30 months from the sputum of 23 pediatric and 2 adult antifungal-naive CF patients at Children’s Hospital Tunis and characterized the genotype and phenotype of a subset of strains using multilocus sequence typing (MLST) and growth assays on multiple stress-, filamentous growth- and biofilm-inducing media. Out of 16 patients regularly sampled for at least 9 months, 8 and 4 were chronically and transiently colonized with C. albicans , respectively. MLST analyses of 56 strains originating from 15 patients indicated that each patient was colonized with a single strain, while 8 patients (53%) carried isolates from clade 4 known to be enriched with strains from Middle East-Africa. A subset of these isolates with the same sequence type and colonizing 3 unrelated patients displayed altered susceptibility to cell wall-perturbing agents, suggesting changes in cell wall structure/function during growth in the CF lung. We also observed differential ability to filament and/or form biofilms in a set of identical isolates from clade 10 sampled over a period of 9 months in a pediatric CF patient, suggesting alterations in phenotypes associated with virulence. Our findings will rely on future whole-genome sequencing analyses to identify polymorphisms that could explain the emergence of new traits in C. albicans strains thriving in the CF host environment.

BACKGROUND & OBJECTIVES:Cystic fibrosis (CF) is caused by mutations in the gene encoding the CF transmembrane regulator (CFTR) protein, a chloride channel located in the epithelial cell membrane. Over than 2,000 CFTR mutations have been identified, which contribute to the variety of clinical phenotypes of CF. We performed a case-control study to determine p.Met470Val (M470V), p.Thr854= (T854) and p.Gln1463= (Q1463) polymorphisms frequencies in CF patients and healthy controls and to elaborate haplotype based on these SNPs.METHODS:The genotyping of M470V (exon 10), T854 (exon 14a), and Q1463 (exon 24) variants were identified using polymorphism restriction fragment length polymorphism (RFLP).RESULTS & CONCLUSION:Statistical difference was noted in the genotype distribution of two markers, M470V and T854, between CF and control groups. However, the Q1463 polymorphism is not identified in two studied groups. Three haplotypes were found in CF patients and controls. An exclusive association between the ancestral haplotype 1-1-2 and p.Phe508del (F508del) mutation was shown. In Tunisia, this is the first work to be interested in the analysis of M470V, T854 and Q1463 polymorphisms and haplotypes associated with the most common mutation, F508del, in the Tunisian population and worldwide.

Aim: To establish a preliminary national report on clinical and genetic features of cystic fibrosis (CF) in Tunisian children as a first measure for a better health care organization.Methods: All children with CF diagnosed by positive sweat tests between 1996 and 2015 in children's departments of Tunisian university hospitals were included. Data was recorded at diagnosis and during the follow-up from patients' medical records.Results: In 12 departments, 123 CF children were collected. The median age at diagnosis was 5 months with a median diagnosis delay of 3 months. CF was revealed mostly by recurrent respiratory tract infections (69.9%), denutrition (55.2%), and/ or chronic diarrhea (41.4%). The mean sweat chloride concentration was 110.9mmol/L. At least one mutation was found in 95 cases (77.2%). The most frequent mutations were Phe508del (n=58) and E1104X (n=15). Fifty-five patients had a Pseudomonas Aeruginosa chronic colonization at a median age of 30 months. Cirrhosis and diabetes appeared at a mean age of 5.5 and 12.5 years respectively in 4 patients each. Sixty-two patients died at a median age of 8 months. Phe508del mutation and hypotrophy were associated with death (p=0.002 and p<0.001, respectively).Conclusion: CF is life-shortening in Tunisia. Setting-up appropriate management is urgent.

•International Women's day on 6th March is focussed on gender equity.•We are an international panel of women working in cystic fibrosis, who have come together at this time to raise awareness of gender issues.•Gender issues affect our patient population, in whom there is a gap in outcomes in many patient registries globally, with women being at a clinical disadvantage.•We provide anecdotal examples of the challenges we have faced personally in our careers, and examples of good practice (and those requiring improvement) from our various regions.•We wish to motivate our male colleagues to be supportive allies, our institutions and professional societies to actively consider areas of good practice and, most importantly, the next generation of CF clinicians and researchers to strive for an equitable and fair future.

West Nile virus is currently one of the most widely distributed zoonotic arbovirus in the world, progressing into epidemics in many countries. While most infected patients experience mild to no symptoms, thousands of West Nile virus-associated neuroinvasive cases, presenting as meningitis, encephalitis, or acute flaccid paralysis, have been reported, even in children. However, few neonatal cases have been described in literature. West Nile Virus neuroinvasive disease can lead to severe neurological disability or death, especially in infant. We report the first tunisian case of West Nile Virus meningoencephalitis in a newborn and its outcome.

L’oxygénothérapie avec lunettes nasales à haut débit (LNHD) est une nouvelle technique de ventilation non invasive dont l’apport dans la prise en charge de la bronchiolite est en cours d’évaluation. Le but de notre étude est d’évaluer l’efficacité de cette technique et sa sûreté dans la prise en charge de la bronchiolite sévère. Il s’agit d’une étude rétrospective incluant les cas de bronchiolite sévère, âgés de moins de 1 an. Nous avons comparé deux groupes : – un premier groupe incluant les cas de bronchiolite sévère ayant bénéficié d’une oxygénothérapie avec LNHD (n = 42) ; – un deuxième groupe incluant les cas de bronchiolite sévère mis sous oxygénothérapie conventionnelle, par faute de disponibilité de LNHD. Le seuil de signification des tests statistiques était fixé à 5 %. L’âge moyen de notre population était de 2,3 mois ± 1,5. Le score de Wang, la fréquence respiratoire, la saturation en oxygène et les signes de luttes à H24 étaient améliorés dans le groupe oxygénothérapie avec LNHD comparé au groupe oxygénothérapie conventionnelle. Aucun pneumothorax ou pneumo-médiastin n’a été noté dans le groupe oxygénothérapie avec LNHD. Le transfert en réanimation secondairement était plus fréquent dans le groupe ayant bénéficié d’oxygénothérapie conventionnelle. Un score de Wang ≥ 7 était un facteur de risque indépendant d’échec de l’oxygénothérapie avec LNHD. L’oxygénothérapie avec LNHD semble une technique efficace et dénuée de risque dans la prise en charge de la bronchiolite. Elle semble prévenir le transfert en unité de soins intensifs dans 60 % des cas.

BACKGROUND:Due to the marked decline of maternal-fetal rhesus incompatibility, ABO alloimmunization has become the leading cause of the newborn hemolytic disease. It is estimated that 15-25 % of all pregnancies are concerned by ABO incompatibility.AIM:Neonatal blood group B seems to be more predisposing to acute hemolysis and severe hyperbilirubinemia. We propose to find if the newborn's blood group B represents a risk factor for severe hemolysis and/or severe hyperbilirubinemia.METHODS:We conducted a comparative study in the pediatrics department "B" of the Children Hospital of Tunis. We collected retrospectively the medical files of the newborn hospitalized for ABO alloimmunization (January 2011 - March 2014), then we compared two groups, OA group with OA alloimmunization and OB group with OB alloimmunization. A significant threshold was fixed to 0.05.RESULTS:We collected 98 cases of newborn ABO hemolytic disease. Both groups, OA and OB, were similar for the onset of jaundice, age of hospitalization, initial hemoglobin and indirect bilirubin levels. There were no statistically significant difference in the severity of hyperbilirubinemia and the use of exchange transfusion for the two groups. However, transfusion was statistically more frequent in the OB group compared to OA group (81.6‰ vs 10.2‰, p = 0,039, OR=2.9, 95% IC (1.1 - 7.8)).CONCLUSION:OB alloimmunization seems to induce more active hemolysis than OA one, with no difference for severe hyperbilirubinemia in both groups.

BACKGROUND:Cystic fibrosis is rare in Tunisia. Its diagnosis requires experienced specialists. Its prognosis is poor in developing countries.OBJECTIVES:To study the epidemiologic, clinical, genetic features and the therapeutic challenges of cystic fibrosis in Tunisian children.METHODS:Covering a period of 21 years, this retrospective study included all patients with a definite diagnosis of cystic fibrosis from the Pediatrics Department B of The Children's Hospital of Tunis.RESULTS:Data from 32 children (14 boys and 18 girls) were collected. The diagnosis was made during the first year of life in 28 cases. Meconium ileus was found in 5 cases, respiratory manifestations in 22 cases, chronic diarrhea in 19 cases, faltering growth in 17 cases and a pseudo Barter syndrome in 2 cases. The sweat chloride test was positive in all cases. The most frequent mutation was F508del (56% of cases). Respiratory complications marked the outcome. Among our 32 patients, 15 patients (50%) died at an average age of 5 years and 3 months, mainly due to respiratory failure. The mean age of the surviving patients was 5 years.CONCLUSION:Cystic fibrosis prognosis is poor in our series compared to developed countries due to the longer diagnostic delay and the limited therapeutic options.