Travel-related MERS-CoV cases: An assessment of exposures and risk factors in a group of Dutch travellers returning from the Kingdom of Saudi Arabia, May 2014

__Background:__ In May 2014, Middle East respiratory syndrome coronavirus (MERS-CoV) infection, with closely related viral genomes, was diagnosed in two Dutch residents, returning from a pilgrimage to Medina and Mecca, Kingdom of Saudi Arabia (KSA). These patients travelled with a group of 29 other Dutch travellers. We conducted an epidemiological assessment of the travel group to identify likely source(s) of infection and presence of potential risk factors. __Methods:__ All travellers, including the two cases, completed a questionnaire focussing on potential human, animal and food exposures to MERS-CoV. The questionnaire was modified from the WHO MERS-CoV questionnaire, taking into account the specific route and activities of the travel group. __Results:__ Twelve non-cases drank unpasteurized camel milk and had contact with camels. Most travellers, including one of the two patients (Case 1), visited local markets, where six of them consumed fruits. Two travellers, including Case 1, were exposed to coughing patients when visiting a hospital in Medina. Four travellers, including Case 1, visited two hospitals in Mecca. All travellers had been in contact with Case 1 while he was sick, with initially non-respiratory complaints. The cases were found to be older than the other travellers and both had co-morbidities. __Conclusions:__ This epidemiological study revealed the complexity of MERS-CoV outbreak investigations with multiple potential exposures to MERS-CoV reported such as healthcare visits, camel exposure, and exposure to untreated food products. Exposure to MERS-CoV during a hospital visit is considered a likely source of infection for Case 1 but not for Case 2. For Case 2, the most likely source could not be determined. Exposure to MERS-CoV via direct contact with animals or dairy products seems unlikely for the two Dutch cases. Furthermore, exposure to a common but still unidentified source cannot be ruled out. More comprehensive research into sources of infection in the Arabian Peninsula is needed to strengthen and specify the prevention of MERS-CoV infections

Travel-related MERS-CoV cases: an assessment of exposures and risk factors in a group of Dutch travellers returning from the Kingdom of Saudi Arabia, May 2014

BACKGROUND: In May 2014, Middle East respiratory syndrome coronavirus (MERS-CoV) infection, with closely related viral genomes, was diagnosed in two Dutch residents, returning from a pilgrimage to Medina and Mecca, Kingdom of Saudi Arabia (KSA). These patients travelled with a group of 29 other Dutch travellers. We conducted an epidemiological assessment of the travel group to identify likely source(s) of infection and presence of potential risk factors. METHODS: All travellers, including the two cases, completed a questionnaire focussing on potential human, animal and food exposures to MERS-CoV. The questionnaire was modified from the WHO MERS-CoV questionnaire, taking into account the specific route and activities of the travel group. RESULTS: Twelve non-cases drank unpasteurized camel milk and had contact with camels. Most travellers, including one of the two patients (Case 1), visited local markets, where six of them consumed fruits. Two travellers, including Case 1, were exposed to coughing patients when visiting a hospital in Medina. Four travellers, including Case 1, visited two hospitals in Mecca. All travellers had been in contact with Case 1 while he was sick, with initially non-respiratory complaints. The cases were found to be older than the other travellers and both had co-morbidities. CONCLUSIONS: This epidemiological study revealed the complexity of MERS-CoV outbreak investigations with multiple potential exposures to MERS-CoV reported such as healthcare visits, camel exposure, and exposure to untreated food products. Exposure to MERS-CoV during a hospital visit is considered a likely source of infection for Case 1 but not for Case 2. For Case 2, the most likely source could not be determined. Exposure to MERS-CoV via direct contact with animals or dairy products seems unlikely for the two Dutch cases. Furthermore, exposure to a common but still unidentified source cannot be ruled out. More comprehensive research into sources of infection in the Arabian Peninsula is needed to strengthen and specify the prevention of MERS-CoV infections

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P < 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

Comprehensive dna analysis in dutch ARVD/C patients

Introduction: Familial Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C) is an autosomal dominantly inherited disease with incomplete penetrance and highly variable expression. Mutations in genes encoding 5 desmosomal proteins and TMEM43 usually underlie ARVD/C. Aim: Comprehensive sequencing of all 6 genes in a large cohort of Dutch ARVD/C patients (pts) correlated with phenotypic characteristics. Methods: Inclusion of 109 ARVD/C pts (81 men, age 49±14 yrs) according to diagnostic Task Force Criteria (TFC). Clinical history and data on separate TFC were collected. DNA of all 109 pts was directly sequenced for mutations in desmosomal genes PKP2, DSC2, DSG2, DSP and JUP. In 81 cases TMEM43 was also analyzed. Pathogenic mutations were defined as DNA sequence variations disrupting conserved residues and not present in 200 ethnically-matched controls. Clinical characteristics were related to specific genes, type (truncating or not) and number of mutations. Results: In 63 of 109 pts (58%) single mutations were observed: 19 different PKP2 mutations in 57 cases, 5 in DSG2 and 1 in DSC2. Five more pts carried 2 mutations: in PKP2 and additionally in DSG2 (n=2), DSP (n=2) or TMEM43 (n=1). Mutations occurred equally in men and women. Phenotype variations were not related to gene or type of mutations. First arrhythmic event was at significantly younger age in pts with mutation than those without, and youngest in those 5 pts with bigenic involvement (mean age for 0, 1 and 2 mutations: 43, 34 and 21 yrs, resp). Also, between groups with 0, 1 and 2 mutations, occurrence of negative T waves in leads V1-3 (41, 80 and 100%, resp) and major structural abnormalities (46, 65 and 100% resp) was significantly different. Frequency of all other parameters was similar. Conclusions: In 68 of 109 (62%) Dutch ARVD/C patients pathogenic mutations were observed, mainly in PKP2, with multiple mutations in 5 cases. Mutation carriers more often had negative T waves in V1-3 and structural abnormalities. Moreover, they presented at younger age than patients without mutations; this age was even younger when multiple genes were affected. Screening of all relevant genes is needed for appropriate genotype-phenotype correlation

Genotype-phenotype analysis in arrhythmogenic right ventricular dysplasia/cardiomyopathy:Follow-up of a large series of dutch index-patients and family members

Background: In Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C) causative mutations in genes encoding 5 desmosomal proteins or TMEM43 are found in the majority of patients. One of the primary clinical challenges in ARVD/C is timely diagnosis of those still asymptomatic. However, previous studies mainly involved overt ARVD/C index-patients. Follow-up data on relatives are scarce. Therefore, we sequenced all 6 genes in a large cohort of ARVD/C families and correlated results with clinical follow-up. Methods: 149 ARVD/C index-patients (111 men, age 49±13 years) according to 2010 Task Force Criteria (TFC) and 302 family members from 93 different families (282 asymptomatic, 135 men, age 44±13 years) were clinically and genetically analyzed. DNA analysis comprised sequencing of PKP2, DSC2, DSG2, DSP, JUP and TMEM43 and multiple ligation-dependent probe amplification (MLPA) to identify large PKP2 deletions. Results: Pathogenic mutations were found in 87 of 149 index-patients (58%): 90% PKP2 and multiple mutations in 4 cases. MLPA revealed 3 large PKP2 deletions (2%). Mutation carriers presented at younger age than non-carriers (35±12 vs 40±14 years; p=0.042). Familial cases were identified in 42 of 93 (45%) of index-patients with relatives screened: 90% with mutations. In total, 57 of 282 asymptomatic relatives (20%) showed signs of ARVD/C (age 47±18 years, 48 with mutations). See table 2. Terminal activation duration (TAD) 7ge;55ms occurred more than negative T waves in V1-3 (12 vs 7%), especially in those age

Arrhythmogenic right ventricular dysplasia/cardiomyopathy: Pathogenic desmosome mutations in index-patients predict outcome of family screening: Dutch arrhythmogenic right ventricular dysplasia/cardiomyopathy genotype-phenotype follow-up study

Background-: Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an autosomal dominant inherited disease with incomplete penetrance and variable expression. Causative mutations in genes encoding 5 desmosomal proteins are found in ≈50% of ARVD/C index patients. Previous genotype-phenotype relation studies involved mainly overt ARVD/C index patients, so follow-up data on relatives are scarce. Methods and Results-: One hundred forty-nine ARVD/C index patients (111 male patients; age, 49±13 years) according to 2010 Task Force criteria and 302 relatives from 93 families (282 asymptomatic; 135 male patients; age, 44±13 years) were clinically and genetically characterized. DNA analysis comprised sequencing of plakophilin-2 (PKP2), desmocollin-2, desmoglein-2, desmoplakin, and plakoglobin and multiplex ligation-dependent probe amplification to identify large deletions in PKP2. Pathogenic mutations were found in 87 index patients (58%), mainly truncating PKP2 mutations, including 3 cases with multiple mutations. Multiplex ligation-dependent probe amplification revealed 3 PKP2 exon deletions. ARVD/C was diagnosed in 31% of initially asymptomatic mutation-carrying relatives and 5% of initially asymptomatic relatives of index patients without mutation. Prolonged terminal activation duration was observed more than negative T waves in V1 to V3, especially in mutation-carrying relatives <20 years of age. In 45% of screened families, ≥1 affected relatives were identified (90% with mutations). Conclusions-: Pathogenic desmosomal gene mutations, mainly truncating PKP2 mutations, underlie ARVD/C in the majority (58%) of Dutch index patients and even 90% of familial cases. Additional multiplex ligation-dependent probe amplification analysis contributed to discovering pathogenic mutations underlying ARVD/C. Discovering pathogenic mutations in index patients enables those relatives who have a 6-fold increased risk of ARVD/C diagnosis to be identified. Prolonged terminal activation duration seems to be a first sign of ARVD/C in young asymptomatic relatives

Paediatric COVID-19 mortality: a database analysis of the impact of health resource disparity

Background The impact of the COVID-19 pandemic on paediatric populations varied between high-income countries (HICs) versus low-income to middle-income countries (LMICs). We sought to investigate differences in paediatric clinical outcomes and identify factors contributing to disparity between countries.Methods The International Severe Acute Respiratory and Emerging Infections Consortium (ISARIC) COVID-19 database was queried to include children under 19 years of age admitted to hospital from January 2020 to April 2021 with suspected or confirmed COVID-19 diagnosis. Univariate and multivariable analysis of contributing factors for mortality were assessed by country group (HICs vs LMICs) as defined by the World Bank criteria.Results A total of 12 860 children (3819 from 21 HICs and 9041 from 15 LMICs) participated in this study. Of these, 8961 were laboratory-confirmed and 3899 suspected COVID-19 cases. About 52% of LMICs children were black, and more than 40% were infants and adolescent. Overall in-hospital mortality rate (95% CI) was 3.3% [=(3.0% to 3.6%), higher in LMICs than HICs (4.0% (3.6% to 4.4%) and 1.7% (1.3% to 2.1%), respectively). There were significant differences between country income groups in intervention profile, with higher use of antibiotics, antivirals, corticosteroids, prone positioning, high flow nasal cannula, non-invasive and invasive mechanical ventilation in HICs. Out of the 439 mechanically ventilated children, mortality occurred in 106 (24.1%) subjects, which was higher in LMICs than HICs (89 (43.6%) vs 17 (7.2%) respectively). Pre-existing infectious comorbidities (tuberculosis and HIV) and some complications (bacterial pneumonia, acute respiratory distress syndrome and myocarditis) were significantly higher in LMICs compared with HICs. On multivariable analysis, LMIC as country income group was associated with increased risk of mortality (adjusted HR 4.73 (3.16 to 7.10)).Conclusion Mortality and morbidities were higher in LMICs than HICs, and it may be attributable to differences in patient demographics, complications and access to supportive and treatment modalities