Background During the first wave of the COVID-19 pandemic older patients had an increased risk of hospitalisation and death. Reports on the association of frailty with poor outcome have been conflicting. Objective The aim of the present study was to investigate the independent association between frailty and in-hospital mortality in older hospitalised COVID-19 patients in the Netherlands. Methods This was a multi-centre retrospective cohort study in 15 hospitals in the Netherlands, including all patients aged ≥70 years, who were hospitalised with clinically confirmed COVID-19 between February and May 2020. Data were collected on demographics, co-morbidity, disease severity and Clinical Frailty Scale (CFS). Primary outcome was in-hospital mortality. Results A total of 1,376 patients were included (median age 78 years (IQR 74–84), 60% male). In total, 499 (38%) patients died during hospital admission. Parameters indicating presence of frailty (CFS 6–9) were associated with more co-morbidities, shorter symptom duration upon presentation (median 4 vs. 7 days), lower oxygen demand and lower levels of CRP. In multivariable analyses, the CFS was independently associated with in-hospital mortality: compared to patients with CFS 1–3, patients with CFS 4–5 had a two times higher risk (odds ratio (OR) 2.0 (95%CI 1.3–3.0) and patients with CFS 6–9 had a three times higher risk of in-hospital mortality (OR 2.8 (95%CI 1.8–4.3)). Conclusions The in-hospital mortality of older hospitalised COVID-19 patients in the Netherlands was 38%. Frailty was independently associated with higher in-hospital mortality, even though COVID-19 patients with frailty presented earlier to the hospital with less severe symptoms.

Context Fibrous dysplasia/McCune-Albright syndrome (FD/MAS) is a rare bone and endocrine disorder resulting in fractures, pain, and disability. There are no targeted or effective therapies to alter the disease course. Disease arises from somatic gain-of-function variants at the R201 codon in GNAS, replacing arginine by either cysteine or histidine. The relative pathogenicity of these variants is not fully understood. Objective 1) To determine whether the most common GNAS variants (R201C and R201H) are associated with a specific clinical phenotype, and 2) to determine the prevalence of the most common GNAS variants in a large patient cohort. Design Retrospective cross-sectional analysis Main Outcome Measures Correlation between genotype and phenotype characterized by clinical, biochemical, and radiographic data. Results Sixty-one subjects were genotyped using DNA extracted from tissue or circulating cell-free DNA. Twenty-two subjects (36.1%) had the R201C variant, and 39 (63.9%) had the R201H variant. FD skeletal disease burden, hypophosphatemia prevalence, fracture incidence, and ambulation status were similar between the two groups. There was no difference in the prevalence of endocrinopathies, ultrasonographic gonadal or thyroid abnormalities, or pancreatic involvement. There was a non-significant association of cancer with the R201H variant. Conclusion There is no clear genotype-phenotype correlation in patients with the most common FD/MAS pathogenic variants. The predominance of the R201H variant observed in our cohort and reported in the literature indicates it is likely responsible for a larger burden of disease in the overall population of patients with FD/MAS, which may have important implications for future development of targeted therapies.

Fibrous dysplasia/McCune‐Albright syndrome (FD/MAS) is a rare bone and endocrine disorder arising along a broad spectrum. Long‐bone fractures are a common, painful, and potentially disabling complication. However, fracture prevalence and risk factors have not been well‐established, making it difficult to predict which patients are at risk for a severe course. Clinical and imaging data were reviewed from two large, well‐phenotyped cohorts (National Institutes of Health [NIH] in the United States and the Leiden University Medical Center [LUMC] in the Netherlands) to identify long‐bone fractures at FD sites. Skeletal burden score was quantified using bone scintigraphy. Multiple linear regressions were performed to identify clinical associations with fractures. A total of 419 patients were included (186 NIH, 233 LUMC); 194 (46%) had MAS endocrinopathies. Median age at last follow‐up was 30.2 years (range 3.2–84.6, interquartile range [IQR] 25.5), and median skeletal burden score was 16.6 (range 0–75, IQR 33). A total of 48 (59%) patients suffered one or more lifetime fracture (median 1, range 0–70, IQR 4). Median age at first fracture was 8 years (range 1–76, IQR 10). Fracture rates peaked between 6 and 10 years of age and decreased thereafter. Lifetime fracture rate was associated with skeletal burden score (β = 0.40, p < 0.01) and MAS hyperthyroidism (β = 0.22, p = 0.01). Younger age at first fracture was associated with skeletal burden score (β = −0.26, p = 0.01) and male sex (β = −0.23, p = 0.01). Both skeletal burden score >25 and age at first fracture ≤7 years were associated with a higher total number of lifetime fractures (median 4, range 1–70, IQR 5 versus median 1, range 1–13, IQR 1) (p < 0.01). In conclusion, higher skeletal burden score and MAS hyperthyroidism are associated with long‐bone fractures in FD/MAS. Both skeletal burden score ≥25 and age at first fracture ≤7 years are associated with a higher lifetime long‐bone fracture risk and may predict a more severe clinical course. These results may allow clinicians to identify FD/MAS patients at risk for severe disease who may be candidates for early therapeutic interventions. © 2021 American Society for Bone and Mineral Research (ASBMR). This article has been contributed to by US Government employees and their work is in the public domain in the USA.

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