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1.
Genet Med ; 2022 May 05.
Article in English | MEDLINE | ID: covidwho-1819495

ABSTRACT

PURPOSE: Emerging evidence suggest that infection-dependent hyperactivation of complement system (CS) may worsen COVID-19 outcome. We investigated the role of predicted high impact rare variants - referred as qualifying variants (QVs) - of CS genes in predisposing asymptomatic COVID-19 in elderly individuals, known to be more susceptible to severe disease. METHODS: Exploiting exome sequencing data and 56 CS genes, we performed a gene-based collapsing test between 164 asymptomatic subjects (aged ≥60 years) and 56,885 European individuals from the Genome Aggregation Database. We replicated this test comparing the same asymptomatic individuals with 147 hospitalized patients with COVID-19. RESULTS: We found an enrichment of QVs in 3 genes (MASP1, COLEC11, and COLEC10), which belong to the lectin pathway, in the asymptomatic cohort. Analyses of complement activity in serum showed decreased activity of lectin pathway in asymptomatic individuals with QVs. Finally, we found allelic variants associated with asymptomatic COVID-19 phenotype and with a decreased expression of MASP1, COLEC11, and COLEC10 in lung tissue. CONCLUSION: This study suggests that genetic rare variants can protect from severe COVID-19 by mitigating the activity of lectin pathway and prothrombin. The genetic data obtained through ES of 786 asymptomatic and 147 hospitalized individuals are publicly available at http://espocovid.ceinge.unina.it/.

2.
Healthcare (Basel) ; 10(3)2022 Mar 12.
Article in English | MEDLINE | ID: covidwho-1742404

ABSTRACT

BACKGROUND: Our hospital became a referral center for COVID-19-positive obstetric patients from 1 May 2020. The aim of our study is to illustrate our management protocols for COVID-19-positive obstetric patients, to maintain safety standards for patients and healthcare workers. METHODS: Women who underwent vaginal or operative delivery and induced or spontaneous abortion with a SARS-CoV-2-positive nasopharyngeal swab using real-time PCR (RT-PCR) were included in the study. Severity and onset of new symptoms were carefully monitored in the postoperative period. All the healthcare workers received a nasopharyngeal swab for SARS-CoV-2 using RT-PCR serially every five days. RESULTS: We included 152 parturients with COVID-19 infection. None of the included women had general anesthesia, an increase of severe symptoms or onset of new symptoms. The RT-PCR test was "negative" for the healthcare workers. CONCLUSIONS: In our study, neuraxial anesthesia for parturients' management with SARS-CoV-2 infection has been proven to be safe for patients and healthcare workers. Neuraxial anesthesia decreases aerosolization during preoxygenation, face-mask ventilation, endotracheal intubation, oral or tracheal suctioning and extubation. This anesthesia management protocol can be generalizable.

3.
Int J Mol Sci ; 23(4)2022 Feb 09.
Article in English | MEDLINE | ID: covidwho-1690219

ABSTRACT

The development of prophylactic agents against the SARS-CoV-2 virus is a public health priority in the search for new surrogate markers of active virus replication. Early detection markers are needed to follow disease progression and foresee patient negativization. Subgenomic RNA transcripts (with a focus on sgN) were evaluated in oro/nasopharyngeal swabs from COVID-19-affected patients with an analysis of 315 positive samples using qPCR technology. Cut-off Cq values for sgN (Cq < 33.15) and sgE (Cq < 34.06) showed correlations to high viral loads. The specific loss of sgN in home-isolated and hospitalized COVID-19-positive patients indicated negativization of patient condition, 3-7 days from the first swab, respectively. A new detection kit for sgN, gene E, gene ORF1ab, and gene RNAse P was developed recently. In addition, in vitro studies have shown that 2'-O-methyl antisense RNA (related to the sgN sequence) can impair SARS-CoV-2 N protein synthesis, viral replication, and syncytia formation in human cells (i.e., HEK-293T cells overexpressing ACE2) upon infection with VOC Alpha (B.1.1.7)-SARS-CoV-2 variant, defining the use that this procedure might have for future therapeutic actions against SARS-CoV-2.


Subject(s)
COVID-19/virology , Coronavirus Nucleocapsid Proteins/genetics , SARS-CoV-2/physiology , Virus Replication/physiology , Coronavirus Nucleocapsid Proteins/analysis , Giant Cells/drug effects , Giant Cells/virology , HEK293 Cells , Humans , Limit of Detection , Nasopharynx/virology , Phosphoproteins/analysis , Phosphoproteins/genetics , RNA, Antisense/pharmacology , RNA, Viral , Ribonuclease P/genetics , SARS-CoV-2/drug effects , SARS-CoV-2/genetics , Sensitivity and Specificity , Social Isolation , Viral Load , Viroporin Proteins/genetics , Virus Replication/drug effects
4.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-323217

ABSTRACT

Introduction: Patients with severe pneumonia due COVID-19 are reported to have substantially lower lymphocyte counts and higher plasma concentrations of a number of inflammatory cytokines. In the late stages of COVID-19, cytokine storms are the mainly cause of disease progression and death. We performed a prospective observational study to evaluate the impact of tocilizumab and hydrocortisone on cytokine storm in critically ill patients with COVID-19. Methods: : We included all adult patients with laboratory-confirmed COVID-19 infection and severe respiratory failure admitted to our ICU from March 10 to April 30. As therapeutic options, patients received tocilizumab od hydrocortisone. The primary end point was the evaluation of cytokine storm in terms of variation of the IL-6 and IL-6R, sgp130 and TNF-α concentrations during time to different treatment. Results: : Eight patients received tocilizumab while 15 patients received hydrocortisone. IL-6 levels were lower in the hydrocortisone group with statistical significance was found at the days 2, 3, 8 and 9. The levels of IL-6R were lower during the days in the hydrocortisone group with statistical significance at days 1, 2, 3, 4, 5, 6, 8 and 10. Hydrocortisone group had higher levels of TNF-α at days 2, 3 and 4. The levels of sgo130 between tocilizumab and hydrocortisone groups were not statistically different during the days. Conclusions: : In critically ill patients with severe COVID-19, the use of hydrocortisone allowed a better control of the cytokine storms, was further associated to less days of curarization, pronation and length of stay in ICU, and speed up the time to get negative RT-PCR swab.

5.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-318815

ABSTRACT

Background: To date, very few studies on clinical-histopathological correlations of cutaneous disorders associated with COVID-19 have been conducted. Case presentation: The Case 1 was a 90-year-old man, who tested positive for SARS-CoV-2 from a nasopharyngeal swab. Two days later, he was hospitalized and after eleven days transferred to Intensive Care Unit. A chest CT showed bilateral ground-glass opacities. Just that day, an erythematous maculo-papular rash appeared on trunk, shoulders and neck, becoming purpuric after few days. Histological evaluations revealed a chronic superficial dermatitis with purpuric aspects. The superficial and papillary dermis appeared edematous, with a perivascular lympho-granulocytic infiltrate and erythrocytic extravasation. At intraepithelial level, spongiosis and a granulocyte infiltrate were detected. Arterioles, capillaries and post-capillary venules showed endothelial swelling and appeared ectatic. The patient was treated with hydroxychloroquine, azithromycin, lopinavir-ritonavir and tocilizumab. Regrettably, due to severe lung impairment, he died.The Case 2 was a 85-year-old man, admitted to Intensive Care Unit, where he was intubated. He had tested positive for SARS-CoV-2 from a nasopharyngeal swab two days before. A chest RX showed bilateral atypical pneumonia. After seven days, a cutaneous reddening involving trunk, upper limbs, neck and face developed, configuring a sub-erythroderma. Histological evaluations displayed edema in the papillary and superficial reticular dermis, and a perivascular lymphocytic infiltrate in the superficial dermis. The patient was treated with hydroxychloroquine, azithromycin, lopinavir-ritonavir and tocilizumab. Sub-erythroderma as well as respiratory symptoms gradually improved until healing. Conclusions: : The endothelial swelling detected in the Case 1 could be a morphological expression of SARS-CoV-2-induced endothelial dysfunction. We hypothesize that cutaneous damage could be initiated by endothelial dysfunction, caused by SARS-CoV-2 infection of endothelial cells or induced by immune system activation. The disruption of endothelial integrity could enhance microvascular permeability, extravasation of inflammatory cells and cytokines, with cutaneous injury. The Case 2 developed a sub-erythroderma associated with COVID-19, and a non-specific chronic dermatitis was detected at histological level. We speculate that a purpuric rash could represent the cutaneous sign of a more severe coagulopathy, as highlighted histologically by vascular abnormalities, while a sub-erythroderma could be expression of viral hematogenous spreading, inducing a non-specific chronic dermatitis.

6.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-308974

ABSTRACT

Aim: . To investigate the prevalence and prognostic impact of right heart failure and right ventricular-arterial uncoupling in Corona Virus Infectious Disease 2019 ( COVID-19) complicated by an acute respiratory distress syndrome (ARDS). Methods: . Ninety-four consecutive patients (mean age 64 yrs) admitted for acute respiratory failure on COVID-19 were enrolled. Coupling of right ventricular function to the pulmonary circulation was evaluated by a comprehensive trans-thoracic echocardiography with focus on the tricuspid annular plane systolic excursion (TAPSE) to systolic pulmonary artery pressure (PASP) ratio Results: . The majority of patients needed ventilatory support, which was non-invasive in 22 and invasive in 37. There were 25 deaths, all in the invasively ventilated patients. Survivors were younger (62±13 vs 68±12 years, p =0.033), less often overweight or usual smokers, had lower NT-proBNP and interleukin-6, and higher arterial partial pressure of oxygen (PaO 2 )/fraction of inspired O 2 (FIO 2 ) ratio (270±104 vs 117±57 mmHg, p <0.001). In the non-survivors, PASP was increased (42±12 vs 30±7 mmHg, p <0.001), while TAPSE was decreased (19±4 vs 25±4 mm, p<0.001). Accordingly the TAPSE/PASP ratio was lower than in the survivors (0.51±0.22 vs 0.89±0.29 mm/mmHg, p <0.001). At univariate/multivariable analysis, the TAPSE/PASP (HR:0.026;95%CI:0.01-0.579;p:0.019) and PaO 2 /FIO 2 (HR:0.988;95%CI:0.988-0.998;p:0.018) ratios were the only independent predictors of mortality, with ROC-determined cut-off values of 159 mmHg and 0.635 mm/mmHg respectively. Conclusions: . COVID-19 ARDS is associated with clinically relevant uncoupling of right ventricular function from the pulmonary circulation;bedside echocardiography of TAPSE/PASP adds to the prognostic relevance of PaO 2 /FIO 2 in ARDS on COVID-19.

7.
Eur J Neurol ; 28(10): 3375-3383, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1604393

ABSTRACT

BACKGROUND AND PURPOSE: In multiple sclerosis (MS), disease-related factors and dysfunctional coping might favor the development of mental distress induced by COVID-19 containment measures. Aim of this study was exploring the relationship between disability, coping strategies, daily life reorganization and neuropsychiatric symptoms in an Italian MS population during the COVID-19 lockdown, in order to identify potentially modifiable factors that could inform clinical management of mental distress in people with MS. METHODS: We explored the relationship between mental distress, disability and coping strategies in the Italian MS population under lockdown. Structural equation modeling was applied to information collected via web survey to identify modifiable factors that could account for mental distress. RESULTS: A total of 845 participants (497 with MS and 348 controls) were included in the study. The MS group had higher scores than the control group for depression (p = 0.005), but not for anxiety, emotional dyscontrol or sleep disturbances. The structural equation modeling explained 74% of the variance observed in depression score. Within the model, three latent factors were characterized from measured variables: motor disability and cognitive dysfunction contributed to disability (ß = 0.509 and ß = 0.836; p < 0.001); positive attitude and exercise contributed to active attitude (ß = 0.386 and ß = 0.297; p < 0.001); and avoidance, social support and watching television contributed to passive attitude (ß = 0.301, ß = 0.243 and ß = 0.212; p < 0.001). With regard to the relationship between latent factors and their influence on depression, disability contributed to passive attitude (ß = 0.855; p < 0.001), while both passive and active attitude significantly influenced depression (ß = 0.729 and ß = -0.456; p < 0.001). CONCLUSION: As a practical implication of our model, favoring exercise would enhance active attitude and its positive impact on mental well-being while, at the same time, reducing the negative impact of disability on depression, representing a valuable tool in facing COVID-19-related mental distress.


Subject(s)
COVID-19 , Disabled Persons , Motor Disorders , Multiple Sclerosis , Anxiety , Communicable Disease Control , Depression/epidemiology , Humans , Multiple Sclerosis/epidemiology , Pandemics , SARS-CoV-2 , Surveys and Questionnaires
8.
J Clin Med ; 10(22)2021 Nov 14.
Article in English | MEDLINE | ID: covidwho-1512417

ABSTRACT

BACKGROUND: The effectiveness of corticosteroids in acute respiratory distress syndrome (ARDS) and COVID-19 still remains uncertain. Since ARDS is due to a hyperinflammatory response to a direct injury, we decided to perform a meta-analysis and an evaluation of robustness of randomised clinical trials (RCTs) investigating the impact of corticosteroids on mortality in ARDS in both COVID-19 and non-COVID-19 patients. We conducted a systematic search of the literature from inception up to 30 October 2020, using the MEDLINE database and the PubMed interface. We evaluated the fragility index (FI) of the included RCTs using a two-by-two contingency table and the p-value produced by the Fisher exact test; the fragility quotient (FQ) was calculated by dividing the FI score by the total sample size of the trial. RESULTS: Thirteen RCTs were included in the analysis; five of them were conducted in COVID-19 ARDS, including 7692 patients, while 8 RCTS were performed in non-COVID ARDS with 1091 patients evaluated. Three out of eight RCTs in ARDS had a FI > 0 while 2 RCTs out of five in COVID-19 had FI > 0. The median of FI for ARDS was 0.625 (0.47) while the median of FQ was 0.03 (0.014). The median of FI for COVID-19 was 6 (2) while the median of FQ was 0.059 (0.055). In this systematic review, we found that FI and FQ of RCTs evaluating the use of corticosteroids in ARDS and COVID-19 were low.

9.
J Clin Med ; 10(21)2021 Oct 25.
Article in English | MEDLINE | ID: covidwho-1480827

ABSTRACT

BACKGROUND: A high incidence of venous thromboembolism (VTE) is reported in hospitalized COVID-19 patients, in particular in patients admitted to the intensive care unit (ICU). In patients with respiratory tract infections, including influenza A (H1N1), many studies have demonstrated an increased incidence of thromboses, but evidence is lacking regarding the risk difference (RD) of the occurrence of VTE between COVID-19 and non-COVID-19 patients. METHODS: In this systematic review with meta-analysis, we evaluated the RD of the occurrence of VTE, pulmonary embolism (PE), and deep venous thrombosis (DVT) between COVID-19 and other pulmonary infection cohorts, in particular H1N1, and in an ICU setting. We searched for all studies comparing COVID-19 vs. non-COVID-19 regarding VTE, PE, and DVT. RESULTS: The systematic review included 12 studies and 1,013,495 patients. The RD for VTE in COVID-19 compared to non-COVID-19 patients was 0.06 (95% CI 0.11-0.25, p = 0.011, I2 = 97%), and 0.16 in ICU (95% CI 0.045-0.27, p = 0.006, I2 = 80%). The RD for PE between COVID-19 and non-COVID-19 patients was 0.03 (95% CI, 0.006-0.045, p = 0.01, I2 = 89%). The RD for PE between COVID-19 and non-COVID-19 patients was 0.021 in retrospective studies (95% CI 0.00-0.04, p = 0.048, I2 = 92%) and 0.11 in ICU studies (95% CI 0.06-0.16, p < 0.001, I2 = 0%). CONCLUSIONS: The growing awareness and understanding of a massive inflammatory response combined with a hypercoagulable state that predisposes patients to thrombosis in COVID-19, in particular in the ICU, may contribute to a more appropriate strategy of prevention and earlier detection of the thrombotic events.

10.
J Clin Med ; 10(21)2021 Oct 24.
Article in English | MEDLINE | ID: covidwho-1480825

ABSTRACT

The Coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, has rapidly spread to become a global pandemic, putting a strain on health care systems. SARS-CoV-2 infection may be associated with mild symptoms or, in severe cases, lead patients to the intensive care unit (ICU) or death. The critically ill patients suffer from acute respiratory distress syndrome (ARDS), sepsis, thrombotic complications and multiple organ failure. For optimization of hospital resources, several molecular markers and algorithms have been evaluated in order to stratify COVID-19 patients, based on the risk of developing a mild, moderate, or severe disease. Here, we propose the soluble urokinase receptor (suPAR) as a serum biomarker of clinical severity and outcome in patients who are hospitalized with COVID-19. In patients with mild disease course, suPAR levels were increased as compared to healthy controls, but they were dramatically higher in severely ill patients. Since early identification of disease progression may facilitate the individual management of COVID-19 symptomatic patients and the time of admission to the ICU, we suggest paying more clinical attention on patients with high suPAR levels.

11.
Clin Case Rep ; 9(8): e04192, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1366215

ABSTRACT

The best anesthesiologic approach to severe AS patient has not been adequately studied in literature. Although the current guidelines have a cautious attitude in this regard, Combined Spinal-Epidural Anesthesia (CSEA) has proved to be a safe technique. Therefore, we would like to provide our experience with a severe AS and COVID-19 patient.

12.
Semin Thromb Hemost ; 48(1): 100-108, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1356593

ABSTRACT

Coagulation abnormalities, thrombosis, and endothelial dysfunction have been described in COVID-19 patients. Spontaneous muscle hematoma (SMH) is a rare complication in COVID-19. The aims of this study are to: (1) perform a systematic review of the literature to better define the clinical SMH characteristics, (2) describe the prevalence and the clinical characteristics of SMH in COVID-19 patients referring to a Department of Internal Medicine (IM) (Federico II University of Naples), a Department of Sub-Intensive Care Medicine (SIM) (Ospedale Del Mare), and a Department of Intensive Care Unit (ICU) (Federico II University). The systematic review was performed according to PRISMA criteria. The local prevalence of SMH in COVID-19 was evaluated retrospectively. The medical records of all COVID-19 patients referring to IM and ICU from March 11th, 2020, to February 28th, 2021 were examined for SMH occurrence. In our retrospective analysis, we describe 10 cases of COVID-19 patients with SMH not previously reported in literature, with a prevalence of 2.1%. The literature review, inclusive of our case series, describes a total of 50 SMHs in COVID-19 patients (57.4% males; mean age 68.8 ± 10.0 years). The SMH sites were ileo-psoas, vastus intermedius, gluteus, sternocleidomastoid, and pectoralis major muscles. Males developed SMH earlier than females (9.5 ± 7.8 vs. 17.1 ± 9.7 days). Ileo-psoas hematoma was more frequent in males (69.2 vs. 30.8%), while pectoralis major hematoma occurred only in females. The in-hospital mortality rate of SMH in COVID-19 patients was 32.4%. SMH is a rare but severe complication in COVID-19 hospitalized patients, associated with high mortality. A gender difference seems to be present in the clinical presentation of the disorder.


Subject(s)
COVID-19 , Aged , Animals , Female , Hematoma/diagnostic imaging , Hematoma/etiology , Horses , Humans , Male , Middle Aged , Muscles , Retrospective Studies , SARS-CoV-2
14.
J Clin Med ; 10(12)2021 Jun 21.
Article in English | MEDLINE | ID: covidwho-1282524

ABSTRACT

Increased concentrations of B-type natriuretic peptide (BNP), N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity troponin I (HsTnI) in COVID-19 patients have already been reported. The aim of this study is to evaluate which of these common markers of cardiac disease is the most useful predictor of fatal outcome in COVID-19 patients. One hundred and seventy-four patients affected with COVID-19 were recruited, and markers of cardiac disease and the clinical history of the patients were collected at admission in the infectious disease unit or intensive care unit. NT-proBNP, BNP and HsTnI values were higher in in-hospital non-surviving patients. Receiver operating characteristic (ROC) curve analysis of NT-proBNP, BNP and HsTnI was performed, with NT-proBNP (AUC = 0.951) and HsTnI (AUC = 0.947) being better performers (p = 0.01) than BNP (AUC = 0.777). Logistic regression was performed assessing the relation of HsTnI and NT-proBNP to fatal outcome adjusting for age and gender, with only NT-proBNP being significant. The population was then divided into two groups, one with higher NT-proBNP values at admission than the cut-off resulted from the ROC curve (511 ng/L) and a second one with lower values. The Kaplan-Meier analysis showed an absence of fatal outcome in the group of patients with NT-proBNP values lower than the cut-off (p < 0.001). NT-proBNP proved to be the best prognostic tool for fatal outcome among markers of cardiac disease in COVID-19 patients.

15.
J Clin Med ; 10(12)2021 Jun 16.
Article in English | MEDLINE | ID: covidwho-1273471

ABSTRACT

BACKGROUND: Tracheostomy can be performed safely in patients with coronavirus disease 2019 (COVID-19). However, little is known about the optimal timing, effects on outcome, and complications. METHODS: A multicenter, retrospective, observational study. This study included 153 tracheostomized COVID-19 patients from 11 intensive care units (ICUs). The primary endpoint was the median time to tracheostomy in critically ill COVID-19 patients. Secondary endpoints were survival rate, length of ICU stay, and post-tracheostomy complications, stratified by tracheostomy timing (early versus late) and technique (surgical versus percutaneous). RESULTS: The median time to tracheostomy was 15 (1-64) days. There was no significant difference in survival between critically ill COVID-19 patients who received tracheostomy before versus after day 15, nor between surgical and percutaneous techniques. ICU length of stay was shorter with early compared to late tracheostomy (p < 0.001) and percutaneous compared to surgical tracheostomy (p = 0.050). The rate of lower respiratory tract infections was higher with surgical versus percutaneous technique (p = 0.007). CONCLUSIONS: Among critically ill patients with COVID-19, neither early nor percutaneous tracheostomy improved outcomes, but did shorten ICU stay. Infectious complications were less frequent with percutaneous than surgical tracheostomy.

16.
Genes (Basel) ; 12(6)2021 06 08.
Article in English | MEDLINE | ID: covidwho-1264428

ABSTRACT

To identify host genetic determinants involved in humoral immunity and associated with the risk of developing severe COVID-19, we analyzed 500 SARS-CoV-2 positive subjects from Southern Italy. We examined the coding sequences of 10 common variable immunodeficiency-associated genes obtained by the whole-exome sequencing of 121 hospitalized patients. These 10 genes showed significant enrichment in predicted pathogenic point mutations in severe patients compared with the non-severe ones. Moreover, in the TNFRSF13C gene, the minor allele of the p.His159Tyr variant, which is known to increase NF-kB activation and B-cell production, was significantly more frequent in the 38 severe cases compared to both the 83 non-severe patients and the 375 asymptomatic subjects further genotyped. This finding identified a potential genetic risk factor of severe COVID-19 that not only may serve to unravel the mechanisms underlying the disease severity but, also, may contribute to build the rationale for individualized management based on B-cell therapy.


Subject(s)
B-Cell Activation Factor Receptor/genetics , COVID-19/etiology , COVID-19/genetics , Female , Gene Frequency , Humans , Italy , Male , Middle Aged , Polymorphism, Single Nucleotide , Retrospective Studies , Severity of Illness Index
17.
J Infect Public Health ; 14(7): 906-909, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1244769

ABSTRACT

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is most closely related to severe respiratory syndrome; however, recent reports showed that it is capable of causing neurological disease. Here we report a case-series of 4 critically ill COVID-19 patients who recovered from pneumonia but showed serious neurological symptoms and eventually died.


Subject(s)
Brain Diseases , COVID-19 , Brain/diagnostic imaging , Critical Illness , Humans , SARS-CoV-2
18.
Int J Mol Sci ; 22(10)2021 May 20.
Article in English | MEDLINE | ID: covidwho-1244036

ABSTRACT

Genome-wide association studies (GWAS) found locus 3p21.31 associated with severe COVID-19. CCR5 resides at the same locus and, given its known biological role in other infection diseases, we investigated if common noncoding and rare coding variants, affecting CCR5, can predispose to severe COVID-19. We combined single nucleotide polymorphisms (SNPs) that met the suggestive significance level (P ≤ 1 × 10-5) at the 3p21.31 locus in public GWAS datasets (6406 COVID-19 hospitalized patients and 902,088 controls) with gene expression data from 208 lung tissues, Hi-C, and Chip-seq data. Through whole exome sequencing (WES), we explored rare coding variants in 147 severe COVID-19 patients. We identified three SNPs (rs9845542, rs12639314, and rs35951367) associated with severe COVID-19 whose risk alleles correlated with low CCR5 expression in lung tissues. The rs35951367 resided in a CTFC binding site that interacts with CCR5 gene in lung tissues and was confirmed to be associated with severe COVID-19 in two independent datasets. We also identified a rare coding variant (rs34418657) associated with the risk of developing severe COVID-19. Our results suggest a biological role of CCR5 in the progression of COVID-19 as common and rare genetic variants can increase the risk of developing severe COVID-19 by affecting the functions of CCR5.


Subject(s)
COVID-19/genetics , COVID-19/metabolism , Genetic Predisposition to Disease , Receptors, CCR5/genetics , Receptors, CCR5/metabolism , Alleles , Bronchi/metabolism , Bronchi/pathology , Bronchi/virology , COVID-19/physiopathology , Chromosomes, Human/genetics , Cohort Studies , Computational Biology , Databases, Genetic , Genome-Wide Association Study , Genotype , Humans , Lung/metabolism , Lung/pathology , Lung/virology , Polymorphism, Single Nucleotide , Whole Exome Sequencing
20.
iScience ; 24(4): 102322, 2021 Apr 23.
Article in English | MEDLINE | ID: covidwho-1144743

ABSTRACT

The established risk factors of coronavirus disease 2019 (COVID-19) are advanced age, male sex, and comorbidities, but they do not fully explain the wide spectrum of disease manifestations. Genetic factors implicated in the host antiviral response provide for novel insights into its pathogenesis. We performed an in-depth genetic analysis of chromosome 21 exploiting the genome-wide association study data, including 6,406 individuals hospitalized for COVID-19 and 902,088 controls with European genetic ancestry from the COVID-19 Host Genetics Initiative. We found that five single nucleotide polymorphisms within TMPRSS2 and near MX1 gene show associations with severe COVID-19. The minor alleles of the five single nucleotide polymorphisms (SNPs) correlated with a reduced risk of developing severe COVID-19 and high level of MX1 expression in blood. Our findings demonstrate that host genetic factors can influence the different clinical presentations of COVID-19 and that MX1 could be a potential therapeutic target.

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