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1.
Viruses ; 14(1):63, 2022.
Article in English | MDPI | ID: covidwho-1580399

ABSTRACT

Background: Testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is neither always accessible nor easy to perform in children. We aimed to propose a machine learning model to assess the need for a SARS-CoV-2 test in children (<16 years old), depending on their clinical symptoms. Methods: Epidemiological and clinical data were obtained from the REDCap®registry. Overall, 4434 SARS-CoV-2 tests were performed in symptomatic children between 1 November 2020 and 31 March 2021, 784 were positive (17.68%). We pre-processed the data to be suitable for a machine learning (ML) algorithm, balancing the positive-negative rate and preparing subsets of data by age. We trained several models and chose those with the best performance for each subset. Results: The use of ML demonstrated an AUROC of 0.65 to predict a COVID-19 diagnosis in children. The absence of high-grade fever was the major predictor of COVID-19 in younger children, whereas loss of taste or smell was the most determinant symptom in older children. Conclusions: Although the accuracy of the models was lower than expected, they can be used to provide a diagnosis when epidemiological data on the risk of exposure to COVID-19 is unknown.

2.
Enferm Infecc Microbiol Clin (Engl Ed) ; 39(8): 415-416, 2021 10.
Article in English | MEDLINE | ID: covidwho-1461030
4.
Front Pediatr ; 9: 754744, 2021.
Article in English | MEDLINE | ID: covidwho-1441127

ABSTRACT

Objective: We describe and analyze the childhood (<18 years) COVID-19 incidence in Catalonia, Spain, during the first 36 weeks of the 2020-2021 school-year and to compare it with the incidence in adults. Methods: Data on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) tests were obtained from the Catalan Agency for Quality and Health Assessment. Overall, 7,203,663 SARS-CoV-2 tests were performed, of which 491,819 were positive (6.8%). We collected epidemiological data including age-group incidence, diagnostic effort, and positivity rate per 100,000 population to analyze the relative results for these epidemiological characteristics. Results: Despite a great diagnostic effort among children, with a difference of 1,154 tests per 100,000 population in relation to adults, the relative incidence of SARS-CoV-2 for <18 years was slightly lower than for the general population, and it increased with the age of the children. Additionally, positivity of SARS-CoV-2 in children (5.7%) was lower than in adults (7.2%), especially outside vacation periods, when children were attending school (4.9%). Conclusions: A great diagnostic effort, including mass screening and systematic whole-group contact tracing when a positive was detected in the class group, was associated with childhood SARS-CoV-2 incidence and lower positivity rate in the 2020-2021 school year. Schools have been a key tool in epidemiological surveillance rather than being drivers of SARS-CoV-2 incidence in Catalonia, Spain.

5.
Sci Immunol ; 6(62)2021 08 19.
Article in English | MEDLINE | ID: covidwho-1434876

ABSTRACT

Autosomal inborn errors of type I IFN immunity and autoantibodies against these cytokines underlie at least 10% of critical COVID-19 pneumonia cases. We report very rare, biochemically deleterious X-linked TLR7 variants in 16 unrelated male individuals aged 7 to 71 years (mean: 36.7 years) from a cohort of 1,202 male patients aged 0.5 to 99 years (mean: 52.9 years) with unexplained critical COVID-19 pneumonia. None of the 331 asymptomatically or mildly infected male individuals aged 1.3 to 102 years (mean: 38.7 years) tested carry such TLR7 variants (p = 3.5 × 10-5). The phenotypes of five hemizygous relatives of index cases infected with SARS-CoV-2 include asymptomatic or mild infection (n=2, 5 and 38 years), or moderate (n=1, 5 years), severe (n=1, 27 years), or critical (n=1, 29 years) pneumonia. Two boys (aged 7 and 12 years) from a cohort of 262 male patients with severe COVID-19 pneumonia (mean: 51.0 years) are hemizygous for a deleterious TLR7 variant. The cumulative allele frequency for deleterious TLR7 variants in the male general population is < 6.5x10-4 We also show that blood B cell lines and myeloid cell subsets from the patients do not respond to TLR7 stimulation, a phenotype rescued by wild-type TLR7 The patients' blood plasmacytoid dendritic cells (pDCs) produce low levels of type I IFNs in response to SARS-CoV-2. Overall, X-linked recessive TLR7 deficiency is a highly penetrant genetic etiology of critical COVID-19 pneumonia, in about 1.8% of male patients below the age of 60 years. Human TLR7 and pDCs are essential for protective type I IFN immunity against SARS-CoV-2 in the respiratory tract.


Subject(s)
COVID-19/complications , Genetic Diseases, X-Linked/complications , Immune System Diseases/complications , Toll-Like Receptor 7/deficiency , Adolescent , Adult , Aged , Aged, 80 and over , Alleles , Child , Child, Preschool , Humans , Infant , Male , Middle Aged , Pedigree , Penetrance , Toll-Like Receptor 7/genetics , Young Adult
6.
Clin Infect Dis ; 73(6): e1261-e1269, 2021 09 15.
Article in English | MEDLINE | ID: covidwho-1413797

ABSTRACT

BACKGROUND: The role of children in household transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains unclear. We describe the epidemiological and clinical characteristics of children with coronavirus disease 2019 (COVID-19) in Catalonia, Spain, and investigate the household transmission dynamics. METHODS: A prospective, observational, multicenter study was performed during summer and school periods (1 July 2020-31 October 2020) to analyze epidemiological and clinical features and viral household transmission dynamics in COVID-19 patients aged <16 years. A pediatric index case was established when a child was the first individual infected. Secondary cases were defined when another household member tested positive for SARS-CoV-2 before the child. The secondary attack rate (SAR) was calculated, and logistic regression was used to assess associations between transmission risk factors and SARS-CoV-2 infection. RESULTS: The study included 1040 COVID-19 patients. Almost half (47.2%) were asymptomatic, 10.8% had comorbidities, and 2.6% required hospitalization. No deaths were reported. Viral transmission was common among household members (62.3%). More than 70% (756/1040) of pediatric cases were secondary to an adult, whereas 7.7% (80/1040) were index cases. The SAR was significantly lower in households with COVID-19 pediatric index cases during the school period relative to summer (P = .02) and compared to adults (P = .006). No individual or environmental risk factors associated with the SAR. CONCLUSIONS: Children are unlikely to cause household COVID-19 clusters or be major drivers of the pandemic, even if attending school. Interventions aimed at children are expected to have a small impact on reducing SARS-CoV-2 transmission.


Subject(s)
COVID-19 , SARS-CoV-2 , Adult , Child , Family Characteristics , Humans , Pandemics , Prospective Studies
8.
Clin Infect Dis ; 72(9): e397-e401, 2021 05 04.
Article in English | MEDLINE | ID: covidwho-1387751

ABSTRACT

Some clusters of children with a multisystem inflammatory syndrome (MIS-C) associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have been reported. We describe the epidemiological and clinical features of children with MIS-C in Spain. MIS-C is a potentially severe condition that presents in children with recent SARS-CoV-2 infection.


Subject(s)
COVID-19 , SARS-CoV-2 , Child , Humans , Spain/epidemiology , Syndrome , Systemic Inflammatory Response Syndrome
9.
Sci Immunol ; 6(62)2021 08 19.
Article in English | MEDLINE | ID: covidwho-1367380

ABSTRACT

Autosomal inborn errors of type I IFN immunity and autoantibodies against these cytokines underlie at least 10% of critical COVID-19 pneumonia cases. We report very rare, biochemically deleterious X-linked TLR7 variants in 16 unrelated male individuals aged 7 to 71 years (mean: 36.7 years) from a cohort of 1,202 male patients aged 0.5 to 99 years (mean: 52.9 years) with unexplained critical COVID-19 pneumonia. None of the 331 asymptomatically or mildly infected male individuals aged 1.3 to 102 years (mean: 38.7 years) tested carry such TLR7 variants (p = 3.5 × 10-5). The phenotypes of five hemizygous relatives of index cases infected with SARS-CoV-2 include asymptomatic or mild infection (n=2, 5 and 38 years), or moderate (n=1, 5 years), severe (n=1, 27 years), or critical (n=1, 29 years) pneumonia. Two boys (aged 7 and 12 years) from a cohort of 262 male patients with severe COVID-19 pneumonia (mean: 51.0 years) are hemizygous for a deleterious TLR7 variant. The cumulative allele frequency for deleterious TLR7 variants in the male general population is < 6.5x10-4 We also show that blood B cell lines and myeloid cell subsets from the patients do not respond to TLR7 stimulation, a phenotype rescued by wild-type TLR7 The patients' blood plasmacytoid dendritic cells (pDCs) produce low levels of type I IFNs in response to SARS-CoV-2. Overall, X-linked recessive TLR7 deficiency is a highly penetrant genetic etiology of critical COVID-19 pneumonia, in about 1.8% of male patients below the age of 60 years. Human TLR7 and pDCs are essential for protective type I IFN immunity against SARS-CoV-2 in the respiratory tract.


Subject(s)
COVID-19/complications , Genetic Diseases, X-Linked/complications , Immune System Diseases/complications , Toll-Like Receptor 7/deficiency , Adolescent , Adult , Aged , Aged, 80 and over , Alleles , Child , Child, Preschool , Humans , Infant , Male , Middle Aged , Pedigree , Penetrance , Toll-Like Receptor 7/genetics , Young Adult
10.
Pediatr Infect Dis J ; 40(11): 955-961, 2021 11 01.
Article in English | MEDLINE | ID: covidwho-1331604

ABSTRACT

BACKGROUND: We analyzed contagions of coronavirus disease 2019 inside school bubble groups in Catalonia, Spain, in the presence of strong nonpharmaceutical interventions from September to December 2020. More than 1 million students were organized in bubble groups and monitored and analyzed by the Health and the Educational departments. METHODS: We had access to 2 data sources, and both were employed for the analysis, one is the Catalan school surveillance system and the other of the educational department. As soon as a positive index case is detected by the health system, isolation is required for all members of the bubble group, in addition to a mandatory proactive systematic screening of each individual. All infected cases are reported. It permits the calculation of the average reproductive number (R*), corresponding to the average number of infected individuals per index case. RESULTS: We found that propagation inside of the bubble group was small. Among 75% index cases, there was no transmission to other members in the classroom, with an average R* across all ages inside the bubble of R* = 0.4. We found a significant age trend in the secondary attack rates, with the R* going from 0.2 in preschool to 0.6 in high school youth. CONCLUSIONS: The secondary attack rate depends on the school level and therefore on the age. Super-spreading events (outbreaks of 5 cases or more) in childhood were rare, only occurring in 2.5% of all infections triggered from a pediatric index case.


Subject(s)
COVID-19/epidemiology , COVID-19/virology , SARS-CoV-2 , Schools , Students , Adolescent , Age Factors , Algorithms , Child , Child, Preschool , Disease Outbreaks , Female , Humans , Male , Models, Statistical , Population Surveillance , Spain/epidemiology
11.
Pediatr Infect Dis J ; 40(8): e287-e293, 2021 08 01.
Article in English | MEDLINE | ID: covidwho-1305449

ABSTRACT

BACKGROUND: We aimed to identify risk factors causing critical disease in hospitalized children with COVID-19 and to build a predictive model to anticipate the probability of need for critical care. METHODS: We conducted a multicenter, prospective study of children with SARS-CoV-2 infection in 52 Spanish hospitals. The primary outcome was the need for critical care. We used a multivariable Bayesian model to estimate the probability of needing critical care. RESULTS: The study enrolled 350 children from March 12, 2020, to July 1, 2020: 292 (83.4%) and 214 (73.7%) were considered to have relevant COVID-19, of whom 24.2% required critical care. Four major clinical syndromes of decreasing severity were identified: multi-inflammatory syndrome (MIS-C) (17.3%), bronchopulmonary (51.4%), gastrointestinal (11.6%), and mild syndrome (19.6%). Main risk factors were high C-reactive protein and creatinine concentration, lymphopenia, low platelets, anemia, tachycardia, age, neutrophilia, leukocytosis, and low oxygen saturation. These risk factors increased the risk of critical disease depending on the syndrome: the more severe the syndrome, the more risk the factors conferred. Based on our findings, we developed an online risk prediction tool (https://rserver.h12o.es/pediatria/EPICOAPP/, username: user, password: 0000). CONCLUSIONS: Risk factors for severe COVID-19 include inflammation, cytopenia, age, comorbidities, and organ dysfunction. The more severe the syndrome, the more the risk factor increases the risk of critical illness. Risk of severe disease can be predicted with a Bayesian model.


Subject(s)
COVID-19/diagnosis , Systemic Inflammatory Response Syndrome/diagnosis , Adolescent , Bayes Theorem , COVID-19/epidemiology , Child , Child, Preschool , Comorbidity , Critical Care , Critical Illness , Female , Humans , Infant , Infant, Newborn , Male , Prospective Studies , Risk Factors , SARS-CoV-2/isolation & purification , Severity of Illness Index , Systemic Inflammatory Response Syndrome/epidemiology
12.
Front Immunol ; 12: 665824, 2021.
Article in English | MEDLINE | ID: covidwho-1273337

ABSTRACT

Multisystem Inflammatory Syndrome in Children (MIS-C) associated with COVID-19 is characterized by hypercytokinemia leading to overwhelming inflammation. We describe the use of a hemadsorption device as part of the supportive treatment for cytokine storm.


Subject(s)
COVID-19/complications , Hemoperfusion/methods , Systemic Inflammatory Response Syndrome/therapy , Adolescent , COVID-19/therapy , Humans , Male , SARS-CoV-2
14.
J Clin Immunol ; 41(7): 1457-1462, 2021 10.
Article in English | MEDLINE | ID: covidwho-1252168

ABSTRACT

While adults with Down syndrome (DS) are at increased risk of severe COVID-19 pneumonia, little is known about COVID-19 in children with DS. In children without DS, SARS-CoV-2 can rarely cause severe COVID-19 pneumonia, or an even rarer and more typically pediatric condition, multisystem inflammatory syndrome in children (MIS-C). Although the underlying mechanisms are still unknown, MIS-C is thought to be primarily immune-mediated. Here, we describe an atypical, severe form of MIS-C in two infant girls with DS who were hospitalized for over 4 months. Immunological evaluation revealed pronounced neutrophilia, B cell depletion, increased circulating IL-6 and IL-8, and elevated markers of immune activation ICAM1 and FcÉ£RI. Importantly, uninfected children with DS presented with similar but less stark immune features at steady state, possibly explaining risk of further uncontrolled inflammation following SARS-CoV-2 infection. Overall, a severe, atypical form of MIS-C may occur in children with DS.


Subject(s)
COVID-19/diagnosis , Down Syndrome/diagnosis , SARS-CoV-2/physiology , Systemic Inflammatory Response Syndrome/diagnosis , COVID-19/complications , Down Syndrome/complications , Fatal Outcome , Female , Hospitalization , Humans , Infant , Syndrome
15.
EBioMedicine ; 66: 103339, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-1184942

ABSTRACT

BACKGROUND: Patients infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for the coronavirus disease 2019 (COVID-19), exhibit a wide spectrum of disease behaviour. Since DNA methylation has been implicated in the regulation of viral infections and the immune system, we performed an epigenome-wide association study (EWAS) to identify candidate loci regulated by this epigenetic mark that could be involved in the onset of COVID-19 in patients without comorbidities. METHODS: Peripheral blood samples were obtained from 407 confirmed COVID-19 patients ≤ 61 years of age and without comorbidities, 194 (47.7%) of whom had mild symptomatology that did not involve hospitalization and 213 (52.3%) had a severe clinical course that required respiratory support. The set of cases was divided into discovery (n = 207) and validation (n = 200) cohorts, balanced for age and sex of individuals. We analysed the DNA methylation status of 850,000 CpG sites in these patients. FINDINGS: The DNA methylation status of 44 CpG sites was associated with the clinical severity of COVID-19. Of these loci, 23 (52.3%) were located in 20 annotated coding genes. These genes, such as the inflammasome component Absent in Melanoma 2 (AIM2) and the Major Histocompatibility Complex, class I C (HLA-C) candidates, were mainly involved in the response of interferon to viral infection. We used the EWAS-identified sites to establish a DNA methylation signature (EPICOVID) that is associated with the severity of the disease. INTERPRETATION: We identified DNA methylation sites as epigenetic susceptibility loci for respiratory failure in COVID-19 patients. These candidate biomarkers, combined with other clinical, cellular and genetic factors, could be useful in the clinical stratification and management of patients infected with the SARS-CoV-2. FUNDING: The Unstoppable campaign of the Josep Carreras Leukaemia Foundation, the Cellex Foundation and the CERCA Programme/Generalitat de Catalunya.


Subject(s)
COVID-19/genetics , DNA Methylation , Epigenome , Respiratory Insufficiency/virology , Adult , COVID-19/etiology , Cohort Studies , CpG Islands , Female , Genome-Wide Association Study , Humans , Interferons/genetics , Interferons/metabolism , Male , Middle Aged , Reproducibility of Results , Respiratory Insufficiency/genetics , Severity of Illness Index , Spain , Young Adult
16.
Clin Infect Dis ; 73(6): e1261-e1269, 2021 09 15.
Article in English | MEDLINE | ID: covidwho-1132467

ABSTRACT

BACKGROUND: The role of children in household transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains unclear. We describe the epidemiological and clinical characteristics of children with coronavirus disease 2019 (COVID-19) in Catalonia, Spain, and investigate the household transmission dynamics. METHODS: A prospective, observational, multicenter study was performed during summer and school periods (1 July 2020-31 October 2020) to analyze epidemiological and clinical features and viral household transmission dynamics in COVID-19 patients aged <16 years. A pediatric index case was established when a child was the first individual infected. Secondary cases were defined when another household member tested positive for SARS-CoV-2 before the child. The secondary attack rate (SAR) was calculated, and logistic regression was used to assess associations between transmission risk factors and SARS-CoV-2 infection. RESULTS: The study included 1040 COVID-19 patients. Almost half (47.2%) were asymptomatic, 10.8% had comorbidities, and 2.6% required hospitalization. No deaths were reported. Viral transmission was common among household members (62.3%). More than 70% (756/1040) of pediatric cases were secondary to an adult, whereas 7.7% (80/1040) were index cases. The SAR was significantly lower in households with COVID-19 pediatric index cases during the school period relative to summer (P = .02) and compared to adults (P = .006). No individual or environmental risk factors associated with the SAR. CONCLUSIONS: Children are unlikely to cause household COVID-19 clusters or be major drivers of the pandemic, even if attending school. Interventions aimed at children are expected to have a small impact on reducing SARS-CoV-2 transmission.


Subject(s)
COVID-19 , SARS-CoV-2 , Adult , Child , Family Characteristics , Humans , Pandemics , Prospective Studies
17.
EBioMedicine ; 65: 103246, 2021 Mar.
Article in English | MEDLINE | ID: covidwho-1108220

ABSTRACT

BACKGROUND: While SARS-CoV-2 similarly infects men and women, COVID-19 outcome is less favorable in men. Variability in COVID-19 severity may be explained by differences in the host genome. METHODS: We compared poly-amino acids variability from WES data in severely affected COVID-19 patients versus SARS-CoV-2 PCR-positive oligo-asymptomatic subjects. FINDINGS: Shorter polyQ alleles (≤22) in the androgen receptor (AR) conferred protection against severe outcome in COVID-19 in the first tested cohort (both males and females) of 638 Italian subjects. The association between long polyQ alleles (≥23) and severe clinical outcome (p = 0.024) was also validated in an independent cohort of Spanish men <60 years of age (p = 0.014). Testosterone was higher in subjects with AR long-polyQ, possibly indicating receptor resistance (p = 0.042 Mann-Whitney U test). Inappropriately low serum testosterone level among carriers of the long-polyQ alleles (p = 0.0004 Mann-Whitney U test) predicted the need for intensive care in COVID-19 infected men. In agreement with the known anti-inflammatory action of testosterone, patients with long-polyQ and age ≥60 years had increased levels of CRP (p = 0.018, not accounting for multiple testing). INTERPRETATION: We identify the first genetic polymorphism that appears to predispose some men to develop more severe disease. Failure of the endocrine feedback to overcome AR signaling defects by increasing testosterone levels during the infection leads to the polyQ tract becoming dominant to serum testosterone levels for the clinical outcome. These results may contribute to designing reliable clinical and public health measures and provide a rationale to test testosterone as adjuvant therapy in men with COVID-19 expressing long AR polyQ repeats. FUNDING: MIUR project "Dipartimenti di Eccellenza 2018-2020" to Department of Medical Biotechnologies University of Siena, Italy (Italian D.L. n.18 March 17, 2020) and "Bando Ricerca COVID-19 Toscana" project to Azienda Ospedaliero-Universitaria Senese. Private donors for COVID-19 research and charity funds from Intesa San Paolo.


Subject(s)
COVID-19/pathology , Peptides/genetics , Receptors, Androgen/genetics , Aged , Case-Control Studies , Critical Care/statistics & numerical data , Female , Genome, Human/genetics , Humans , Male , Middle Aged , Polymorphism, Single Nucleotide/genetics , Risk Factors , SARS-CoV-2 , Severity of Illness Index , Spain , Testosterone/blood
18.
Enferm Infecc Microbiol Clin (Engl Ed) ; 2020 Oct 13.
Article in English, Spanish | MEDLINE | ID: covidwho-856658
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