Hemmen Sabir

Bio: Hemmen Sabir is an academic researcher from University Hospital Bonn. The author has contributed to research in topics: Exome sequencing & Congenital cataracts. The author has an hindex of 1, co-authored 3 publications receiving 5 citations.

TBK1 and TNFRSF13B mutations and an autoinflammatory disease in a child with lethal COVID-19

Abstract: Among children, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections are typically mild. Here, we describe the case of a 3.5-year-old girl with an unusually severe presentation of coronavirus disease (COVID-19). The child had an autoinflammatory disorder of unknown etiology, which had been treated using prednisolone and methotrexate, and her parents were half cousins of Turkish descent. After 5 days of nonspecific viral infection symptoms, tonic-clonic seizures occurred followed by acute cardiac insufficiency, multi-organ insufficiency, and ultimate death. Trio exome sequencing identified a homozygous splice-variant in the gene TBK1, and a homozygous missense variant in the gene TNFRSF13B. Heterozygous deleterious variants in the TBK1 gene have been associated with severe COVID-19, and the variant in the TNFRSF13B gene has been associated with common variable immunodeficiency (CVID). We suggest that the identified variants, the autoinflammatory disorder and its treatment, or a combination of these factors probably predisposed to lethal COVID-19 in the present case.

Trends in accident-related admissions to pediatric intensive care units during the first COVID-19 lockdown in Germany

Abstract: ObjectiveTo compare the number of accident- and injury-related admissions to pediatric intensive care units (PICU) during the first German COVID-19 lockdown with previous years. To investigate if shifts in types of accidents or injuries occurred, especially regarding non-accidental injuries. DesignRetrospective observational multicenter study. Setting37 German PICUs. Patients1444 children and adolescents < 18 years admitted to German PICUs due to trauma or injuries during the first German lockdown period (16.3.-31.5.2020) and during the same periods of the years 2017-2019. InterventionsNone. Measurements and main resultsStandardized morbidity ratios (SMR) and 95% confidence intervals (CI) were calculated for the severity of disease, admission reasons, types of accidents, injury patterns, surgeries and procedures, and outcomes. Disease severity did not differ from previous years. We found an increase in ingestions (SMR 1.41 (CI 0.88 - 2.16)) and a decrease in aspirations (0.77 (0.41 - 1.32)) and burns (0.82 (0.59 - 1.12)). The total number of admissions for trauma remained constant, but traffic accidents (0.76 (0.56 - 1.01) and school/kindergarten accidents (0.25 (0.05 - 0.74) decreased. Household (1.32 (1.05 - 1.64)) and leisure accidents (1.32 (1.05 - 1.65)) increased. Injured structures did not change, but less neurosurgeries (0.69 (0.42 - 1.07)) and more visceral surgeries (2.00 (1.14 - 3.24)) were performed. Non-accidental non-suicidal injuries declined (0.85 (0.50 - 1.37)). Suicide attempts increased in adolescent boys (1.57 (0.58 - 3.42)), while there was a decrease in adolescent girls (0.86 (0.53 - 1.31)). ConclusionsOur study showed shifts in trauma types and associated surgeries during the lockdown period that are generally in line with current literature. The decreased number of non-accidental non-suicidal injuries we observed does not suggest a fundamental increase in severe child abuse during the lockdown period. The decrease in suicide attempts among adolescent girls confirms previous findings, while the increase among boys has not been described yet and deserves further investigation.

Isolated cytokine-enriched pericardial effusion: A likely key feature for Aymé-Gripp syndrome.

Abstract: Ayme-Gripp syndrome is a multisystemic disorder caused by a heterozygous variation in the MAF gene (OMIM*177075). Key features are congenital cataracts, sensorineural hearing loss, and a characteristic facial appearance. In a proportion of individuals, pericardial effusion or pericarditis has been reported as part of the phenotypic spectrum. In the present case, a large persistent cytokine-enriched pericardial effusion was the main pre- and postnatal symptom that led to the clinical and later molecular diagnosis of Ayme-Gripp syndrome. In the postnatal course, the typical Ayme-Gripp syndrome-associated features bilateral cataracts and hearing loss were diagnosed. We propose that activating dominant variants in the cytokine-modulating transcription factor c-MAF causes cytokine-enriched pericardial effusions possibly representing a key feature of Ayme-Gripp syndrome.

Human genetic and immunological determinants of critical COVID-19 pneumonia

Abstract: 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 IFNα, IFNβ and/or IFNω, 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.

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

Abstract: Significance 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.

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

Abstract: 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.

Inherited IFNAR1 Deficiency in a Child with Both Critical COVID-19 Pneumonia and Multisystem Inflammatory Syndrome

Abstract: Inborn errors of immunity (IEI) and autoantibodies to type I interferons (IFNs) underlie critical COVID-19 pneumonia in at least 15% of the patients, while the causes of multisystem inflammatory syndrome in children (MIS-C) remain elusive.To detect causal genetic variants in very rare cases with concomitant critical COVID-19 pneumonia and MIS-C.Whole exome sequencing was performed, and the impact of candidate gene variants was investigated. Plasma levels of cytokines, specific antibodies against the virus, and autoantibodies against type I IFNs were also measured.We report a 3-year-old child who died on day 56 of SARS-CoV-2 infection with an unusual clinical presentation, combining both critical COVID-19 pneumonia and MIS-C. We identified a large, homozygous loss-of-function deletion in IFNAR1, underlying autosomal recessive IFNAR1 deficiency.Our findings confirm that impaired type I IFN immunity can underlie critical COVID-19 pneumonia, while suggesting that it can also unexpectedly underlie concomitant MIS-C. Our report further raises the possibility that inherited or acquired dysregulation of type I IFN immunity might contribute to MIS-C in other patients.