Characterization of novel mutations in the TEL-patch domain of the telomeric factor TPP1 associated with telomere biology disorders.

Telomeres are nucleoprotein structures that protect the chromosome ends from degradation and fusion. Telomerase is a ribonucleoprotein complex essential to maintain the length of telomeres. Germline defects that lead to short and/or dysfunctional telomeres cause telomere biology disorders (TBDs), a group of rare and heterogeneous Mendelian diseases including pulmonary fibrosis, dyskeratosis congenita, and Høyeraal-Hreidarsson syndrome. TPP1, a telomeric factor encoded by the gene ACD, recruits telomerase at telomere and stimulates its activity via its TEL-patch domain that directly interacts with TERT, the catalytic subunit of telomerase. TBDs due to TPP1 deficiency have been reported only in 11 individuals. We here report four unrelated individuals with a wide spectrum of TBD manifestations carrying either heterozygous or homozygous ACD variants consisting in the recurrent and previously described in-frame deletion of K170 (K170∆) and three novel missense mutations G179D, L184R, and E215V. Structural and functional analyses demonstrated that the four variants affect the TEL-patch domain of TPP1 and impair telomerase activity. In addition, we identified in the ACD gene several motifs associated with small deletion hotspots that could explain the recurrence of the K170∆ mutation. Finally, we detected in a subset of blood cells from one patient, a somatic TERT promoter-activating mutation that likely provides a selective advantage over non-modified cells, a phenomenon known as indirect somatic genetic rescue. Together, our results broaden the genetic and clinical spectrum of TPP1 deficiency and specify new residues in the TEL-patch domain that are crucial for length maintenance and stability of human telomeres in vivo.

Impact of the COVID-19 pandemic on severe non-SARS-CoV-2 community-acquired pneumonia in Reunion Island: a multicenter retrospective observational study, 2016-2021.

The Coronavirus 2019 (COVID-19) pandemic has had a considerable impact on the incidence of severe community-acquired pneumonia (CAP) worldwide. The aim of this study was to assess the early impact of the COVID-19 pandemic in the Reunion Island. This multicenter retrospective observational study was conducted from 2016 to 2021 in the hospitals of Reunion Island. The incidence of severe non-SARS-CoV-2 CAP, microorganisms, characteristics and outcomes of patients hospitalized in intensive care unit were compared between the pre-COVID-19 period (January 1, 2016 to February 29, 2020) and the early COVID-19 period (March 1, 2020 to October 31, 2021). Over the study period, 389 patients developed severe non-SARS-CoV-2 CAP. The incidence of severe non-SARS-CoV-2 CAP significantly decreased between the two periods (9.16 vs. 4.13 cases per 100,000 person-years). The influenza virus was isolated in 43.5% patients with severe non-SARS-CoV-2 CAP in the pre-COVID-19 period and in none of the 60 patients in the early COVID-19 period (P < 0.0001). The only virus that did not decrease was rhinovirus. Streptococcus pneumoniae was the most frequently isolated bacterial microorganism, with no significant difference between the two periods. In Reunion Island, the COVID-19 pandemic led to a significant decrease in the incidence of influenza, which likely explains the observed decrease in the incidence of severe non-SARS-CoV-2 CAP. The pandemic had no impact on the incidence of other viral and bacterial severe non-SARS-CoV-2 CAP. Monitoring influenza incidence is crucial now that COVID-19 control measures have been removed.

The French Compassionate Program of elexacaftor-tezacaftor-ivacaftor in people with cystic fibrosis with advanced lung disease and no F508del CFTR variant.

BACKGROUND: The European Medicines Agency has approved the cystic fibrosis transmembrane conductance regulator (CFTR) modulator combination elexacaftor-tezacaftor-ivacaftor (ETI) for people with cystic fibrosis (pwCF) carrying at least one F508del variant. The United States Food and Drug Administration (FDA) also approved ETI for pwCF carrying one of 177 rare variants. METHODS: An observational study was conducted to evaluate the effectiveness of ETI in pwCF with advanced lung disease that were not eligible to ETI in Europe. All patients with no F508del variant and advanced lung disease (defined as having a percent predicted forced expiratory volume (ppFEV1)<40 and/or being under evaluation for lung transplantation) and enrolled in the French Compassionate Program initiated ETI at recommended doses. Effectiveness was evaluated by a centralized adjudication committee at 4-6 weeks in terms of clinical manifestations, sweat chloride concentration and ppFEV1. RESULTS: Among the first 84 pwCF included in the program, ETI was effective in 45 (54%) and 39 (46%) were considered to be non-responders. Among the responders 22/45 (49%) carried a CFTR variant that is not currently approved by FDA for ETI eligibility. Important clinical benefits, including suspending the indication for lung transplantation, a significant decrease in sweat chloride concentration by a median [IQR] -30 [-14;-43]mmol·l-1 (n=42; p<0.0001) and an improvement in ppFEV1 by+10.0 [6.0; 20.5] (n=44, p<0.0001), were observed in those for whom treatment was effective. CONCLUSION: Clinical benefits were observed in a large subset of pwCF with advanced lung disease and CFTR variants not currently approved for ETI.

COVID-19 in patients with pulmonary alveolar proteinosis: a European multicentre study.

Adult PAP patients experience similar #COVID19 rates to the general population, and high rates of hospitalisation and deaths, underscoring their vulnerability and the need for measures to prevent infection. The impact of iGM-CSF must be considered. https://bit.ly/3M0wKnZ.

SARS-CoV-2 with Panton-Valentine leukocidin-producing Staphylococcus aureus healthcare-associated pneumonia in the Indian Ocean.

At this time, the literature reports only one case of superinfection with Panton-Valentine leukocidin (PVL)-producing Staphylococcus aureus in a patient with severe acute respiratory distress syndrome secondary to coronavirus 2 (SARS-CoV-2) pneumonia. Here we report the first two cases of PVL-producing S. aureus healthcare-associated pneumonia in patients hospitalized for SARS-CoV-2 pneumonia in the Indian Ocean region. The two isolated strains of S. aureus were found to belong to the ST152/t355 clone, a known PVL-producing S. aureus clone that circulates in Africa and is responsible for infections imported into Europe. Our two cases reinforce the hypothesis that SARS-CoV-2 infection favors the occurrence of PVL-producing S. aureus pneumonia. Production of PVL should be searched in patients returning from the Indian Ocean region who present with severe SARS-CoV-2 pneumonia complicated by superinfection with S. aureus even in the case of late onset healthcare-associated pneumonia.

Severe community-acquired pneumonia in Reunion Island: Epidemiological, clinical, and microbiological characteristics, 2016-2018.

PURPOSE: No data are available on severe community-acquired pneumonia (CAP) in the French overseas department of Reunion Island. This is unfortunate as the microorganisms responsible for the disease are likely to differ from those in temperate regions due to a tropical climate and proximity to other islands of the Indian Ocean region. The aim of this study was to assess the epidemiological, clinical, prognosis, and microbiological characteristics of patients with severe CAP in Reunion Island. MATERIALS AND METHODS: This retrospective study evaluated all patients with CAP aged >18 years and hospitalized in one of the two intensive care units of Reunion Island between 2016 and 2018. Microorganisms were identified by culture from blood and respiratory samples, multiplex polymerase chain reaction from respiratory samples, urinary antigen tests, and serology. RESULTS: Over the study period, 573 cases of severe CAP were recorded, with a mean incidence of 22 per 100,000 person-years. The most frequently isolated microorganism was influenza (21.9%) followed by Streptococcus pneumoniae (12%). The influenza virus was detected in affected patients all year round. Twenty-four patients with severe CAP came from another island of the Indian Ocean region (4.2%), mainly Madagascar (>50%). Two of these patients presented with melioidosis and 4 were infected with Acinetobacter spp. CONCLUSIONS: Our findings have major implications for the management of severe CAP in tropical regions. The most frequently isolated microorganism in patients with severe CAP in Reunion Island is influenza followed by S. pneumoniae. Physicians should be aware that influenza is the main cause of severe CAP in patients living in or returning from Reunion Island, where this virus circulates all year round.

Co-infection in patients with hypoxemic pneumonia due to COVID-19 in Reunion Island.

ABSTRACT: This study aimed to evaluate the incidence of co-infection with different types of pathogens in patients with hypoxemic pneumonia due to coronavirus disease 2019 (COVID-19) in Reunion Island.This observational study using a prospectively collected database of hypoxemic pneumonia due to COVID-19 cases was conducted at Félix Guyon University Hospital in Reunion Island, France.Between 18 March 2020 and 15 April 2020, 156 patients were admitted to our hospital for COVID-19. A total of 36 patients had hypoxemic pneumonia (23.1%) due to COVID-19. Thirty of these cases (83.3%) were imported by travelers returning mainly from metropolitan France and Spain. Patients were screened for co-infection with other pathogens at admission: 31 (86.1%) by multiplex polymerase chain reaction (PCR) and 16 (44.4%) by cytobacteriological examination of sputum culture. Five patients (13.9%) were found to have co-infection: 1 with influenza virus A H1N1 (pdm09) associated with Branhamella catarrhalis, 1 with Streptococcus pneumoniae associated with Haemophilus influenzae, 1 with Human Coronavirus 229E, 1 with Rhinovirus, and 1 with methicillin-susceptible Staphylococcus aureus. Patients with co-infection had higher D-dimer levels than those without co-infection (1.36 [1.34-2.36] µg/mL vs 0.63 [0.51-1.12] µg/mL, P = .05).The incidence of co-infection in our cohort was higher than expected (13.9%). Three co-infections (with influenza virus A(H1N1) pdm09, Streptococcus pneumoniae, and Staphylococcus aureus) required specific treatment. Patients with hypoxemic pneumonia due to COVID-19 should be screened for co-infection using respiratory cultures or multiplex PCR. Whilst our study has a number of limitations, the results from our study suggest that in the absence of screening, patients should be commenced on treatment for co-infection in the presence of an elevated D-dimer.

High Prevalence of Nontuberculous Mycobacteria in Cystic Fibrosis Patients in Tropical French Reunion Island.

BACKGROUND: Reunion Island is a French overseas department located in a tropical area, where cystic fibrosis incidence is high. Cystic fibrosis (CF) patients are at risk of developing nontuberculous mycobacteria (NTM) infection. Epidemiologic studies are lacking in Reunion Island. METHODS: From 2002 to 2015, a retrospective review was performed in university hospitals on Reunion Island. All CF patients having at least 1 positive NTM isolate were included. Clinical, radiologic, and microbiologic data were collected from patient records. RESULTS: Fifty-one CF patients were included. The overall estimated prevalence of NTM was 26.4% in total CF population and 36.9% in patients over 12 years of age. Mycobacterium abscessus and Mycobacterium avium were the most frequently identified species found in 31 patients (60.8%) and 14 patients (27.4%), respectively. A rare NTM species: Mycobacterium simiae was found in 4 patients (7.8%). Twenty-nine patients (56.9%) met the American Thoracic Society (ATS) criteria for infection. They were more likely younger with a low body mass index and more frequently infected by Mycobacterium abscessus (22/29). CONCLUSION: The overall prevalence of NTM in tropical Reunion Island is 3 times higher than in metropolitan France. A different environmental exposure in a tropical climate or risk factors related to cystic fibrosis or its treatment in Reunion patients could explain it.

Differential diagnoses of severe COVID-19 in tropical areas: the experience of Reunion Island.

OBJECTIVE: To identify the differential diagnoses of severe COVID-19 and the distinguishing characteristics of critically ill COVID-19 patients in Reunion Island to help improve the triage and management of patients in this tropical setting. METHODS: This retrospective observational study was conducted from 11 March to 4 May 2020 in the only intensive care unit (ICU) authorised to manage COVID-19 patients in Reunion Island, a French overseas department located in the Indian Ocean region. All patients with unknown COVID-19 status were tested by polymerase chain reaction (PCR) on ICU admission; those who tested negative were transferred to the COVID-19-free area of the ICU. RESULTS: Over the study period, 99 patients were admitted to our ICU. A total of 33 patients were hospitalised in the COVID-19 isolation ward, of whom 11 were positive for COVID-19. The main differential diagnoses of severe COVID-19 were as follows: community-acquired pneumonia, dengue, leptospirosis causing intra-alveolar haemorrhage and cardiogenic pulmonary oedema. The median age of COVID-19-positive patients was higher than that of COVID-19-negative patients (71 [58-74] vs. 54 [46-63.5] years, P = 0.045). No distinguishing clinical, biological or radiological characteristics were found between the two groups of patients. All COVID-19-positive patients had recently travelled or been in contact with a recent traveller. CONCLUSIONS: In Reunion Island, dengue and leptospirosis are key differential diagnoses of severe COVID-19, and travel is the only distinguishing characteristic of COVID-19-positive patients. Our findings apply only to the particular context of Reunion Island at this time of the epidemic.

A comprehensive strategy for the early treatment of COVID-19 with azithromycin/hydroxychloroquine and/or corticosteroids: Results of a retrospective observational study in the French overseas department of Réunion Island.

BACKGROUND: This study aimed to evaluate the prognosis of COVID-19 patients in Reunion Island, with a particular focus on the management of patients with hypoxemic pneumonia. METHODS: This retrospective observational study was conducted from 11 March to 17 April 2020 at the only hospital authorized to manage patients with COVID-19 in Reunion Island. RESULTS: Over the study period, 164 out of 398 patients (41.2%) infected with COVID-19 were admitted to Félix Guyon University Hospital. Of these, 36 (22%) developed hypoxemic pneumonia. Patients with hypoxemic pneumonia were aged 66 [56-77] years, 69% were male and 33% had hypertension. Ten patients (27.8%) were hospitalized in intensive care unit (ICU). Hydroxychloroquine/azithromycin treatment was associated with a lower ICU admission rate (P=0.008). None of the 6 patients treated with corticosteroids were hospitalized in ICU (P=0.16). There were no deaths at follow up (minimum 80 days). CONCLUSIONS: Despite the risk profile of COVID-19 patients with severe hypoxemic pneumonia, the mortality rate of the disease in Reunion Island was 0%. This may be due to the care bundle used in our hospital (early hospitalisation, treatment with hydroxychloroquine/azithromycin and/or corticosteroids, non-invasive respiratory support, etc).

Detection of Pulmonary Embolism in Returning Travelers with Hypoxemic Pneumonia due to COVID-19 in Reunion Island.

The aim of this study was to evaluate the occurrence of pulmonary embolism in returning travelers with hypoxemic pneumonia due to COVID-19. All returning travelers to Reunion Island with hypoxemic pneumonia due to COVID-19 underwent computed tomography pulmonary angiography (CTPA) and were included in the cohort. Thirty-five patients were returning travelers with hypoxemic pneumonia due to COVID-19 and had recently returned from one of the countries most affected by the COVID-19 outbreak (mainly from France and Comoros archipelago). Five patients (14.3%) were found to have pulmonary embolism and two (5.9%) were incidentally found to have deep vein thrombosis on CTPA. Patients with pulmonary embolism or deep vein thrombosis had higher D-dimer levels than those without pulmonary embolism or deep vein thrombosis (P = 0.04). Returning travelers with hypoxemic pneumonia due to COVID-19 should be systematically screened for pulmonary embolism.

Medical evacuation from abroad of critically ill patients: A case report and ethical issues.

RATIONALE: Patients repatriated from foreign hospitals are sources of extensively drug-resistant (XDR) bacteria outbreaks. Thus, an individual benefit potential for the patient opposes a collective ecological risk potential. These ethical issues have not been well studied. PATIENT CONCERNS: We report the case of a 74-year-old patient repatriated from Mauritius to the French island of Reunion who presented mesenteric infarction evolving over several days, and who suffered a cardiac arrest before transfer. DIAGNOSES: In Reunion Island, a CT-scan revealed a multisegmental enlarged parietal enlargement associated with free peritoneal effusion and a suboccluded aspect of the superior mesenteric artery. INTERVENTIONS: Surgical exploration showed a severe mesenteric infarction with peritonitis, and a resection of 120cm of the small intestine was conducted. This patient was infected with a vanA glycopeptide-resistant Enterococcus faecium and a carbapenem-resistant Klebsiella pneumoniae which produced carbapenemases NDM-1 and OXA-181, which required specific care and could have led to a local epidemic. OUTCOMES: The patient died after 9 days after being admitted to the ICU. LESSONS: Repatriation of critically ill patients from abroad should be considered according to ethical criteria, evaluating, if possible, the expected benefits, and ecological risks incurred. Limiting unnecessary transfers could be an effective measure to limit the spread of XDR bacteria.

Clinical, Radiological, and Microbiological Characteristics of Mycobacterium simiae Infection in 97 Patients.

Mycobacterium simiae is a rare species of slow-growing nontuberculous mycobacteria (NTM). From 2002 to 2017, we conducted a retrospective study that included all patients with NTM-positive respiratory samples detected in two university hospitals of the French overseas department of Reunion Island. We recorded the prevalence of M. simiae in this cohort, as well as the clinical, radiological, and microbiological features of patients with at least 1 sample positive for M. simiae In our cohort, 97 patients (15.1%) were positive for M. simiae Twenty-one patients (21.6%) met the American Thoracic Society (ATS) criteria for infection. M. simiae infection was associated with bronchiectasis, micronodular lesions, and weight loss. Antibiotic susceptibility testing was performed for 60 patients, and the isolates were found to have low susceptibility to antibiotics, except for amikacin, fluoroquinolones, and clarithromycin. Treatment failed for 4 of the 8 patients treated for M. simiae infection. Here, we describe a specific cluster corresponding to a large cohort of patients with M. simiae, a rare nontuberculous mycobacterium associated with low pathogenicity and poor susceptibility to antibiotics.

First case of pleural empyema and pulmonary abscess caused by Eggerthia catenaformis.

Few data are available on the anaerobic bacterium Eggerthia catenaformis. Here we report the first clinical case of a patient with sepsis caused by pulmonary infection with E. catenaformis, and present the minimal inhibitory concentrations of different antimicrobial agents.

Case Report: Severe Imported Influenza Infections Developed during Travel in Reunion Island.

We report two cases of severe influenza infection imported by tourist patients from their country of origin and developed during travel. While studies have reported cases of influenza infections acquired during travel, here we examine two cases of severe influenza infection contracted in the country of origin that led to diagnosis and therapeutic problems in the destination country. No international recommendation exists concerning influenza vaccination before travel, and few countries recommend it for all travelers. Our study suggests that travel should be canceled when infectious signs are observed before departure. Influenza is a very common infection that is often benign, but sometimes very severe. The most severe cases include shock, acute respiratory distress syndrome (ARDS), myocarditis, rhabdomyolysis, and multiple organ failure. Management can require exceptional therapies, such as extracorporeal membrane oxygenation. A number of studies have focused on influenza infection in travelers. Cases of influenza acquired during travel have been reported in this literature, but no study has examined cases of influenza imported from the country of origin and developed while abroad. The latter situation may lead to 1) diagnostic problems during the nonepidemic season or in places where diagnostic techniques are lacking and 2) therapeutic difficulties resulting from the unavailability of techniques for the management of severe influenza infection in tourist areas. Here, we report two cases of extremely severe influenza infection imported by tourists from their country of origin and developed during travel.