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Long-term complications after coronavirus disease 2019 (COVID-19) are common in hospitalized patients, but the spectrum of symptoms in milder cases needs further investigation. We conducted a long-term follow-up in a prospective cohort study of 312 patients—247 home-isolated and 65 hospitalized—comprising 82% of total cases in Bergen during the first pandemic wave in Norway. At 6 months, 61% (189/312) of all patients had persistent symptoms, which were independently associated with severity of initial illness, increased convalescent antibody titers and pre-existing chronic lung disease. We found that 52% (32/61) of home-isolated young adults, aged 16–30 years, had symptoms at 6 months, including loss of taste and/or smell (28%, 17/61), fatigue (21%, 13/61), dyspnea (13%, 8/61), impaired concentration (13%, 8/61) and memory problems (11%, 7/61). Our findings that young, home-isolated adults with mild COVID-19 are at risk of long-lasting dyspnea and cognitive symptoms highlight the importance of infection control measures, such as vaccination. Analysis of a prospectively enrolled cohort of patients with SARS-CoV-2 infections in Bergen, Norway, reveals a high proportion of patients who experienced long COVID symptoms at 6 months, despite being relatively young and having only mild to moderate acute COVID-19 symptoms.

Fabry nephropathy is a major cause of kidney failure in Fabry disease, caused by pathogenic GLA variants that reduce α-galactosidase A activity and lead to globotriaosylceramide (Gb3) accumulation. In recent years, rapid advances in experimental modeling and emerging therapeutic strategies have dramatically reshaped understanding and treatment prospects for Fabry nephropathy. Experimental models - including cellular systems, patient-derived kidney organoids, and animal models such as zebrafish, Drosophila, mice and rats - have been pivotal in elucidating classic Gb3-dependent and novel Gb3-independent pathogenic mechanisms. These insights challenge the traditional Gb3-centric paradigm by highlighting other contributors, such as its metabolite lyso-Gb3, as well as α-synuclein accumulation and endothelial dysfunction. Despite established therapies for Fabry nephropathy, such as enzyme replacement and pharmacological chaperones, disease progression remains a clinical challenge, underscoring the urgent need for deeper mechanistic understanding and precision medicine approaches. This timely Review summarizes diverse model systems' unique strengths, limitations and translational potential to guide future research and therapeutic development for this complex disease.

Background Pegunigalsidase alfa is a novel, PEGylated α-galactosidase-A enzyme-replacement therapy approved in the EU and US to treat patients with Fabry disease (FD). Objective/methods BRIDGE is a phase 3 open-label, switch-over study designed to assess safety and efficacy of 12 months of pegunigalsidase alfa (1 mg/kg every 2 weeks) treatment in adults with FD who had been previously treated with agalsidase alfa (0.2 mg/kg every 2 weeks) for ≥ 2 years. Results Twenty-seven patients were screened; 22 met eligibility criteria; and 20 (13 men, 7 women) completed the study. Pegunigalsidase alfa was well-tolerated, with 97% of treatment-emergent adverse events (TEAEs) being of mild or moderate severity. The incidence of treatment-related TEAEs was low, with 2 (9%) discontinuations due to TEAEs. Five patients (23%) reported infusion-related reactions. Overall mean (SD; n = 22) baseline estimated glomerular filtration rate (eGFR) was 82.5 (23.4) mL/min/1.73 m 2 and plasma lyso-Gb 3 level was 38.3 (41.2) nmol/L (men: 49.7 [45.8] nmol/L; women: 13.8 [6.1] nmol/L). Before switching to pegunigalsidase alfa, mean (standard error [SE]) annualized eGFR slope was − 5.90 (1.34) mL/min/1.73 m 2 /year; 12 months post-switch, the mean eGFR slope was − 1.19 (1.77) mL/min/1.73 m 2 /year; and mean plasma lyso-Gb 3 reduced by 31%. Seven (35%) out of 20 patients were positive for pegunigalsidase alfa antidrug antibodies (ADAs) at ≥ 1 study timepoint, two of whom had pre-existing ADAs at baseline. Mean (SE) changes in eGFR slope for ADA-positive and ADA-negative patients were + 5.47 (3.03) and + 4.29 (3.15) mL/min/1.73 m 2 /year, respectively, suggesting no negative impact of anti-pegunigalsidase alfa ADAs on eGFR slope. Conclusion Pegunigalsidase alfa may offer a safe and effective treatment option for patients with FD, including those previously treated with agalsidase alfa. TRN : NCT03018730. Date of registration: January 2017.

Background: Lower respiratory tract infections remain a major cause of morbidity and mortality in infants worldwide. Newborns possess an immature immune system but acquire passive immunity through maternal antibodies transferred via the placenta (IgG) and breast milk (IgA). Maternal vaccination may enhance this protection. This study aimed to quantify antibody levels against respiratory viruses in serum and breast milk from lactating women. Methods: Serum and breast milk samples were collected from 26 lactating mothers. Antibody levels were measured using an indirect enzyme-linked immunosorbent assay (ELISA) targeting seven viral antigens: influenza A (A/Thailand, A/California), influenza B (B/Phuket, B/Austria), SARS-CoV-2 (Spike and receptor-binding domain, RBD) and RSV F pre-fusion protein. Antibody isotypes IgG, IgA and IgM were analysed. Results: Virus-specific IgG and IgA antibodies were detected in all samples. Breast milk showed the highest levels of IgA, whereas serum contained higher IgG levels. A moderate positive correlation was observed between serum and milk IgG. No correlation was found between serum IgG and milk IgA, but both levels were elevated. Conclusions: Breast milk and serum contain relatively high levels of antibodies against the tested respiratory viruses. The elevated levels of serum IgG and milk IgA indicate a coordinated defence between systemic and mucosal immunity in response to infections. The levels and correlation of specific isotypes point to the source of the antibodies: milk IgG probably originates from the blood, whereas milk IgA is produced locally.

Background Fabry disease (FD) is a rare lysosomal storage disorder caused by mutations in the GLA gene, resulting in reduced or lack of α-galactosidase A activity. This results in the accumulation of globotriaosylceramide (Gb3) and other glycosphingolipids in lysosomes causing cellular impairment and organ failures. While current therapies focus on reversing Gb3 accumulation, they do not address the altered cellular signaling in FD. Therefore, this study aims to explore Gb3-independent mechanisms of kidney damage in Fabry disease and identify potential biomarkers. Methods To investigate these mechanisms, we utilized a zebrafish (ZF) gla −/− mutant (MU) model. ZF naturally lack A4GALT gene and, therefore, cannot synthesize Gb3. We obtained kidney samples from both wild-type (WT) (n = 8) and MU (n = 8) ZF and conducted proteome profiling using untargeted mass spectrometry. Additionally, we examined mitochondria morphology and cristae morphology using electron microscopy. To assess oxidative stress, we measured total antioxidant activity. Finally, immunohistochemistry was conducted on kidney samples to validate specific proteins. Results Our proteomics analysis of renal tissues from zebrafish revealed downregulation of lysosome and mitochondrial-related proteins in gla −/− MU renal tissues, while energy-related pathways including carbon, glycolysis, and galactose metabolisms were disturbed. Moreover, we observed abnormal mitochondrial shape, disrupted cristae morphology, altered mitochondrial volume and lower antioxidant activity in gla −/− MU ZF. Conclusions These results suggest that the alterations observed at the proteome and mitochondrial level closely resemble well-known GLA mutation-related alterations in humans. Importantly, they also unveil novel Gb3-independent pathogenic mechanisms in Fabry disease. Understanding these mechanisms could potentially lead to the development of innovative drug screening approaches. Furthermore, the findings pave the way for identifying new clinical targets, offering new avenues for therapeutic interventions in Fabry disease. The zebrafish gla − /− mutant model proves valuable in elucidating these mechanisms and may contribute significantly to advancing our knowledge of this disorder. Graphical Abstract

BackgroundPegunigalsidase alfa is a PEGylated α-galactosidase A enzyme replacement therapy. BALANCE (NCT02795676) assessed non-inferiority of pegunigalsidase alfa versus agalsidase beta in adults with Fabry disease with an annualised estimated glomerular filtration rate (eGFR) slope more negative than −2 mL/min/1.73 m2/year who had received agalsidase beta for ≥1 year.MethodsPatients were randomly assigned 2:1 to receive 1 mg/kg pegunigalsidase alfa or agalsidase beta every 2 weeks for 2 years. The primary efficacy analysis assessed non-inferiority based on median annualised eGFR slope differences between treatment arms.ResultsSeventy-seven patients received either pegunigalsidase alfa (n=52) or agalsidase beta (n=25). At baseline, mean (range) age was 44 (18–60) years, 47 (61%) patients were male, median eGFR was 74.5 mL/min/1.73 m2 and median (range) eGFR slope was −7.3 (−30.5, 6.3) mL/min/1.73 m2/year. At 2 years, the difference between median eGFR slopes was −0.36 mL/min/1.73 m2/year, meeting the prespecified non-inferiority margin. Minimal changes were observed in lyso-Gb3 concentrations in both treatment arms at 2 years. Proportions of patients experiencing treatment-related adverse events and mild or moderate infusion-related reactions were similar in both groups, yet exposure-adjusted rates were 3.6-fold and 7.8-fold higher, respectively, with agalsidase beta than pegunigalsidase alfa. At the end of the study, neutralising antibodies were detected in 7 out of 47 (15%) pegunigalsidase alfa-treated patients and 6 out of 23 (26%) agalsidase beta-treated patients. There were no deaths.ConclusionsBased on rate of eGFR decline over 2 years, pegunigalsidase alfa was non-inferior to agalsidase beta. Pegunigalsidase alfa had lower rates of treatment-emergent adverse events and mild or moderate infusion-related reactions.Trial registration number NCT02795676.

Background Enzyme replacement therapies (ERTs) approved for Fabry disease require infusions every 2 weeks (E2W). Pegunigalsidase alfa, a PEGylated ERT with a prolonged half-life vs. other ERTs, may allow extension of the dosing interval to every 4 weeks (E4W). BRIGHT F51 (NCT03614234) is an ongoing phase III, open-label extension study evaluating long-term efficacy and safety of pegunigalsidase alfa 2 mg/kg E4W in adults with Fabry disease previously treated with agalsidase alfa or beta E2W for ≥ 3 years who completed one year of pegunigalsidase alfa treatment in the BRIGHT study. This interim analysis reports results following 3–5 years of treatment (cutoff date December 31, 2022). Results Twenty-nine patients were enrolled. Median (interquartile range [IQR]) annualized eGFR slope during treatment was ‒2.2 (‒2.9; ‒1.1) mL/min/1.73 m 2 /year (males: ‒2.4 [‒2.9; ‒1.0, n = 23]; females: ‒1.8 [‒2.4; ‒1.3, n = 6]; anti-drug antibody [ADA]-positive: ‒2.6 [‒4.0; ‒1.7, n = 9 all male]; ADA-negative: ‒1.8 [‒2.7; ‒0.6, n = 20]). Median (IQR) change in plasma lyso-Gb3 from baseline to Week 208 was 3.2 (‒3.9; 8.5, n = 17) nM in males; concentrations remained low and stable in females. Overall, 51/477 treatment-emergent adverse events in 13 patients (45%) were considered treatment-related (all mild/moderate). Nine patients (31%) experienced mild/moderate infusion-related reactions. One patient developed transient de novo ADAs. Conclusions Long-term treatment with pegunigalsidase alfa 2 mg/kg E4W was well-tolerated and maintained disease stability, especially in females and ADA-negative males; more data are needed to better understand outcomes in ADA-positive males. Clinical outcomes should be closely monitored during E4W treatment. The final results of this extension study will further assess the feasibility of this dosing regimen. Trial registration details ClinicalTrials.gov, NCT03614234. Registered July 30, 2018; https://clinicaltrials.gov/study/NCT03614234 . Graphical Abstract

Introduction Fabry disease (FD) is a lysosomal storage disorder resulting in progressive nervous system, kidney and heart disease. Enzyme replacement therapy (ERT) may halt or attenuate disease progression. Since administration is burdensome and expensive, appropriate use is mandatory. We aimed to define European consensus recommendations for the initiation and cessation of ERT in patients with FD. Methods A Delphi procedure was conducted with an online survey (n = 28) and a meeting (n = 15). Patient organization representatives were present at the meeting to give their views. Recommendations were accepted with ≥75% agreement and no disagreement. Results For classically affected males, consensus was achieved that ERT is recommended as soon as there are early clinical signs of kidney, heart or brain involvement, but may be considered in patients of ≥16 years in the absence of clinical signs or symptoms of organ involvement. Classically affected females and males with non-classical FD should be treated as soon as there are early clinical signs of kidney, heart or brain involvement, while treatment may be considered in females with non-classical FD with early clinical signs that are considered to be due to FD. Consensus was achieved that treatment should not be withheld from patients with severe renal insufficiency (GFR < 45 ml/min/1.73 m 2 ) and from those on dialysis or with cognitive decline, but carefully considered on an individual basis. Stopping ERT may be considered in patients with end stage FD or other co-morbidities, leading to a life expectancy of <1 year. In those with cognitive decline of any cause, or lack of response for 1 year when the sole indication for ERT is neuropathic pain, stopping ERT may be considered. Also, in patients with end stage renal disease, without an option for renal transplantation, in combination with advanced heart failure (NYHA class IV), cessation of ERT should be considered. ERT in patients who are non-compliant or fail to attend regularly at visits should be stopped. Conclusion The recommendations can be used as a benchmark for initiation and cessation of ERT, although final decisions should be made on an individual basis. Future collaborative efforts are needed for optimization of these recommendations.

Background The high prevalence of long-term persisting symptoms after COVID-19 (coronavirus disease 2019), termed long COVID or post-COVID-19 condition, even among those with mild initial disease, may have a large public health impact. Apart from avoiding infection, there is no proven prevention or treatment for long COVID. We will perform a randomized placebo-controlled clinical trial to assess whether treatment with the novel antiviral, nirmatrelvir and ritonavir (Paxlovid®) for acute COVID-19 can prevent the development of long COVID. Methods This is a randomized double-blinded placebo-controlled trial that aims to recruit 2000 nonpregnant persons aged 18 to 64 years with acute COVID-19 with positive PCR and/or antigen test and symptom duration of not more than 5 days. Participants will be randomized 1:1 to a 5-day course of Paxlovid (two tablets 150-mg nirmatrelvir and one tablet 100-mg ritonavir twice daily) or a 5-day course of placebo (similar number of tablets of equal appearance). The primary endpoint will be persistent symptoms compatible with long COVID, assessed as the prevalence of a dichotomous variable corresponding to the presence (1) or absence (0) of one or more of the following symptoms: (i) fatigue, (ii) dyspnea, and (iii) cognitive symptoms (memory and/or concentration problems). The primary outcome will be evaluated at 3-month follow-up and then re-evaluated at 6, 12, and 24 months. Discussion As more than 750 million people with confirmed COVID-19 have survived globally, the potential burden of long COVID on societies is formidable. If a simple 5-day oral treatment course with nirmatrelvir/ritonavir is shown to prevent long COVID, it would be a highly attractive intervention at an individual level and a mitigation of its public health consequences. Trial registration ClinicalTrials.gov NCT05852873. Registered on May 2023.

BackgroundGlomerular filtration rate (GFR) estimated by creatinine- and/or cystatin C-based equations (eGFR) is widely used in daily practice. The purpose of our study was to compare new and old eGFR equations with measured GFR (mGFR) by iohexol clearance in a cohort of children with chronic kidney disease (CKD).MethodsWe examined 96 children (median age 9.2 years (range 0.25–17.5)) with CKD stages 1–5. A 7-point iohexol clearance (GFR7p) was defined as the reference method (median mGFR 66 mL/min/1.73 m2, range 6–153). Ten different eGFR equations, with or without body height, were evaluated: Schwartzbedside, SchwartzCKiD, SchwartzcysC, CAPA, LMREV, (LMREV + CAPA) / 2, FAScrea, FAScysC, FAScombi, FASheight. The accuracy was evaluated with percentage within 10 and 30% of GFR7p (P10 and P30).ResultsIn the group with mGFR below 60 mL/min/1.73 m2, the SchwartzcysC equation had the lowest median bias (interquartile range; IQR) 3.27 (4.80) mL/min/1.73 m2 and the highest accuracy with P10 of 44% and P30 of 85%. In the group with mGFR above 60 mL/min/1.73 m2, the SchwartzCKiD presented with the lowest bias 3.41 (13.1) mL/min/1.73 m2 and P10 of 62% and P30 of 98%. Overall, the SchwartzcysC had the lowest bias − 1.49 (13.5) mL/min/1.73 m2 and both SchwartzcysC and SchwartzCKiD showed P30 of 90%. P10 was 44 and 48%, respectively.ConclusionsThe SchwartzcysC and the combined SchwartzCKiD present with lower bias and higher accuracy as compared to the other equations. The SchwartzcysC equation is a good height-independent alternative to the SchwartzCKiD equation in children and can be reported directly by the laboratory information system.Clinical Trial RegistrationClinicalTrials.gov, Identifier NCT01092260, https://clinicaltrials.gov/ct2/show/NCT01092260?term=tondel&rank=2