Screening of SARS-CoV-2 among homeless people, asylum-seekers and other people living in precarious conditions in Marseille, France, March-April 2020.

BACKGROUND: Surveillance of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection among sheltered homeless and other vulnerable people might provide the information needed to prevent its spread within accommodation centres. METHODS: Data were obtained from 698 participants in different accommodation centres (411 homeless individuals, 77 asylum-seekers, 58 other people living in precarious conditions and 152 employees working in these accommodation centres) who completed questionnaires and had nasal samples collected between 26 March and 17 April 2020. SARS-CoV-2 carriage was assessed by quantitative PCR. RESULTS: We found a high acceptance rate (78.9%) for testing. Overall, 49 people (7.0%) were positive for SARS-CoV-2, including 37 homeless individuals (of 411, 9.0%) and 12 employees (of 152, 7.9%). SARS-CoV-2 positivity correlated with symptoms, although 51% of patients who tested positive did not report respiratory symptoms or fever. Among homeless people, being young (18-34 years) (odds ratio 3.83, 95% confidence interval 1.47-10.0, p = 0.006) and being housed in one specific shelter (odds ratio 9.13, 95% confidence interval 4.09-20.37, p < 0.001) were independent factors associated with SARS-CoV-2 positivity (rates of 11.4% and 20.6%, respectively). DISCUSSION: Symptom screening alone is insufficient to prevent SARS-CoV-2 transmission in vulnerable sheltered people. Systematic testing should be promoted.

Variations in respiratory pathogen carriage among a homeless population in a shelter for men in Marseille, France, March-July 2020: cross-sectional 1-day surveys.

We aimed to compare respiratory pathogen carriage by PCR during three different time periods in 2020 in sheltered homeless people in Marseille, France. The overall prevalence of respiratory pathogen carriage in late March-early April (69.9%) was significantly higher than in late April (42.3%) and mid-July (45.1%). Bacterial carriage significantly decreased between late March-early April and late April. SARS-CoV-2 was detected only in late March-early April samples (20.6%). Measures aiming at mitigating SARS-CoV-2 transmission were effective and also impacted bacterial carriage. Seasonal variations of bacterial carriage between winter and summer in this population were not marked.

Temporal and age distributions of SARS-CoV-2 and other coronaviruses, southeastern France.

OBJECTIVES: The SARS-CoV-2 epidemic presents a poorly understood epidemiological cycle. We aimed to compare the age and weekly distributions of the five human coronaviruses, including SARS-CoV-2, that circulated in southeastern France. METHODS: We analyzed all available diagnoses of respiratory viruses, including SARS-CoV-2, performed between 09/2013 and 05/2020 at the University Hospital Institute Méditerranée Infection in Marseille, southeastern France. RESULTS: For SARS-CoV-2, positive children <15 years of age represented 3.4% (228/6,735) of all positive cases, which is significantly less than for endemic coronaviruses (46.1%; 533/1,156; p < 0.001). Among 10,026 patients tested for SARS-CoV-2 and endemic coronaviruses in 2020, children <15 years represented a significantly lower proportion of all positive cases for SARS-CoV-2 than for endemic coronaviruses [2.2% (24/1,067) vs. 33.5% (149/445), respectively; p < 0.001]. Epidemic curves for endemic coronaviruses and SARS-CoV-2 in 91,722 patients showed comparable bell-shaped distributions with a slight time lag. In contrast, the age distribution of endemic coronaviruses and 14 other respiratory viruses differed significantly compared to that of SARS-CoV-2, which was the only virus to relatively spare children. CONCLUSIONS: We observed for SARS-CoV-2 a temporal distribution resembling that of endemic coronaviruses but an age distribution that relatively spares the youngest subjects, who are those the most exposed to endemic coronaviruses.

Children account for a small proportion of diagnoses of SARS-CoV-2 infection and do not exhibit greater viral loads than adults.

Previous reports have suggested that children are less affected than adults by SARS-CoV-2. We analyzed SARS-CoV-2 diagnoses between February 27, 2020, and March 14, 2020, and mortality among positive patients in Marseille university hospitals. Of 4050 tested individuals, 228 were positive. Deaths occurred in 2/99 documented cases (both > 85 year-old). Children were majorly asymptomatic. Incidence increased by 7.4-fold between 1-5 and 45-65 years then decreased. It was significantly lower among 0-1 year- (0%) and 1-5 (1.1%) and 5-10 (3.6%)-year-old children than among subjects > 18 years (6.5%). Viral loads did not differ between children and adults. Children may not contribute significantly to virus circulation.

Early treatment of COVID-19 patients with hydroxychloroquine and azithromycin: A retrospective analysis of 1061 cases in Marseille, France.

BACKGROUND: In France, the combination hydroxychloroquine (HCQ) and azithromycin (AZ) is used in the treatment of COVID-19. METHODS: We retrospectively report on 1061 SARS-CoV-2 positive tested patients treated for at least three days with the following regimen: HCQ (200 mg three times daily for ten days) + AZ (500 mg on day 1 followed by 250 mg daily for the next four days). Outcomes were death, clinical worsening (transfer to ICU, and >10 day hospitalization) and viral shedding persistence (>10 days). RESULTS: A total of 1061 patients were included in this analysis (46.4% male, mean age 43.6 years - range 14-95 years). Good clinical outcome and virological cure were obtained in 973 patients within 10 days (91.7%). Prolonged viral carriage was observed in 47 patients (4.4%) and was associated to a higher viral load at diagnosis (p < .001) but viral culture was negative at day 10. All but one, were PCR-cleared at day 15. A poor clinical outcome (PClinO) was observed for 46 patients (4.3%) and 8 died (0.75%) (74-95 years old). All deaths resulted from respiratory failure and not from cardiac toxicity. Five patients are still hospitalized (98.7% of patients cured so far). PClinO was associated with older age (OR 1.11), severity of illness at admission (OR 10.05) and low HCQ serum concentration. PClinO was independently associated with the use of selective beta-blocking agents and angiotensin II receptor blockers (p < .05). A total of 2.3% of patients reported mild adverse events (gastrointestinal or skin symptoms, headache, insomnia and transient blurred vision). CONCLUSION: Administration of the HCQ+AZ combination before COVID-19 complications occur is safe and associated with a very low fatality rate in patients.

New ZMPSTE24 (FACE1) mutations in patients affected with restrictive dermopathy or related progeroid syndromes and mutation update.

Restrictive dermopathy (RD) is a rare and extremely severe congenital genodermatosis, characterized by a tight rigid skin with erosions at flexure sites, multiple joint contractures, low bone density and pulmonary insufficiency generally leading to death in the perinatal period. RD is caused in most patients by compound heterozygous or homozygous ZMPSTE24 null mutations. This gene encodes a metalloprotease specifically involved in lamin A post-translational processing. Here, we report a total of 16 families for whom diagnosis and molecular defects were clearly established. Among them, we report seven new ZMPSTE24 mutations, identified in classical RD or Mandibulo-acral dysplasia (MAD) affected patients. We also report nine families with one or two affected children carrying the common, homozygous thymine insertion in exon 9 and demonstrate the lack of a founder effect. In addition, we describe several new ZMPSTE24 variants identified in unaffected controls or in patients affected with non-classical progeroid syndromes. In addition, this mutation update includes a comprehensive search of the literature on previously described ZMPSTE24 mutations and associated phenotypes. Our comprehensive analysis of the molecular pathology supported the general rule: complete loss-of-function of ZMPSTE24 leads to RD, whereas other less severe phenotypes are associated with at least one haploinsufficient allele.

Restrictive dermopathy in a Turkish newborn.

A 4-day-old boy presented with tight, translucent skin, prominent vessels, skin erosions, and dysmorphic findings, including hypertelorism, antimongoloid axis, sparse eyelashes and eyebrows, pinched nose, natal teeth, microretrognathia, and an "o-shaped" mouth. Multiple joint contractures, dysplastic clavicles, and thin ribs were also observed. He died at 2 weeks of age of respiratory distress. The patient was diagnosed as being affected with restrictive dermopathy, which is a rare, lethal genodermatosis caused by recessive mutations of the zinc metalloproteinase ZMPSTE24 gene or less frequently, by dominant lamin A/C gene mutations. Direct sequencing of the ZMPSTE24 gene was performed, and the most common, homozygous, inactivating mutation in exon 9 was identified in the patient (c.1085_1086insT; p.Leu362PhefsX19). Autosomal recessive transmission was confirmed by parental DNA analysis. After genetic counseling, a prenatal diagnosis could be performed during the subsequent pregnancy. ZMPSTE24 screening was performed by direct sequencing and fluorescent fragment analysis on DNA derived from a chorionic villus sample after exclusion of maternal contamination. The fetus had inherited both normal parental alleles, avoiding the recurrence of the disease.

LBR mutation and nuclear envelope defects in a patient affected with Reynolds syndrome.

BACKGROUND Lamins are proteins of the nuclear envelope involved in 'laminopathies', an heterogeneous group of diseases sharing clinical similarities with systemic sclerosis (SSc). Methods In this context, a search was undertaken for mutations in LMNA, encoding Lamins A/C, and ZMPSTE24, LBR, LMNB1, LMNB2, MAN1, SYNE1a and LAP2, encoding Lamins A/C molecular partners, in a Caucasian woman affected with Reynolds syndrome, a particular nosologic entity specifically associating limited cutaneous SSc and primary biliary cirrhosis. RESULTS Coding regions and intron-exon boundaries of these genes were PCR amplified and sequenced, revealing a single heterozygous missense mutation in LBR exon 9 (c.1114C/T; p.R372C). This variant was absent in 400 control chromosomes. The mutation was predicted to induce a change in Lamin B receptor (LBR) tertiary structure and molecular interactions by bioinformatic tools. Further functional explorations were performed on the patient's fibroblasts and lymphoblastoid cell lines. On the latter, the expression levels of LBR, Lamins A/C, Lamin B1, Lamin B2, and HP1a were conserved. Conversely, in the patient's skin fibroblasts, LBR and the aforementioned molecular partners showed dramatically reduced or abolished expression levels. The immunofluorescence analyses performed on both cell lines corroborated these findings. CONCLUSION The fibroblast specific abnormalities observed suggest that this particular LBR mutation might have dominant negative deleterious effects in a tissue specific fashion, possibly through the perturbation of the interactions or stability of the nuclear envelope protein network. LBR mutations might thus be associated with Reynolds syndrome.

Novel frameshifting mutations of the ZMPSTE24 gene in two siblings affected with restrictive dermopathy and review of the mutations described in the literature.

Restrictive dermopathy (RD) is a rare, severe, lethal genodermatosis in which tautness of the skin causes fetal akinesia or hypokinesia deformation sequence. To date, about 60 cases of RD were described. The signs of the disease are very characteristic and include intrauterine growth retardation, thin, tightly adherent translucent skin, superficial vessels, typical facial dysmorphism as well as generalized joint contractures. The syndrome is caused in most cases by ZMPSTE24 autosomal recessive mutations, or, less frequently, by LMNA autosomal dominant mutations. We report on two brothers affected with RD, who died in the neonatal period. Molecular analyses were performed in the second child, for whom biological material was available, and both parents. Compound heterozygous frameshifting mutations were identified in exon 1 (c.50delA) and exon 5 (c.584_585delAT) of the ZMPSTE24 gene. The autosomal recessive inheritance was confirmed by the parents' genomic analysis. Besides, a review of the mutations causing RD is made.

Novel LMNA mutation in atypical Werner syndrome presenting with ischemic disease.

BACKGROUND AND PURPOSE: Laminopathies arise through mutations in genes encoding Lamin A/C (LMNA) or associated proteins. They cause 4 different groups of disorders with diverse severity and often overlapping features: diseases of striated muscle (leading to muscular or cardiac involvement), peripheral neuropathy, lipodystrophy syndromes, and accelerated aging disorders. SUMMARY OF CASE: We report on a familial case of atypical Werner syndrome (a progeroid syndrome with Werner syndrome phenotype but without typical RECQL2 mutation) presenting with acute ischemic cerebral disease or peripheral artery disease associated with diffuse atherosclerosis, attributable to transmission of a novel LMNA mutation. CONCLUSIONS: In young patients with ischemic events and a positive family history, other progeroid features have to be searched and LMNA testing has to be considered, allowing for genetic counseling and presymptomatic testing of at-risk relatives.

HGPS and related premature aging disorders: from genomic identification to the first therapeutic approaches.

Progeroid syndromes are heritable human disorders displaying features that recall premature ageing. In these syndromes, premature aging is defined as "segmental" since only some of its features are accelerated. A number of cellular biological pathways have been linked to aging, including regulation of the insulin/growth hormone axis, pathways involving ROS metabolism, caloric restriction, and DNA repair. The number of identified genes associated with progeroid syndromes has increased in recent years, possibly shedding light as well on mechanisms underlying ageing in general. Among these, premature aging syndromes related to alterations of the LMNA gene have recently been identified. This review focuses on Hutchinson-Gilford Progeria syndrome and Restrictive Dermopathy, two well-characterized Lamin-associated premature aging syndromes, pointing out the current knowledge concerning their pathophysiology and the development of possible therapeutic approaches.