Mechanisms underlying host defense and disease pathology in response to severe acute respiratory syndrome (SARS)-CoV2 infection: insights from inborn errors of immunity

Tangye, Stuart G.; Bucciol, Giorgia; Meyts, Isabelle

doi:10.1097/aci.0000000000000786

Cited by 20 publications

(15 citation statements)

References 106 publications

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“…However, as our other SARS-CoV-2 infected A-T patients, including those with a HIgM phenotype, did not have severe COVID-19 (Table S4 ), the ATM mutation identified here is probably underlying the primary antibody deficiency (HIgM) in this patient, but not the critical COVID-19. This notion is supported by previous observations among other SARS-CoV-2 infected IEI patients worldwide where almost no AT patient has been reported despite its high frequency compared to other IEI entities [ 27 , 28 ]. In contrast, the TLR7 mutation, which impairs the function of the protein (Fig.…”

Section: Discussionsupporting

confidence: 85%

X-Linked TLR7 Deficiency Underlies Critical COVID-19 Pneumonia in a Male Patient with Ataxia-Telangiectasia

et al. 2021

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Background Coronavirus disease 2019 (COVID-19) exhibits a wide spectrum of clinical manifestations, ranging from asymptomatic to critical conditions. Understanding the mechanism underlying life-threatening COVID-19 is instrumental for disease prevention and treatment in individuals with a high risk. Objectives We aimed to identify the genetic cause for critical COVID-19 pneumonia in a patient with a preexisting inborn error of immunity (IEI). Methods Serum levels of specific antibodies against the virus and autoantibodies against type I interferons (IFNs) were measured. Whole exome sequencing was performed, and the impacts of candidate gene variants were investigated. We also evaluated 247 ataxia-telangiectasia (A-T) patients in the Iranian IEI registry. Results We report a 7-year-old Iranian boy with a preexisting hyper IgM syndrome who developed critical COVID-19 pneumonia. IgM only specific COVID-19 immune response was detected but no autoantibodies against type I IFN were observed. A homozygous deleterious mutation in the ATM gene was identified, which together with his antibody deficiency, radiosensitivity, and neurological signs, established a diagnosis of A-T. Among the 247 A-T patients evaluated, 36 had SARS-CoV-2 infection, but all had mild symptoms or were asymptomatic except the index patient. A hemizygous deleterious mutation in the TLR7 gene was subsequently identified in the patient. Conclusions We report a unique IEI patient with combined ATM and TLR7 deficiencies. The two genetic defects underlie A-T and critical COVID-19 in this patient, respectively.

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Section: Discussionsupporting

confidence: 85%

X-Linked TLR7 Deficiency Underlies Critical COVID-19 Pneumonia in a Male Patient with Ataxia-Telangiectasia

et al. 2021

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“…The main risk factors of worse outcome in the general population include older age, male sex, and pre-existing comorbidities. Recent studies suggest that the clinical course of the infection may not be different in patient with inborn errors of immunity (IEI) compared to the general population [ 2 – 4 ]. However, since IEI are a heterogeneous group of disorders including more than 400 different clinical conditions [ 5 ], more studies are necessary to better define the outcome of the infection in the different forms.…”

Section: Introductionmentioning

confidence: 99%

The Impact of SARS-CoV-2 Infection in Patients with Inborn Errors of Immunity: the Experience of the Italian Primary Immunodeficiencies Network (IPINet)

Giardino¹,

Milito

Lougaris

et al. 2022

J Clin Immunol

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COVID-19 manifestations range from asymptomatic to life-threatening infections. The outcome in different inborn errors of immunity (IEI) is still a matter of debate. In this retrospective study, we describe the experience of the of the Italian Primary Immunodeficiencies Network (IPINet). Sixteen reference centers for adult or pediatric IEI were involved. One hundred fourteen patients were enrolled including 35 pediatric and 79 adult patients. Median age was 32 years, and male-to-female ratio was 1.5:1. The most common IEI were 22q11.2 deletion syndrome in children (26%) and common variable immunodeficiency (CVID) in adults (65%). Ninety-one patients did not require hospital admission, and among these, 33 were asymptomatic. Hospitalization rate was 20.17%. Older age (p 0.004) and chronic lung disease (p 0.0008) represented risk factors for hospitalization. Hospitalized patients mainly included adults suffering from humoral immunodeficiencies requiring immunoglobulin replacement therapy and as expected had lower B cell counts compared to non-hospitalized patients. Infection fatality rate in the whole cohort was 3.5%. Seroconversion was observed is 86.6% of the patients evaluated and in 83.3% of CVID patients. 16.85% of the patients reported long-lasting COVID symptoms. All but one patient with prolonged symptoms were under IgRT. The fatality rate observed in IEI was slightly similar to the general population. The age of the patients who did not survive was lower compared to the general population, and the age stratified mortality in the 50–60 age range considerable exceeded the mortality from 50 to 60 age group of the Italian population (14.3 vs 0.6%; p < 0.0001). We hypothesize that this is due to the fact that comorbidities in IEI patients are very common and usually appear early in life.

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“…Several studies have documented outcomes of SARS-CoV-2 infection in patients with known IEI, ranging from case reports and single-centre case series to larger, multicentre cohort studies [56]. To our knowledge, a total of 9 larger studies have been conducted that collectively report on 545 IEI patients; the findings of these studies have been summarized in Table 2 [57][58][59][60][61][62][63][64][65].…”

Section: Covid-19 In Patients With Known Inborn Errors Of Immunitymentioning

confidence: 99%

Clinical implications of host genetic variation and susceptibility to severe or critical COVID-19

et al. 2022

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Since the start of the coronavirus disease 2019 (COVID-19) pandemic, important insights have been gained into virus biology and the host factors that modulate the human immune response against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 displays a highly variable clinical picture that ranges from asymptomatic disease to lethal pneumonia. Apart from well-established general risk factors such as advanced age, male sex and chronic comorbidities, differences in host genetics have been shown to influence the individual predisposition to develop severe manifestations of COVID-19. These differences range from common susceptibility loci to rare genetic variants with strongly predisposing effects, or proven pathogenic variants that lead to known or novel inborn errors of immunity (IEI), which constitute a growing group of heterogeneous Mendelian disorders with increased susceptibility to infectious disease, auto-inflammation, auto-immunity, allergy or malignancies. The current genetic findings point towards a convergence of common and rare genetic variants that impact the interferon signalling pathways in patients with severe or critical COVID-19. Monogenic risk factors that impact IFN-I signalling have an expected prevalence between 1 and 5% in young, previously healthy individuals (<60 years of age) with critical COVID-19. The identification of these IEI such as X-linked TLR7 deficiency indicates a possibility for targeted genetic screening and personalized clinical management. This review aims to provide an overview of our current understanding of the host genetic factors that predispose to severe manifestations of COVID-19 and focuses on rare variants in IFN-I signalling genes and their potential clinical implications.

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Mechanisms underlying host defense and disease pathology in response to severe acute respiratory syndrome (SARS)-CoV2 infection: insights from inborn errors of immunity

Cited by 20 publications

References 106 publications

X-Linked TLR7 Deficiency Underlies Critical COVID-19 Pneumonia in a Male Patient with Ataxia-Telangiectasia

X-Linked TLR7 Deficiency Underlies Critical COVID-19 Pneumonia in a Male Patient with Ataxia-Telangiectasia

The Impact of SARS-CoV-2 Infection in Patients with Inborn Errors of Immunity: the Experience of the Italian Primary Immunodeficiencies Network (IPINet)

Clinical implications of host genetic variation and susceptibility to severe or critical COVID-19

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