Presence of Genetic Variants Among Young Men With Severe COVID-19.

Importance: Severe coronavirus disease 2019 (COVID-19) can occur in younger, predominantly male, patients without preexisting medical conditions. Some individuals may have primary immunodeficiencies that predispose to severe infections caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Objective: To explore the presence of genetic variants associated with primary immunodeficiencies among young patients with COVID-19. Design, Setting, and Participants: Case series of pairs of brothers without medical history meeting the selection criteria of young (age <35 years) brother pairs admitted to the intensive care unit (ICU) due to severe COVID-19. Four men from 2 unrelated families were admitted to the ICUs of 4 hospitals in the Netherlands between March 23 and April 12, 2020. The final date of follow-up was May 16, 2020. Available family members were included for genetic variant segregation analysis and as controls for functional experiments. Exposure: Severe COVID-19. Main Outcome and Measures: Results of rapid clinical whole-exome sequencing, performed to identify a potential monogenic cause. Subsequently, basic genetic and immunological tests were performed in primary immune cells isolated from the patients and family members to characterize any immune defects. Results: The 4 male patients had a mean age of 26 years (range, 21-32), with no history of major chronic disease. They were previously well before developing respiratory insufficiency due to severe COVID-19, requiring mechanical ventilation in the ICU. The mean duration of ventilatory support was 10 days (range, 9-11); the mean duration of ICU stay was 13 days (range, 10-16). One patient died. Rapid clinical whole-exome sequencing of the patients and segregation in available family members identified loss-of-function variants of the X-chromosomal TLR7. In members of family 1, a maternally inherited 4-nucleotide deletion was identified (c.2129_2132del; p.[Gln710Argfs*18]); the affected members of family 2 carried a missense variant (c.2383G>T; p.[Val795Phe]). In primary peripheral blood mononuclear cells from the patients, downstream type I interferon (IFN) signaling was transcriptionally downregulated, as measured by significantly decreased mRNA expression of IRF7, IFNB1, and ISG15 on stimulation with the TLR7 agonist imiquimod as compared with family members and controls. The production of IFN-γ, a type II IFN, was decreased in patients in response to stimulation with imiquimod. Conclusions and Relevance: In this case series of 4 young male patients with severe COVID-19, rare putative loss-of-function variants of X-chromosomal TLR7 were identified that were associated with impaired type I and II IFN responses. These preliminary findings provide insights into the pathogenesis of COVID-19.

Nailfold capillaroscopy and candidate-biomarker levels in systemic sclerosis-associated pulmonary hypertension: A cross-sectional study.

Objectives: Pulmonary hypertension is one of the leading causes of death in systemic sclerosis. Early detection and treatment of pulmonary hypertension in systemic sclerosis is crucial. Nailfold capillaroscopy microscopy, vascular autoantibodies AT1R and ETAR, and several candidate-biomarkers have the potential to serve as noninvasive tools to identify systemic sclerosis patients at risk for developing pulmonary hypertension. Here, we explore the classifying potential of nailfold capillaroscopy microscopy characteristics and serum levels of selected candidate-biomarkers in a sample of systemic sclerosis patients with and without different forms of pulmonary hypertension. Methods: A total of 81 consecutive systemic sclerosis patients were included, 40 with systemic sclerosis pulmonary hypertension and 41 with no pulmonary hypertension. In each group, quantitative and qualitative nailfold capillaroscopy microscopy characteristics, vascular autoantibodies AT1R and ETAR, and serum levels of 24 soluble serum factors were determined. For evaluation of the nailfold capillaroscopy microscopy characteristics, linear regression analysis accounting for age, sex, and diffusing capacity of the lungs for carbon monoxide percentage predicted was used. Autoantibodies and soluble serum factor levels were compared using two-sample t test with equal variances. Results: No statistically significant differences were observed in quantitative or qualitative nailfold capillaroscopy microscopy characteristics, or vascular autoantibody ETAR and AT1R titer between systemic sclerosis-pulmonary hypertension and systemic sclerosis-no pulmonary hypertension. In contrast, several serum levels of soluble factors differed between groups: Endostatin, sVCAM, and VEGFD were increased, and CXCL4, sVEGFR2, and PDGF-AB/BB were decreased in systemic sclerosis-pulmonary hypertension. Random forest classification identified Endostatin and CXCL4 as the most predictive classifiers to distinguish systemic sclerosispulmonary hypertension from systemic sclerosis-no pulmonary hypertension. Conclusion: This study shows the potential for several soluble serum factors to distinguish systemic sclerosis-pulmonary hypertension from systemic sclerosis-no pulmonary hypertension. We found no classifying potential for qualitative or quantitative nailfold capillaroscopy microscopy characteristics, or vascular autoantibodies.

Gallium-68 labelled RGD PET/CT imaging of endothelial activation in COVID-19 patients.

In coronavirus disease 2019 (COVID-19), endothelial cells play a central role and an inadequate response is associated with vascular complications. PET imaging with gallium-68 labelled RGD-peptide (68Ga-RGD) targets αvß3 integrin expression which allows quantification of endothelial activation. In this single-center, prospective observational study, we included ten hospitalized patients with COVID-19 between October 2020 and January 2021. Patients underwent 68Ga-RGD PET/CT followed by iodine mapping of lung parenchyma. CT-based segmentation of lung parenchyma, carotid arteries and myocardium was used to quantify tracer uptake by calculating standardized uptake values (SUV). Five non-COVID-19 patients were used as reference. The study population was 68.5 (IQR 52.0-74.5) years old, with median oxygen need of 3 l/min (IQR 0.9-4.0). 68Ga-RGD uptake quantified as SUV ± SD was increased in lungs (0.99 ± 0.32 vs. 0.45 ± 0.18, p < 0.01) and myocardium (3.44 ± 1.59 vs. 0.65 ± 0.22, p < 0.01) of COVID-19 patients compared to reference but not in the carotid arteries. Iodine maps showed local variations in parenchymal perfusion but no correlation with SUV. In conclusion, using 68Ga-RGD PET/CT in COVID-19 patients admitted with respiratory symptoms, we demonstrated increased endothelial activation in the lung parenchyma and myocardium. Our findings indicate the involvement of increased and localized endothelial cell activation in the cardiopulmonary system in COVID-19 patients.Trail registration: NCT04596943.

[Chest pain and dyspnea during the recovery period of COVID-19 pneumonia]. / Een man met dyspneu na een COVID-19-pneumonie.

A 31-year-old non-smoking male patient admitted with and intubated for COVID-19 pneumonia experienced acute chest pain and dyspnea during his recovery period. He was diagnosed with a pneumothorax based on major bullae formation due to COVID-19. The bullae were not visible after extubation and developed rapidly within a few days.

Limitations of questioning asthma to assess asthma control in general practice.

BACKGROUND: The monitoring of children with asthma in primary care is based on the occurrence and frequency of asthma symptoms. We questioned whether the current approach is adequate to identify all children in whom a sufficient level of asthma control is not achieved. AIM: The aim of this study is to illustrate that in some children asthma was incorrectly considered controlled, because the children failed to report current symptoms of asthma. PATIENTS AND METHODS: One hundred and nineteen children were identified with recent wheezing plus moderate or severe airway hyperresponsiveness. We analyzed whether these children reported current symptoms of asthma (as normally questioned during a routine visit). RESULTS: In 20 children (18%) current asthma symptoms were absent despite moderately or severe airway hyperresponsiveness and wheezing in the last year. In addition, the usage of controller medication was very poor. CONCLUSION: We conclude that the general practitioner has insufficient tools to adequately assess asthma control in all children. The assessment of airway hyperresponsiveness as an additional guide to manage asthma in children in general practice is recommended. In this way, better asthma control can be achieved.

Assessment of inhalation technique in children in general practice: increased risk of incorrect performance with new device.

In a general practice based population 76% of 530 children inhaling asthma medication inhaled correctly. However, important differences among inhalers were found. Children with a pressurized metered-dose inhaler without a spacer device performed worst, with only 22% inhaling without essential errors. At a second evaluation of the inhaler technique, one year after the first assessment, performances with a new device were more often incorrect versus the unchanged devices (21.1% and 10.8%, respectively; p = 0.01). Providing children with a new device should be carefully controlled over time especially because these children are error prone.

[Respiratory complications in early elective caesarean section]. / Respiratoire complicaties bij vroege electieve sectio caesarea.

Two neonates were born via elective caesarean section, after 38 2/7 and 38 0/7 weeks of gestation, respectively. They developed serious respiratory complications: a pneumothorax and respiratory insufficiency, respectively, for which they were transferred to a neonatal intensive care unit and were mechanically ventilated. If a caesarean section is performed before 39 0/7 weeks of gestation, the risk of respiratory complications, such as idiopathic respiratory distress syndrome or wet lung disease, is increased. Despite this scientific evidence, elective caesarean sections continue to be planned before 39 weeks of gestation.

Implementation of an asthma guideline for the management of childhood asthma in general practice: a randomised controlled trial.

AIM: The aim of the study was to assess, in a randomised, controlled design, the efficacy of different strategies to improve childhood asthma management. METHOD: Three interventions directed to three groups of general practitioners were compared: Group A - dissemination of a guideline; Group B - guideline dissemination plus an educational session; Group C - guideline dissemination, educational session, plus individualised treatment advice based on airway hyperresponsiveness (AHR) and symptoms. Efficacy of the three strategies was assessed by evaluating change in AHR in 362 children after one year. RESULTS: The overall between-group effect of the severity of AHR was not significantly different (P=0.09). In Groups A and C an improvement was seen in nocturnal symptoms (P=0.02) and in Group C an improvement was seen in the prescription of inhaled corticosteroids (P=0.03). CONCLUSION: In this study, the combined implementation strategy did not show a clear improvement in the management of children with asthma in general practice.

Validation of a single concentration methacholine inhalation provocation test (SCIPT) in children.

A new method to assess bronchial hyperresponsiveness (BHR) using a single concentration methacholine has already been validated in adults with asthma. Because the geometrical dimensions of the airways in children are different, the results from studies in adults cannot be extrapolated to children. In this study, we validated the single concentration methacholine inhalation provocation test (SCIPT) in children. Twenty-two children performed three methacholine inhalation challenge tests in random order. Two challenges were performed according to the SCIPT: doubling doses (0.03-1.8 mg; maximal cumulated dose 3.6 mg) were administered with an Aerosol Provocation System (Masterscope, Jaeger). The third challenge was performed according to a standard dosimeter method (SDM): doubling doses (0.002-1.8 mg; maximal cumulative dose 3.5 mg) were administered with a DeVillbiss 646 nebulizer. The degree of BHR is expressed as a PD20. A difference of < 1.5 dose step was assumed to be due to intraindividual variation. We found an intraclass correlation of 0.91 between both tests according to the SCIPT and of 0.80 between the SCIPT and SDM. We found, according to the method of Bland and Altman, good agreement when comparing these two challenge tests. The single concentration inhalation provocation test is reproducible and shows good agreement with a standard dosimeter method to test bronchial responsiveness in children.