Increased incidence of Graves' disease during the SARS-CoV2 pandemic.

INTRODUCTION: COVID-19 has a wide spectrum of clinical severity and there is evidence that SARS-Cov2 affects several organs and systems. Among the organs affected since the beginning of the pandemic, the relationship between SARS-CoV-2 infection and thyroid involvement has been demonstrated. Novel and highly effective messenger RNA and DNA-based vaccines have been rapidly developed to decrease SARS-CoV-2 morbidity and mortality. Early after mass vaccinations, cases of thyroid dysfunction mainly including episodes of subacute thyroiditis, began to be reported like adverse effects. The objective of this study is to determine the impact of the pandemic, both due to SARS-CoV2 infections and vaccinations, on the incidence of Graves' disease (GD). METHODS: Cross-sectional, observational study comparing incidence of GD in adult population (over 18 years) before (2017-2019) and after (2020-2021) Covid-19 pandemic. Only patients with new cases of GD, no relapsed diseases, were included. SARS-CoV-2 diagnosis was based on nucleic acid amplification tests on nasopharyngeal swabs or measurement of class M and class G antibodies to SARS-CoV-2 by highly specific assays. Data on incidence and vaccination related to SARS-CoV-2 infection were obtained from the public records from Castilla y León autonomous regional government. RESULTS: A total of 180 subjects were diagnosed and treated for GD during the study period. We observed a notable increase in expected GD cases in 2021 compared to 2017-19. The number of GD cases was higher in the second (Q2) quarter. Among 2021 GD cases, 42/66 patients (63.6%) had been vaccinated in the 90 days before symptom onset, but none of them in the first quarter of the year. A total of 97.7% were women with a mean age of 48.9 (SD 15.6) years. On average they were diagnosed 19.9 (SD 17.6) days after receiving the vaccine. A total of 7/42 (16.67%) had another previously diagnosed autoimmune disease and 11/42 (26.19%) were smokers. DISCUSSION: Our results show a notable increase in the incidence of GD during the year 2021, specially in women with a history of smoking. Hyper activation of the immune system induced by SARS-CoV2 and by the recently released SARS-COV-2 vaccines has been highlighted in recent months. To assess whether this observed increase in the incidence of GD is sustained in the coming years or has simply been a precipitous trigger for individuals who were already predisposed to develop the disease, future studies will be needed.

Unexpected relevant role of gene mosaicism in patients with primary immunodeficiency diseases.

BACKGROUND: Postzygotic de novo mutations lead to the phenomenon of gene mosaicism. The 3 main types are called somatic, gonadal, and gonosomal mosaicism, which differ in terms of the body distribution of postzygotic mutations. Mosaicism has been reported occasionally in patients with primary immunodeficiency diseases (PIDs) since the early 1990s, but its real involvement has not been systematically addressed. OBJECTIVE: We sought to investigate the incidence of gene mosaicism in patients with PIDs. METHODS: The amplicon-based deep sequencing method was used in the 3 parts of the study that establish (1) the allele frequency of germline variants (n = 100), (2) the incidence of parental gonosomal mosaicism in families with PIDs with de novo mutations (n = 92), and (3) the incidence of mosaicism in families with PIDs with moderate-to-high suspicion of gene mosaicism (n = 36). Additional investigations evaluated body distribution of postzygotic mutations, their stability over time, and their characteristics. RESULTS: The range of allele frequency (44.1% to 55.6%) was established for germline variants. Those with minor allele frequencies of less than 44.1% were assumed to be postzygotic. Mosaicism was detected in 30 (23.4%) of 128 families with PIDs, with a variable minor allele frequency (0.8% to 40.5%). Parental gonosomal mosaicism was detected in 6 (6.5%) of 92 families with de novo mutations, and a high incidence of mosaicism (63.9%) was detected among families with moderate-to-high suspicion of gene mosaicism. In most analyzed cases mosaicism was found to be both uniformly distributed and stable over time. CONCLUSION: This study represents the largest performed to date to investigate mosaicism in patients with PIDs, revealing that it affects approximately 25% of enrolled families. Our results might have serious consequences regarding treatment and genetic counseling and reinforce the use of next-generation sequencing-based methods in the routine analyses of PIDs.

Bone marrow fibrosis in myelodysplastic syndromes: a prospective evaluation including mutational analysis.

The biological and molecular events that underlie bone marrow fibrosis in patients with myelodysplastic syndromes are poorly understood, and its prognostic role in the era of the Revised International Prognostic Scoring System (IPSS-R) is not yet fully determined. We have evaluated the clinical and biological events that underlie bone marrow fibrotic changes, as well as its prognostic role, in a well-characterized prospective patient cohort (n=77) of primary MDS patients. The degree of marrow fibrosis was linked to parameters of erythropoietic failure, marrow cellularity, p53 protein accumulation, WT1 gene expression, and serum levels of CXCL9 and CXCL10, but not to other covariates including the IPSS-R score. The presence of bone marrow fibrosis grade 2 or higher was associated with the presence of mutations in cohesin complex genes (31.5% vs. 5.4%, p=0.006). By contrast, mutations in CALR, JAK2, PDGFRA, PDGFRB,and TP53 were very rare. Survival analysis showed that marrow fibrosis grade 2 or higher was a relevant significant predictor for of overall survival, and independent of age, performance status, and IPSS-R score in multivariate analysis.

Experience in IVIg therapy for selected women with recurrent reproductive failure and NK cell expansion.

PROBLEM: Recurrent reproductive failure (RRF) has been associated with expansion of circulating NK cells, key cells for maternal tolerance, decidual vasculogenesis and embryo growth. This study reports our experience in intravenous immunoglobulin (IVIg) therapy of a large cohort of women with RRF with expanded circulating NK and/or NKT-like cells (blood NKT cells are a heterogeneous subset of T cells that share properties of both T cells and NK cells). METHOD OF STUDY: Observational study of RRF women with NK or NKT-like expansion (>12% or 10% cutoff levels of total lymphocytes, respectively), treated with IVIg for the next gestation. RESULTS: By multivariant logistic regression analysis after adjusting for age, NK cells subsets and other therapies, IVIg significantly improved the live birth rate to 96.3% in women with recurrent miscarriage (RM) compared with 30.6% in case not receiving IVIg (P < 0.0001). In women with recurrent implantation failure (RIF), in comparison with women not receiving IVIg, treatment increased the pregnancy rate from 26.2 to 93.8% (P ≤ 0.0001) and the live birth rate from 17.9 to 80.0% in RIF (P ≤ 0.0001). CONCLUSIONS: Immunomodulation with IVIg in our selected group of RRF patients with immunologic alterations enhanced clinical pregnancy and live birth rates. Our results may facilitate the design of future clinical trials of IVIg in this pathology.

Do serum C-reactive protein and interleukin-6 predict kidney scarring after urinary tract infection?

OBJECTIVE: To investigate if serum C-reactive protein (s-CRP) and interleukin 6 (s-IL6) provide information for predicting renal damage and for DMSA patient selection in children with urinary tract infection (UTI). METHODS: This observational study was carried out in children with UTI. s-CRP and s-IL6 were measured at UTI diagnosis. Patients forming renal scarring were identified by DMSA scans. The usefulness of s-CRP and s-IL6 measurements for nephropathy scarring diagnosis was evaluated using diagnostic quality and efficiency indexes. RESULTS: Thirty-two children were included in the study. Eight showed renal scarring after the follow-up. The s-CRP was 110.23 ± 59.69 mg/L and 52.46 ± 63.13 mg/L for patients with and without renal scarring. The s-IL6 concentration was 18.34 ± 11.80 pg/mL and 8.07 ± 9.51 pg/mL respectively. The cut-off points for optimum nephropathy scarring diagnosis were 115 mg/L for s-CRP and 20 pg/mL for s-IL6. The value of highest sensitivity for s-CRP was >5 mg/L (S:100 %) and greatest specificity was >150 mg/L (Sp:95.83). The highest sensitivity for s-IL6 was >4 pg/mL (S:100 %) and the maximum specificity was >40 pg/mL (Sp:100 %). CONCLUSIONS: Results confirm that children who will develop renal scarring show higher levels of s-IL6 and s-CRP at UTI diagnosis. However, none of the techniques provide sufficient information for predicting renal damage in all patients and for DMSA patient selection.