Higher COVID-19 pneumonia risk associated with anti-IFN-α than with anti-IFN-ω auto-Abs in children

We found that 19 (10.4%) of 183 unvaccinated children hospitalized for COVID-19 pneumonia had autoantibodies (auto-Abs) neutralizing type I IFNs (IFN-alpha 2 in 10 patients: IFN-alpha 2 only in three, IFN-alpha 2 plus IFN-omega in five, and IFN-alpha 2, IFN-omega plus IFN-beta in two; IFN-omega only in nine patients). Seven children (3.8%) had Abs neutralizing at least 10 ng/ml of one IFN, whereas the other 12 (6.6%) had Abs neutralizing only 100 pg/ml. The auto-Abs neutralized both unglycosylated and glycosylated IFNs. We also detected auto-Abs neutralizing 100 pg/ml IFN-alpha 2 in 4 of 2,267 uninfected children (0.2%) and auto-Abs neutralizing IFN-omega in 45 children (2%). The odds ratios (ORs) for life-threatening COVID-19 pneumonia were, therefore, higher for auto-Abs neutralizing IFN-alpha 2 only (OR [95% CI] = 67.6 [5.7-9,196.6]) than for auto-Abs neutralizing IFN-. only (OR [95% CI] = 2.6 [1.2-5.3]). ORs were also higher for auto-Abs neutralizing high concentrations (OR [95% CI] = 12.9 [4.6-35.9]) than for those neutralizing low concentrations (OR [95% CI] = 5.5 [3.1-9.6]) of IFN-omega and/or IFN-alpha 2

Pediatric Neutropenic Patients Care In Turkey

Objective: Infection is a common complication in children with malignancies. There is no consistent guidance for environmental infection control and isolation precautions for neutropenic patients (NP). There are differences between centers. The aim of this questionnaire study was to determine these differences in Turkey. Material and Methods: A multicenter-descriptive questionnaire was conducted on 36 centers from different geografical locations of Turkey. Bone marrow transplantation units were excluded. Each center was contacted at least three-times. Questionnaire was answered by two different doctors from each center. Results: Thirty-six centers including 20 (55.5%) University Hospitals, 12 (%33.3) Research Hospitals, three (8.3%) State Hospital and one Private University Hospital participated in this survey. 94.3% of the centers had a bed capacity of 50 beds and over. Twenty-one (58.3%) centers had pediatric infection ward that followed febrile NP. All centers had an infection control committee. 25% (9/36) of the centers always followed pediatric neutropenic fever patients in a single room. 66.6% (24/36) of the centers had toilet in all patients' room. The door features of patients' room included mostly (94.1%, 32/34) manually opened door. Ten (27.7%) centers had hepa filter system, five of them had positive-negative pressure room. Thirteen (38.2%, 13/34) centers prefered hickmann catheter for accessing a patient's central line. Training was given for catheteter care in all centers. Sixteen (44.4%) centers had determined policies about keeping toys in patient rooms. Visitor restrictions were performed in all centers. None of the centers allowed plants or flowers in hospital rooms. There was a neutropenic diet specific for pediatric NP provided in twenty-seven centers (75%). Conclusion: The prevention and control of infection contributes to the improvement of the prognosis of patients with hematological malignancies. Physicians must be aware of the infection risks and take precautions for infectious complications through the neutropenic period and standard protocols should be established and implemented for patients with hematological malignancies.WoSScopu

Türkiye’ de Pediatrik Nötropenik Hasta İzlemi

Objective: Infection is a common complication in children with malignancies. There is no consistent guidance for environmental infection control and isolation precautions for neutropenic patients (NP). There are differences between centers. the aim of this questionnaire study was to determine these differences in Turkey. Material and Methods: A multicenter-descriptive questionnaire was conducted on 36 centers from different geografical locations of Turkey. Bone marrow transplantation units were excluded. Each center was contacted at least three-times. Questionnaire was answered by two different doctors from each center. Results: Thirty-six centers including 20 (55.5%) University Hospitals, 12 (%33.3) Research Hospitals, three (8.3%) State Hospital and one Private University Hospital participated in this survey. 94.3% of the centers had a bed capacity of 50 beds and over. Twenty-one (58.3%) centers had pediatric infection ward that followed febrile NP. All centers had an infection control committee. 25% (9/36) of the centers always followed pediatric neutropenic fever patients in a single room. 66.6% (24/36) of the centers had toilet in all patients’ room. the door features of patients’ room included mostly (94.1%, 32/34) manually opened door. Ten (27.7%) centers had hepa filter system, five of them had positive-negative pressure room. Thirteen (38.2%, 13/34) centers prefered hickmann catheter for accessing a patient’s central line. Training was given for catheteter care in all centers. Sixteen (44.4%) centers had determined policies about keeping toys in patient rooms. Visitor restrictions were performed in all centers. None of the centers allowed plants or flowers in hospital rooms. There was a neutropenic diet specific for pediatric NP provided in twenty-seven centers (75%). Conclusion: the prevention and control of infection contributes to the improvement of the prognosis of patients with hematological malignancies. Physicians must be aware of the infection risks and take precautions for infectious complications through the neutropenic period and standard protocols should be established and implemented for patients with hematological malignancies.Giriş: Maligniteli hastaların tedavi sürecindeki en önemli komplikasyonlardan biri enfeksiyonlardır. Nötropenik hastalarda enfeksiyon kontrolü ve izolasyon önlemleri için merkezden merkeze değişen farklı uygulamalar mevcuttur. Anket çalışmasının amacı Türkiye’deki bu farklılıkları ve ihtiyaçları belirlemektir. Gereç ve Yöntemler: Çok merkezli tanımlayıcı çalışmaya Türkiye’nin farklı coğrafik bölgelerinden pediatrik nötropenik hasta takip eden 36 merkez dahil edildi. Kemik iliği transplantasyon üniteleri çalışmaya alınmadı. Her merkezle en az üç kez iletişime geçildi. Anketi her merkezden iki doktor yanıtladı. Anket kişisel, genel hasta bakımı ve nötropenik hasta bakımını içeren 64 sorudan oluşmaktaydı. Bulgular: Çalışmaya katılan merkezlerin 20 (%55.5)’si üniversite hastanesi, 12 (%33.3)’si eğitim araştırma hastanesi, 3 (%8.3)’ ü devlet hastanesi ve bir tanesi de özel üniversite hastanesi idi. Merkezlerin %94.3’ünün yatak kapasitesi 50 yatak ve üzerinde idi. Yirmi bir (%58) merkezin çocuk enfeksiyon hastalıkları servisi mevcuttu. Tüm merkezlerin enfeksiyon kontrol komitesi vardı. Merkezlerin %25 (n= 9)‘inde nötropenik ateş (NPA) tanısı alan çocuk hastalar tek kişilik odalarda izleniyordu. Tüm odalarda tuvalet bulunan merkez sayısı 24 (%66.6) idi. Hasta odalarının büyük çoğunluğunda elle açılıp kapanır kapı (%94.1) ve musluk (%97.1) mevcuttu. on (%27.7) merkezin oda havalandırması için hepa-filtreli sistemi vardı. Beşinde negatif basınçlı oda mevcuttu. on üç merkezde kateter olarak hickman kateter tercih edilmişti. Tüm merkezlerde kateter bakımı için eğitim verilmekte idi. Hiçbir merkezde hasta ziyaretine ve hastane odasında bitki veya çiçek bulundurmaya izin verilmemekteydi. Merkezlerin %45.7’sinde hastanede oyuncak bulundurma ile ilgili hastane politikası vardı. Sonuç: Sonuç olarak, nötropenik hastaları enfeksiyondan korumak için hastanelerde çeşitli yaklaşımlar uygulanmaktadır. Rehberler belirlenip bu rehberler ışığında hastane koşulları düzenlenmeli ve nötropenik hasta izlemi yapılmalıdır

Epidemiological, Clinical, and Laboratory Features of Children With COVID-19 in Turkey

Objectives: The aim of this study is to identify the epidemiological, clinical, and laboratory features of coronavirus disease 2019 (COVID-19) in children

Human genetic and immunological determinants of critical COVID-19 pneumonia

SARS-CoV-2 infection is benign in most individuals but, in around 10% of cases, it triggers hypoxaemic COVID-19 pneumonia, which leads to critical illness in around 3% of cases. The ensuing risk of death (approximately 1% across age and gender) doubles every five years from childhood onwards and is around 1.5 times greater in men than in women. Here we review the molecular and cellular determinants of critical COVID-19 pneumonia. Inborn errors of type I interferons (IFNs), including autosomal TLR3 and X-chromosome-linked TLR7 deficiencies, are found in around 1-5% of patients with critical pneumonia under 60 years old, and a lower proportion in older patients. Pre-existing auto-antibodies neutralizing IFN alpha, IFN beta and/or IFN omega, which are more common in men than in women, are found in approximately 15-20% of patients with critical pneumonia over 70 years old, and a lower proportion in younger patients. Thus, at least 15% of cases of critical COVID-19 pneumonia can be explained. The TLR3- and TLR7-dependent production of type I IFNs by respiratory epithelial cells and plasmacytoid dendritic cells, respectively, is essential for host defence against SARS-CoV-2. In ways that can depend on age and sex, insufficient type I IFN immunity in the respiratory tract during the first few days of infection may account for the spread of the virus, leading to pulmonary and systemic inflammation

Recessive inborn errors of type I IFN immunity in children with COVID-19 pneumonia

In an international cohort of 112 children hospitalized for moderate to critical COVID-19 pneumonia, we identified 12 children with one of four known recessive inborn errors of type I interferon immunity: X-linked TLR7 and autosomal IFNAR1, STAT2, and TYK2 deficiencies.Recessive or dominant inborn errors of type I interferon (IFN) immunity can underlie critical COVID-19 pneumonia in unvaccinated adults. The risk of COVID-19 pneumonia in unvaccinated children, which is much lower than in unvaccinated adults, remains unexplained. In an international cohort of 112 children (<16 yr old) hospitalized for COVID-19 pneumonia, we report 12 children (10.7%) aged 1.5-13 yr with critical (7 children), severe (3), and moderate (2) pneumonia and 4 of the 15 known clinically recessive and biochemically complete inborn errors of type I IFN immunity: X-linked recessive TLR7 deficiency (7 children) and autosomal recessive IFNAR1 (1), STAT2 (1), or TYK2 (3) deficiencies. Fibroblasts deficient for IFNAR1, STAT2, or TYK2 are highly vulnerable to SARS-CoV-2. These 15 deficiencies were not found in 1,224 children and adults with benign SARS-CoV-2 infection without pneumonia (P = 1.2 x 10(-11)) and with overlapping age, sex, consanguinity, and ethnicity characteristics. Recessive complete deficiencies of type I IFN immunity may underlie similar to 10% of hospitalizations for COVID-19 pneumonia in children

Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

BackgroundWe previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15-20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in similar to 80% of cases.MethodsWe report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded.ResultsNo gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5-528.7, P=1.1x10(-4)) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR=3.70[95%CI 1.3-8.2], P=2.1x10(-4)). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR=19.65[95%CI 2.1-2635.4], P=3.4x10(-3)), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR=4.40[9%CI 2.3-8.4], P=7.7x10(-8)). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD]=43.3 [20.3] years) than the other patients (56.0 [17.3] years; P=1.68x10(-5)).ConclusionsRare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old