[Cystic fibrosis in Morroco : what do words mean without action ?] / Mucoviscidose au Maroc : que valent les mots sans les actes ?

It is estimated that in highly medicalised countries, median life expectancy for most newborns with cystic fibrosis now exceeds 70 years, approaching that of the general population. However, socio-economic disparities between countries continue to have a devastating impact on the prognosis of patients in Eastern Europe, Africa, India and South America. In Morocco, very limited genetic data suggest that the prevalence of this disease is at least of the same order as in Belgium. But as it is not really recognised by the national health system, patients are denied access even to symptomatic treatment. As a result, their outcome is tragic, similar to what it was 60 years ago in the most medicalised countries. A pilot project for a first paediatric reference centre in Casablanca is currently being set up. If properly resourced, this project can only be a success and should be the first step on the road towards cystic fibrosis care in this country. In a very humble way, several Belgian stakeholders are trying to support this project.

Dans les pays les plus médicalisés, l'espérance de vie médiane de la plupart des nouveau-nés atteints de mucoviscidose excède aujourd'hui 70 ans et se rapproche de celle de la population générale. Ailleurs, en Europe de l'Est comme en Afrique, en Inde ou en Amérique du Sud, les disparités socio-économiques des pays continuent à impacter très durement le pronostic des patients. Au Maroc, des données génétiques très fragmentaires suggèrent que la prévalence de la mucoviscidose est au moins du même ordre qu'en Belgique. Mais la maladie n'y est pas réellement reconnue par le système de santé, de telle sorte que même le traitement symptomatique reste inaccessible aux patients et leur pronostic est tragique, similaire à ce qu'il était il y a 60 ans dans les pays les plus médicalisés. À Casablanca, le projet pilote d'un premier Centre pédiatrique de Référence est en train de se mettre en place. S'il bénéficie d'un support adéquat, ce projet ne peut être qu'un succès et doit constituer un tout premier pas sur le chemin vers une prise en charge des patients dans ce pays. Très modestement, plusieurs intervenants belges tentent d'y apporter leur soutien.

[Stridor due to a subglottic hemangioma compressing the trachea]. / L'image du mois. Stridor secondaire à un hémangiome sous-glottique comprimant la trachée.

Subglottic haemangioma can cause stridor in young children, and sometimes be life-threatening. Larynx ultrasound is a useful, non-irradiating screening test, but the diagnosis must be confirmed by bronchial fibroscopy and injected chest CT scan. Nowadays propranolol is the first-line treatment. If treated early, the prognosis is excellent.

L'hémangiome sous-glottique peut être responsable d'un stridor chez le jeune enfant et, parfois, menacer le pronostic vital. L'échographie du larynx est un examen utile et non irradiant pour le dépistage, mais le diagnostic sera confirmé par une fibroscopie bronchique et un scanner thoracique avec injection de produit de contraste. Le traitement en première intention est le propranolol. Lors d'une prise en charge précoce, le pronostic est excellent.

[Cystic fibrosis - ETI and type 2 N-of-1 trials : the next step]. / Mucoviscidose : valider un traitement révolutionnaire par de brefs essais thérapeutiques individuels bien supervisés.

In evidence-based medicine, N-of-1 trials are increasingly attractive for rare and heterogeneous conditions. A recent French study illustrates this convincingly in the field of cystic fibrosis. A highly effective triple therapy (ETI) is currently available in Europe, which will eventually help the 85 % of Belgian patients carrying at least one copy of the F508del mutation. Most other 2.000 or so putative mutations of this gene are poorly characterised and very rare or private. To predict the efficacy of ETI at the individual level in currently ineligible patients, sophisticated tools are advocated, but they are expensive, not widely available, often partially standardised and there still remains a «grey area¼ concerning their reliability in this context. With-out using them, the French study suggests that more than half of these patients show clinically meaningful responses to a 4-6 weeks trial of ETI. What makes this pragmatic, cost-effective, non-invasive and simplified approach possible (type 2 N-of-1 trials) is the dramatic and rapid efficacy of a life-saving treatment without alternative and the fact that it can be assessed using simple and robust clinical and paraclinical outcomes. Here, we describe one such trial and discuss the value and limitations of this approach.

Dans la médecine basée sur les preuves, les essais de taille 1 suscitent un intérêt croissant dans les affections rares et hétérogènes. Une récente étude française l'illustre de manière convaincante dans la mucoviscidose. Une trithérapie extrêmement efficace (ETI) est actuellement disponible en Europe, concernant à terme en Belgique les 85 % de patients porteurs d'au moins une copie de la mutation F508del. La majorité des quelque 2.000 autres mutations putatives de ce gène sont mal caractérisées et rarissimes. Des techniques sophistiquées sont évoquées pour prédire, à l'échelle individuelle, l'efficacité d'ETI chez les patients actuellement non éligibles, mais elles sont peu disponibles, coûteuses, souvent imparfaitement standardisées et leur interprétabilité conserve une «zone grise¼. Sans y recourir, l'étude française montre que plus de la moitié de ces patients répondent d'une manière évidente à un essai d'ETI pendant quelques semaines seulement. Ce qui permet cette approche pragmatique, économique, non invasive et simplifiée (essai de taille 1, de type 2), c'est l'efficacité spectaculaire et rapide d'un traitement salvateur sans alternative et le fait qu'elle puisse être appréhendée à partir de critères cliniques et paracliniques simples et robustes. Nous rapportons ici un essai de ce type et discutons l'intérêt et les limites de cette approche.

[Recurrent atelectasis in an infant : about one case of false-negative newborn screening for cystic fibrosis]. / Atélectasie récidivante chez un nourrisson : à propos d'un cas de faux-négatif du dépistage néonatal pour la mucoviscidose.

In infants as well as in older children, persistent or recurrent atelectasis remains a classic indication for sweat testing, even if neonatal screening for cystic fibrosis has been considered normal. Atelectasis is a common complication of cystic fibrosis. Yet, it has rarely been reported in infants. In cystic fibrosis, chronic atelectasis worsens the prognosis, especially when involving a lower lobe. Therefore, early and effective intervention is required. Antibiotic therapy, intensive chest physiotherapy together with inhaled mucolytics often allow to relieve bronchial obstruction but bronchoscopy with local aspiration and Dornase alpha instillation is sometimes necessary. In a two-month-old infant, we describe here the first reported case of false-negative cystic fibrosis newborn screening in Belgium.

Chez le nourrisson comme chez l'enfant plus âgé, une atélectasie persistante ou récidivante reste une indication classique de test à la sueur, même si le dépistage néonatal de la mucoviscidose a été considéré comme normal. Rarement rapportées chez le nourrisson, les atélectasies sont une complication commune de la mucoviscidose. Dans cette affection, l'atélectasie chronique d'un territoire péjore le pronostic, en particulier si elle concerne un lobe inférieur. Une intervention précoce et efficace est donc requise. Antibiothérapie, kinésithérapie respiratoire intensive et recours aux fluidifiants par voie de nébulisation suffisent souvent à lever l'obstruction bronchique, mais une endoscopie avec aspiration locale et instillation de dornase alpha est parfois nécessaire. Chez un nourrisson de 2 mois, nous rapportons ici le premier cas de faux-négatif du programme belge de dépistage néonatal de la mucoviscidose.

[How I treat vitamin D intoxication in a child with cystic fibrosis]. / Comment je traite une intoxication à la vitamine D chez un enfant atteint de mucoviscidose.

At least 80 % of persons with cystic fibrosis are pancreatic insufficient and benefit from daily supplementation with fat-soluble vitamins (ADEK). Magistral formulations offer ideal flexibility for prescriptions tailored to vitamin A, D and E blood levels. However, they expose to human errors, mainly leading to vitamin D intoxication whose clinical features are related to hypercalcaemia. Symptoms are mostly digestive (vomiting, constipation, abdominal pain …) and, less frequently, renal (nycturia …) complaints. When symptoms and/or serum calcium levels ≥ 14 mg/100 ml are present, prompt management is required. Besides interruption of supplementation, rapid intravenous hyperhydration (saline) is essential. Once hydration has been restored, and still under close biological supervision, a loop diuretic (furosemide) may be used but the drug of choice to achieve rapid normalization of blood calcium levels will often be intravenous pamidronate. Normalization of serum vitamin 25(OH)-D levels may take several months but the prognosis is very good. In Belgium, the very late reimbursement of a fixed combination of fat-soluble vitamins (Dekas®) meeting the standards of the pharmaceutical industry is expected to reduce the incidence of these intoxications, at the price, however, of less flexible prescription.

Au moins 80 % des patients atteints de mucoviscidose présentent une insuffisance pancréatique exocrine et bénéficient quotidiennement d'une supplémentation en vitamines liposolubles (ADEK). Une préparation magistrale offre alors une souplesse idéale de prescription. Elle expose cependant à des erreurs humaines, qui mènent surtout à des intoxications à la vitamine D. Les symptômes, souvent surtout digestifs (vomissements, constipation, douleurs abdominales …), voire rénaux (nycturie …), sont liés à l'hypercalcémie. En cas de symptômes et/ou de calcémie ≥ 14 mg/100 ml, une prise en charge immédiate est nécessaire. Outre l'interruption de la supplémentation, elle inclut d'abord une hyperhydratation rapide, par voie intraveineuse (sérum physiologique). Une fois l'hydratation restaurée, et toujours sous contrôles biologiques rapprochés, un diurétique de l'anse (furosémide) peut être utilisé, mais c'est souvent une administration intraveineuse de pamidronate qui permettra la normalisation rapide de la calcémie. Le taux sérique de vitamine 25(OH)-D peut mettre plusieurs mois à se normaliser, mais le pronostic est très bon. Remboursée tardivement en Belgique, une combinaison fixe de vitamines liposolubles (Dekas®), répondant aux normes de l'industrie pharmaceutique, devrait limiter le nombre de ces intoxications au prix, toutefois, d'une moindre souplesse de prescription.

Management of parapneumonic pleural effusion in children: Is there a role for corticosteroids when conventional nonsurgical management fails? A single-center 15-year experience.

OBJECTIVE: Description of the use of corticosteroids for the management of parapneumonic pleural effusion in children. METHODS: Retrospective single-center observational study of all children hospitalized with a diagnosis of parapneumonic pleural effusion during a 15-year period. RESULTS: We documented 97 cases of parapneumonic effusion during the study period, with a median age (interquartile range [IQR]) of 43 (33-61) months. Most of the children benefited from an evacuation of the pleural effusion (89/97, 91.8%): 21 patients (21.6%) were treated with needle thoracocentesis only, while a chest tube was inserted in 68 children (70.1%). Thirty-two patients (33%) were treated with intrapleural fibrinolysis. Fifty-five children (56.7%) received corticosteroids for persistent fever. The median time (IQR) between hospital admission and initiation of corticosteroids was 5.5 (4-7) days. When corticosteroids were initiated, children had been febrile for 9 (IQR: 8-11) days. The fever ceased in a median (IQR) of 0 (0-1) day after corticosteroids initiation. Only one patient required a video-assisted thoracoscopy that was necessary for morphological reasons (morbid obesity). No children treated with corticosteroids required surgery. All children were discharged from hospital. The median (IQR) hospital length of stay was 11 (8-14) days, with no difference between children with and those without corticosteroids. CONCLUSION: Our findings indicate that corticosteroids may be a part of the therapeutic armamentarium for children with parapneumonic effusion when conventional nonsurgical management fails.

Genomics of an endemic cystic fibrosis Burkholderia multivorans strain reveals low within-patient evolution but high between-patient diversity.

Burkholderia multivorans is a member of the Burkholderia cepacia complex (Bcc), notorious for its pathogenicity in persons with cystic fibrosis. Epidemiological surveillance suggests that patients predominantly acquire B. multivorans from environmental sources, with rare cases of patient-to-patient transmission. Here we report on the genomic analysis of thirteen isolates from an endemic B. multivorans strain infecting four cystic fibrosis patients treated in different pediatric cystic fibrosis centers in Belgium, with no evidence of cross-infection. All isolates share an identical sequence type (ST-742) but whole genome analysis shows that they exhibit peculiar patterns of genomic diversity between patients. By combining short and long reads sequencing technologies, we highlight key differences in terms of small nucleotide polymorphisms indicative of low rates of adaptive evolution within patient, and well-defined, hundred kbps-long segments of high enrichment in mutations between patients. In addition, we observed large structural genomic variations amongst the isolates which revealed different plasmid contents, active roles for transposase IS3 and IS5 in the deactivation of genes, and mobile prophage elements. Our study shows limited within-patient B. multivorans evolution and high between-patient strain diversity, indicating that an environmental microdiverse reservoir must be present for this endemic strain, in which active diversification is taking place. Furthermore, our analysis also reveals a set of 30 parallel adaptations across multiple patients, indicating that the specific genomic background of a given strain may dictate the route of adaptation within the cystic fibrosis lung.

A coherent organization of differentiation proteins is required to maintain an appropriate thyroid function in the Pendred thyroid.

CONTEXT: Pendred syndrome is caused by mutations in the gene coding for pendrin, an apical Cl-/I- exchanger. OBJECTIVE: To analyze intrathyroidal compensatory mechanisms when pendrin is lacking, we investigated the thyroid of a patient with Pendred syndrome. The expression of proteins involved in thyroid hormone synthesis, markers of oxidative stress (OS), cell proliferation, apoptosis, and antioxidant enzymes were analyzed. RESULTS: Three morphological zones were identified: nearly normal follicles with iodine-rich thyroglobulin in the colloid (zone 1.a), small follicles without iodine-rich thyroglobulin in lumina (zone 1.b), and destroyed follicles (zone 2). In zones 1.a, dual oxidase (Duox) and thyroid peroxidase (TPO) were localized at the apical pole, OS and cell apoptosis were absent, but ClC-5 expression was strongly increased. In zones 1.b, Duox and TPO were aberrantly present and increased in the cytosol and associated with high OS, apoptosis, cell proliferation, and increased expression of peroxiredoxin-5, catalase, and dehalogenase-1 but moderate ClC-5 expression. CONCLUSION: In conclusion, the absence of pendrin is accompanied by increased ClC-5 expression that may transiently compensate for apical iodide efflux. In more affected follicles, Duox and TPO are relocated in the cytosol, leading to abnormal intracellular thyroid hormone synthesis, which results in cell destruction presumably because intracellular OS cannot be buffered by antioxidant defenses.

Role of caveolin-1 in thyroid phenotype, cell homeostasis, and hormone synthesis: in vivo study of caveolin-1 knockout mice.

In human thyroid, caveolin-1 is localized at the apex of thyrocytes, but its role there remains unknown. Using immunohistochemistry, (127)I imaging, transmission electron microscopy, immunogold electron microscopy, and quantification of H(2)O(2), we found that in caveolin-1 knockout mice thyroid cell homeostasis was disrupted, with evidence of oxidative stress, cell damage, and apoptosis. An even more striking phenotype was the absence of thyroglobulin and iodine in one-half of the follicular lumina and their presence in the cytosol, suggesting that the iodide organification and binding to thyroglobulin were intracellular rather than at the apical membrane/extracellular colloid interface. The latter abnormality may be secondary to the observed mislocalization of the thyroid hormone synthesis machinery (dual oxidases, thyroperoxidase) in the cytosol. Nevertheless, the overall uptake of radioiodide, its organification, and secretion as thyroid hormones were comparable to those of wild-type mice, suggesting adequate compensation by the normal TSH retrocontrol. Accordingly, the levels of free thyroxine and TSH were normal. Only the levels of free triiodothyronine showed a slight decrease in caveolin-1 knockout mice. However, when TSH levels were increased through low-iodine chow and sodium perchlorate, the induced goiter was more prominent in caveolin-1 knockout mice. We conclude that caveolin-1 plays a role in proper thyroid hormone synthesis as well as in cell number homeostasis. Our study demonstrates for the first time a physiological function of caveolin-1 in the thyroid gland. Because the expression and subcellular localization of caveolin-1 were similar between normal human and murine thyroids, our findings in caveolin-1 knockout mice may have direct relevance to the human counterpart.