Clinical and laboratory evaluation of Turkish children with IgG subclass deficiency

MakaleWOS:000922080700001PubMed ID: 36089538Background: IgG subclass deficiency is a laboratory diagnosis and becomes important with recurrent infections. This study aimed to examine the demographic, clinical, and laboratory results of pediatric cases with IgG subclass deficiency and to improve the understanding of the clinical significance of IgG subclass deficiency. Methods: In this study, the clinical and laboratory features of 111 pediatric patients, with at least one whose serum IgG subclasses was measured as lower than 2 standard deviation of healthy aged-matched control values, were evaluated. The clinical and laboratory features of the cases with isolated IgG subclass deficiency (Group 1) and those with low serum levels of any of IgG, IgA, and IgM in addition to the IgG subclass deficiency (Group 2) were compared. Results: A total of 55 (49.54%) and 56 (50.45 %) patients were included in Groups 1 and 2, respectively. Among our studied cases, 20 (18. 1%) had a history of hospitalization in the neonatal period, 61 (54.95 %) had at least one hospitalization due to infection, and 55 (49.54%) had a history of recurrent infection. The frequencies of these three conditions were statistically significantly higher in Group 2 (p < 0.05). The frequencies of infections in the last year in Groups 1 and 2 were 4.4 +/- 1.2 and 5.4 +/- 1.9, respectively (p < 0.05). As a result of recurrent infections, 43.24% (n = 48) of our patients received antibiotic prophylaxis, and 21.62% (n = 24) had immunoglobulin replacement therapy. Furthermore, the numbers of pa-tients who needed these treatments were higher in Group 2 (p < 0.05).Conclusion: In cases with IgG subclass deficiencies, concomitant main-group immunoglobulin deficiencies may increase the number and severity of infections, leading to hospitalizations, antibiotic prophylaxis, and immunoglobulin therapy. More attention should be paid to cases of immunoglobulin main-group deficiencies in the follow-up of these cases.Copyright (c) 2022, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/ by-nc-nd/4.0/)

In childhood acute lymphoblastic leukemia: Our 10 years single center experience

St. Jude Total therapy XIIIB, BFM 2000 ve BFM 2009 protokolü alan hastalarda hastaların demografik özelliklerini, klinik ve laboratuar bulgularını, kemik iliğinin morfolojik, sitogenetik, immunfenotipik özelliklerini, kemoterapiye yanıtlarını, yaşam sürelerini, prognoza etki eden faktörleri, relapsları ve ölüm nedenlerini değerlendirmektir. Nisan 2006 –Nisan 2016 tarihleri arasında Necmettin Erbakan Üniversitesi Meram tıp Fakültesi Çocuk Hematoloji Anabilim Dalı' nda akut lenfoblastik lösemi tanısı ile takipli, St. Jude Total Therapi, BFM 2000, BFM 2009 protokolleri ile tedavi edilen toplam 167 hastanın dosyaları geriye dönük olarak incelendi. Hastaların tama yakınının kemik iliği örnekleri sitokimyasal boyalarla değerlendirilip, flow sitometri ile immunfenotiplendirme yapılmıştır. Hastaların büyük bir kısmında sitogenetik çalışma yapılmıştır. Tedavinin 8. Gününde periferik kan yayması ve tam kan sonuçları ile blast sayısı, 15. Ve 33. Günde kemik iliği aspirasyon ve biyopsisi ile kemik iliğinin remisyon durumu ve derecesi incelenmiştir. Hastalarımızın yaşları 9 ay ile 204 ay arasında değişiyordu. Median yaş 80 aydı. Hastaların %63,5' i erkek, %36,5' i kızdı. Kız erkek oranı K/E:1/1.7' dir. En sık başvuru sebebi ateşti. Hastaların yaklaşık yarısında hepatomegali, splenomegali ve lenfadenopati mevcuttu. Başvuru anında median lökosit sayısı 9750/mm³, median hemoglobin değeri 7,8 g/dl ve median trombosit sayısı 45000/mm³ idi. Morfolojik sınıflamaya göre L1, L2 ve L3 dağılımları sırasıyla %74,9, %24,6 ve % 0,6 idi. İmmunfenotiplendirme incelendiğinde prekursor B hücreli ALL %85,4 ve T hücreli ALL %12,6 idi. Sitogenetik incelemede hastaların %2,4' ünde t(9,22) sitoanomalisi, %2,4' ünde t(4,11) sitoanomalisi mevcuttu. Hastalarımızın %6,1' inde relaps gelişmiştir. Toplam 20 hastamız kaybedildi (%12). Genel sağ kalım oranımız %88, hastalıksız sağ kalım oranımız %85,6 bulundu. Çalışmanın sonuçları değerlendirildiğinde ürik asit yüksekliğ, 15. Gün kemik iliğinin remisyon durumu ve derecesi, relaps varlığı ve relaps türünün sağ kalım üzerine etkili olduğunu bulduk. Ürik asit ve LDH yüksekliği, 15. Gün kemik iliği değerlendirmesi ise olaysız sağ kalıma etkili bulundu. Bu bulgulara göre tedavi sonuçlarımız St. Jude protokolü, BFM 2000 ve 2009 protokolü uygulanan merkezlerle benzerdir.In this study we aimed to evaluate acute lymphoblastic leukemia patients who were treated with St. Jude, BFM 2000 and BFM 2009 protocols. Clinical and laboratory findings at admission, cytochemical, morphologic and immunologic features of bone marrow, response to chemotherapy, survival rates, causes of death, relapses and prognostic factors have been evaluated. Chart review of from, 167 newly diagnosed acute lymphoblastic leukemia patients who had been admitted to Necmettin Erbakan University Pediatric Hematology Department April 2006 to April 2016 were evaluated retrospectively. All bone marrow samples from patients were evaluated by cytochemical dyes, and by flow cytometry immunophenotyping. Moleculer genetic investigation was performed for t (9; 22), t (4;11) and others. Response to steroid therapy on the eighth day of treatment was evaluated, by peripheral blast count and bone marrow aspiration was repeated at 15th and 33th days. Patients‟ ages were between 9 months to 204 months, with a median of 80 month and female/male ratio of 1/1.7. The most frequent complaint was fever. The median number of leukocytes was 9750/mm³, median number of hemoglobin was 7,8 g/dl, median platelet number was 45000/mm³. Hepatosplenomegaly was present in 1/2, lymphadenomegaly in 1/2 and lymphadenomegaly in 1/2 of cases. According to the morphological classification, L1, L2 and L3 were found in 74,9%, 24,6%, 0.6% of cases respectively. Immunophenotype analysis revealed that the rate of precursor B- acute lymphoblastic leukemia was 85,4% and T- acute lymphoblastic leukemia was 12,6%. Moleculer genetic examination, t(9,22) and t(4; 11) resulted with a positivity in 2,4%. Ten patients (6,1%) relapsed, twenthy of our patients died, overall survival was 88% and event free survival was 85,6%. The results of this study demostrate that, level of uric acide, bone marrow response at 15th day showing M2 or M3 and presence of relapse have negative effect on survival of these patients. Levels of uric acide and LDH, bone marrow response at 15th day showing M2 or M3 have effect on event free survival. According to these findings, our results with St. Jude, BFM 2000 and BFM 2009 protocols are similar to other centers which follow the same protocols

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

Inborn errors of OAS–RNase L in SARS-CoV-2–related multisystem inflammatory syndrome in children

International audienceMultisystem inflammatory syndrome in children (MIS-C) is a rare and severe condition that follows benign COVID-19. We report autosomal recessive deficiencies of OAS1 , OAS2 , or RNASEL in five unrelated children with MIS-C. The cytosolic double-stranded RNA (dsRNA)–sensing OAS1 and OAS2 generate 2′-5′-linked oligoadenylates (2-5A) that activate the single-stranded RNA–degrading ribonuclease L (RNase L). Monocytic cell lines and primary myeloid cells with OAS1, OAS2, or RNase L deficiencies produce excessive amounts of inflammatory cytokines upon dsRNA or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) stimulation. Exogenous 2-5A suppresses cytokine production in OAS1-deficient but not RNase L–deficient cells. Cytokine production in RNase L–deficient cells is impaired by MDA5 or RIG-I deficiency and abolished by mitochondrial antiviral-signaling protein (MAVS) deficiency. Recessive OAS–RNase L deficiencies in these patients unleash the production of SARS-CoV-2–triggered, MAVS-mediated inflammatory cytokines by mononuclear phagocytes, thereby underlying MIS-C

The risk of COVID-19 death is much greater and age dependent with type I IFN autoantibodies

International audienceSignificance There is growing evidence that preexisting autoantibodies neutralizing type I interferons (IFNs) are strong determinants of life-threatening COVID-19 pneumonia. It is important to estimate their quantitative impact on COVID-19 mortality upon SARS-CoV-2 infection, by age and sex, as both the prevalence of these autoantibodies and the risk of COVID-19 death increase with age and are higher in men. Using an unvaccinated sample of 1,261 deceased patients and 34,159 individuals from the general population, we found that autoantibodies against type I IFNs strongly increased the SARS-CoV-2 infection fatality rate at all ages, in both men and women. Autoantibodies against type I IFNs are strong and common predictors of life-threatening COVID-19. Testing for these autoantibodies should be considered in the general population

The risk of COVID-19 death is much greater and age dependent with type I IFN autoantibodies

International audienceSignificance There is growing evidence that preexisting autoantibodies neutralizing type I interferons (IFNs) are strong determinants of life-threatening COVID-19 pneumonia. It is important to estimate their quantitative impact on COVID-19 mortality upon SARS-CoV-2 infection, by age and sex, as both the prevalence of these autoantibodies and the risk of COVID-19 death increase with age and are higher in men. Using an unvaccinated sample of 1,261 deceased patients and 34,159 individuals from the general population, we found that autoantibodies against type I IFNs strongly increased the SARS-CoV-2 infection fatality rate at all ages, in both men and women. Autoantibodies against type I IFNs are strong and common predictors of life-threatening COVID-19. Testing for these autoantibodies should be considered in the general population

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