Quality of life, exercise capacity, cognition, and mental health of Chilean patients after COVID-19: an experience of a multidisciplinary rehabilitation program at a physical and rehabilitation medicine unit.

Background: Post-COVID disabilities, encompassing physical, cognitive, and psychological aspects, constitute the primary health sequelae for survivors. While the rehabilitation needs post COVID-19 are now well understood, each country possesses unique characteristics in terms of populations, healthcare systems, social dynamics, and economic profiles, necessitating context-specific recommendations. This study aims to address two main objectives: (1) analyze the impact of an 8-week multidisciplinary rehabilitation program on the quality of life, functional capacity, cognition, and mental health adaptations in adults recovering from COVID-19 in northern Chile, and (2) propose a personalized model for predicting program dropouts and responses. Methods: A total of 44 subjects were enrolled, forming two groups during the study: a treatment group (n = 32) and a dropout group (n = 12). The treatment group participated in the 8-week multidisciplinary rehabilitation program. Results: The results indicate that (1) After 8 weeks, the quality of life of the patients in the treatment group exhibited significant improvements reflected in all aspects of the Short Form-36 Health Survey (SF36, p < 0.005) and the total score (p < 0.001), with a concurrent decrease in dysfunctionality (p < 0.001). (2) Significant improvements were also observed in various physical performance tests, including the: 6-minute walk test, 1-min sit-to-stand, dynamometry, Tinetti balance, and Berg score (p < 0.001). Moreover, physical therapy led to a reduction in neuropathic symptoms and pain, psychological therapy reduced anxiety and depression, and language therapy enhanced memory and speech (all p < 0.05). (3) Demographic and clinical history characteristics did not predict responses to rehabilitation. (4) A regression model for predicting changes in SF-36 total score, based on physical function, physical role, general health, and mental health, was established based on the data from study (p < 0.01, adjusted R2 = 0.893). (5) Classification models for predicting dropouts achieved 68% accuracy, with key predictors of treatment adherence including diabetes, hypertension, and dyslipidemia, Tinetti balance, physical role, and vitality of SF36, and performance on the 6-minute walk test and 1-minute sit-to-stand. Conclusions: This study demonstrates significant enhancements in quality of life, improved functional performance, and reductions in mental and cognitive burdens within an 8-week rehabilitation program. Additionally, it is possible to identify patients at risk of dropping out using cost-effective, outpatient, and clinically applicable tests.

Head-to-head trial of pegunigalsidase alfa versus agalsidase beta in patients with Fabry disease and deteriorating renal function: results from the 2-year randomised phase III BALANCE study.

BACKGROUND: Pegunigalsidase 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. METHODS: Patients 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. RESULTS: Seventy-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. CONCLUSIONS: Based 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.

Safety and efficacy of pegunigalsidase alfa in patients with Fabry disease who were previously treated with agalsidase alfa: results from BRIDGE, a phase 3 open-label study.

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 m2 and plasma lyso-Gb3 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 m2/year; 12 months post-switch, the mean eGFR slope was - 1.19 (1.77) mL/min/1.73 m2/year; and mean plasma lyso-Gb3 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 m2/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.

Long-term safety and efficacy of pegunigalsidase alfa: A multicenter 6-year study in adult patients with Fabry disease.

PURPOSE: Fabry disease (FD) is a rare lysosomal storage disorder caused by pathogenic variants in the GLA gene encoding α-galactosidase (α-Gal)-A. We evaluated long-term safety/efficacy of pegunigalsidase alfa, a novel PEGylated α-Gal-A enzyme replacement therapy (ERT) now approved for FD. METHODS: In a phase-1/2 dose-ranging study, 15 ERT-naive adults with FD completed 12 months of pegunigalsidase alfa and enrolled in this 60-month open-label extension of 1 mg/kg pegunigalsidase alfa infusions every 2 weeks. RESULTS: Fifteen patients enrolled (8 males; 7 females); 10 completed ≥48 months (60 months total treatment), and 2 completed 60 months (72 months total treatment). During treatment, most treatment-emergent adverse events were mild/moderate in severity and all infusion-related reactions were mild/moderate in severity. Four patients were transiently positive for anti-pegunigalsidase alfa IgG. Patients showed continuous reduction in plasma lyso-Gb3 concentrations with mean (standard error) reduction of 76.1 [25.1] ng/mL from baseline to month 24. At 60 months, the estimated glomerular filtration rate slope was comparable to that observed in patients treated with other ERTs. Cardiac function assessments revealed stability; no cardiac fibrosis was observed. CONCLUSION: In this first long-term assessment of pegunigalsidase alfa administration in patients with FD, we found favorable safety/efficacy. Our data suggest long-term continuous benefits of pegunigalsidase alfa treatment in adults with FD.

Evidence for a Prehypertensive Water Dysregulation Affecting the Development of Hypertension: Results of Very Early Treatment of Vasopressin V1 and V2 Antagonism in Spontaneously Hypertensive Rats.

In addition to long-term regulation of blood pressure (BP), in the kidney resides the initial trigger for hypertension development due to an altered capacity to excrete sodium and water. Betaine is one of the major organic osmolytes, and its betaine/gamma-aminobutyric acid transporter (BGT-1) expression in the renal medulla relates to interstitial tonicity and urinary osmolality and volume. This study investigated altered water and sodium balance as well as changes in antidiuretic hormone (ADH) activity in female spontaneously hypertensive (SHR) and normotensive Wistar Kyoto (WKY) rats from their 3-5 weeks of age (prehypertensive phase) to SHR's 28-30 weeks of age (established hypertension-organ damage). Young prehypertensive SHRs showed a reduced daily urine output, an elevated urine osmolarity, and higher immunostaining of tubule BGT-1, alpha-1-Na-K ATPase in the outer medulla vs. age-matched WKY. ADH circulating levels were not different between young prehypertensive SHR and WKY, but the urine aquaporin2 (AQP2)/creatinine ratio and labeling of AQP2 in the collecting duct were increased. At 28-30 weeks, hypertensive SHR with moderate renal failure did not show any difference in urinary osmolarity, urine AQP2/creatinine ratio, tubule BGT-1, and alpha-1-Na-K ATPase as compared with WKY. These results suggest an increased sensitivity to ADH in prehypertensive female SHR. On this basis, a second series of experiments were set to study the role of ADH V1 and V2 receptors in the development of hypertension, and a group of female prehypertensive SHRs were treated from the 25th to 49th day of age with either V1 (OPC21268) or V2 (OPC 41061) receptor antagonists to evaluate the BP time course. OPC 41061-treated SHRs had a delayed development of hypertension for 5 weeks without effect in OPC 21268-treated SHRs. In prehypertensive female SHR, an increased renal ADH sensitivity is crucial for the development of hypertension by favoring a positive water balance. Early treatment with selective V2 antagonism delays future hypertension development in young SHRs.

Caregivers' and Physicians' Perspectives on Alpha-Mannosidosis: A Report from Italy.

Alpha-mannosidosis is a rare lysosomal storage disorder that generally presents in early childhood. It is a progressive, highly heterogeneous disease that is difficult to recognize, and a diagnosis is usually reached after referrals to multiple specialists. It is important to understand the challenges faced by patients and their caregiver up to and after a diagnosis of alpha-mannosidosis. In this report, we describe the process of alpha-mannosidosis diagnosis and treatment from the caregivers' and physicians' perspectives. For the caregivers' perspective, the mothers of two patients with alpha-mannosidosis ('Adele' aged 35 years and 'Amedeo' aged 40 years) were interviewed in their homes in Italy, and anonymized transcripts were used to describe their experiences. Adele lived in a large city with access to hospitals and specialized centers and was diagnosed with alpha-mannosidosis before 3 years of age. Amedeo was from a small village and was diagnosed when he was 10-11 years old. In both cases, their mothers sought help from pediatricians and other specialists for recurrent infections and delayed speech and motor development in the first years of their lives, but diagnosis was delayed. Although the diagnostic pathway was concerning and frustrating for her mother, Adele was able to live at home and receive multidisciplinary care and psychosocial support locally, but the transition from pediatric to adult services was difficult. She is currently waiting for access to enzyme replacement therapy. Amedeo had to travel widely and frequently to receive a diagnosis and access supportive treatment. The cumulative morbidity resulting from the delays and poor access to care necessitated long-term residential care. From the physicians' perspective, greater awareness of alpha-mannosidosis is required among healthcare professionals and more support is needed for patients and caregivers, particularly those living in rural areas or small centers.

Clinical and Prognostic Significance of Serum IgG4 in Chronic Periaortitis. An Analysis of 113 Patients.

Objective: Chronic periaortitis (CP) is a rare fibro-inflammatory disorder that incorporates idiopathic retroperitoneal fibrosis, inflammatory abdominal aortic aneurysms, and perianeurysmal retroperitoneal fibrosis. CP is included in the spectrum of IgG4-related disease. Since CP patients rarely undergo diagnostic biopsies, serum IgG4 levels are often used to classify CP as IgG4-related. However, the clinical and prognostic significance of serum IgG4 in CP is unknown. Methods: We measured serum IgG4 in active CP patients and compared the clinical characteristics, response to therapy and outcome of patients with high and normal levels. We also tested the diagnostic significance of IgG4 by comparing its levels in CP patients, healthy and disease controls (malignancies, Erdheim-Chester disease, large-, and small-vessel vasculitis). Results: We studied 113 consecutive patients with active CP. Twenty-four (21.2%) had high serum IgG4 (>135 mg/dL). The demographic, laboratory, and clinical characteristics of patients with high and normal IgG4 were similar, and so were the rates of ureteral obstruction and the disease characteristics on CT, MRI, and 18F-FDG-PET. Patients with high IgG4 only had a higher frequency of extra-retroperitoneal fibro-inflammatory lesions (p = 0.005). There were no significant differences in response to therapy and relapses between the two groups. Serum IgG4 levels did not discriminate CP from controls. Conclusions: Serum IgG4 levels are high in a minority of CP patients and do not identify specific clinical or prognostic subgroups; only a higher frequency of extra-retroperitoneal lesions is found in high-IgG4 patients. Serum IgG4 levels do not help in the differential diagnosis between CP and its mimics.

Brief Report: Rituximab for the Treatment of Adult-Onset IgA Vasculitis (Henoch-Schönlein).

OBJECTIVE: Adult-onset IgA vasculitis (Henoch-Schönlein) (IgAV) is a rare systemic vasculitis characterized by IgA1-dominant deposits. The treatment of adult-onset IgAV is controversial and is based on the combination of glucocorticoids and immunosuppressive agents, but many patients have refractory or relapsing disease despite treatment. Rituximab (RTX) is a B cell-depleting antibody of proven efficacy in antineutrophil cytoplasmic antibody-associated vasculitis. We undertook this study to test the efficacy and safety of RTX in a multicenter cohort of patients with adult-onset IgAV. METHODS: In this multicenter observational study, we included patients with adult-onset IgAV who had received RTX either for refractory/relapsing disease or because they had contraindications to conventional glucocorticoid/immunosuppressive therapy. We analyzed the rates of remission (defined on the basis of the Birmingham Vasculitis Activity Score [BVAS]) and relapse as well as the variations over time in estimated glomerular filtration rate (GFR), proteinuria, C-reactive protein (CRP) level, BVAS, and prednisone dose. RESULTS: Twenty-two patients were included; their median duration of follow-up was 24 months (interquartile range 18-48 months). Sixteen patients received RTX as add-on therapy and 6 as monotherapy. Twenty patients (90.9%) achieved remission, and 7 of those 20 patients (35%) had subsequent relapse of disease. There were significant reductions in 24-hour proteinuria (P < 0.0001), CRP level (P = 0.0005), BVAS (P < 0.0001), and prednisone dose (P < 0.0001) from RTX initiation through the last follow-up visit; estimated GFR remained stable. RTX was generally well tolerated. One patient died after 60 months of follow-up. CONCLUSION: Our data suggest that RTX is an effective and safe therapeutic option for adult-onset IgAV.

Idiopathic retroperitoneal fibrosis and its overlap with IgG4-related disease.

Retroperitoneal fibrosis (RPF) is a rare disease characterised by fibrous tissue proliferation in the retroperitoneum, with encasement of the ureters and large vessels of the abdomen as the most destructive of potentially severe complications. It can either be idiopathic, or secondary to infections, malignancies, or the use of certain drugs. The idiopathic form accounts for approximately 75% of the cases, and is usually responsive to immunosuppressive therapy. In recent years, the emergence of a new clinical entity, IgG4-related disease (IgG4-RD), shed light on many fibro-inflammatory disorders once thought to be separate clinical entities, although frequently associated in the so-called multifocal fibrosclerosis. Among these, together with sclerosing pancreatitis and cholangitis, pseudotumour of the orbit, idiopathic mediastinal fibrosis and other conditions, is idiopathic retroperitoneal fibrosis (IRF). Both IRF and IgG4-RD can be associated with a wide variety of disorders, usually governed by immune-mediated (and particularly auto-immune) mechanisms. In our review, we discuss the clinical and therapeutic challenges IRF presents to the internist, as well as the meaning of its recent inclusion in the IgG4-RD spectrum from a clinical practice standpoint.

Severe hypokalemia and hypophosphatemia presenting with carpopedal spasm associated with rhabdomyolysis.

Background Severe hypokalemia, defined as serum potassium < 2.5 mEq/L, may lead to neuromuscular, gastrointestinal, and ECG abnormalities. Neuromuscular consequences of hypokalemia include weakness, cramps, rarely paralysis, eventually progressing to rhabdomyolysis. Case presentation We report a case of a 4-year-old girl presenting carpopedal spasm and rhabdomyolysis due to severe hypokalemia associated to hypophosphatemia and hypovolemia. At one month of age she underwent an ileal resection because of a neonatal necrotizing enterocolitis, and a bowel resection at two years of age, because of sub-occlusive episodes. The child had frequent episodes of diarrhoea and was treated with oral white clay (kaolin) and a restrictive diet. Three days prior the admission to the hospital she had numerous episodes of watery diarrhoea. Laboratory tests revealed severe hypokalemia, hypophosphatemia, normal calcium levels associated with marked dehydration. An ECG demonstrated sinus bradycardia, ST-segment depression, T-wave flattening, U-wave, and long-QTc. Symmetric carpal and pedal spasms were observed. A marked rise of creatinine phosphokinase and myoglobin associated to cola colored urine was observed. Intravenous supplementation of potassium phosphate as well as adequate volume repletion led to an improvement of the clinical condition, to the disappearance of carpal and pedal spasms, to normalisation of ECG.  Conclusions Careful electrolytes and volume supplementation led to the correction of potential life-threatening arrhythmias and obtained a complete recovery from carpopedal spasm and rhabdomyolysis. Dietary restriction and pharmacological preparations as kaolin have to be administered with caution to treat diarrhea in children and particularly in those who may present other pre-existing risk factors.

Low serum ferroxidase I activity is associated with mortality in heart failure and related to both peroxynitrite-induced cysteine oxidation and tyrosine nitration of ceruloplasmin.

RATIONALE: Ceruloplasmin antioxidant function is mainly related to its ferroxidase I (FeOxI) activity, which influences iron-dependent oxidative and nitrosative radical species generation. Peroxynitrite, whose production is increased in heart failure (HF), can affect ceruloplasmin antioxidant function through amino acid modification. OBJECTIVE: We investigated the relationship between FeOxI and ceruloplasmin tyrosine and cysteine modification and explored in a cohort of patients with HF the potential clinical relevance of serum FeOxI. METHODS AND RESULTS: In patients with chronic HF (n=96, 76 ± 9 years; New York Heart Association class, 2.9 ± 0.8) and age-matched controls (n=35), serum FeOxI, FeOxII, ceruloplasmin, nitrotyrosine-bound ceruloplasmin, B-type natriuretic peptide, norepinephrine, and high-sensitivity C-reactive protein were measured, and the patients were followed up for 24 months. Ceruloplasmin, B-type natriuretic peptide, norepinephrine, and high-sensitivity C-reactive protein were increased in HF versus controls. FeOxI was decreased in HF (-20%) and inversely related to nitrotyrosine-bound ceruloplasmin (r, -0.305; P=0.003). In HF, FeOxI lower tertile had a mortality rate doubled compared with middle-higher tertiles. FeOxI emerged as a mortality predictor (hazard ratio, 2.95; 95% confidence intervals [1.29-6.75]; P=0.011) after adjustment for age, sex, hypertension, smoking, sodium level, estimated glomerular filtration rate, and high-sensitivity C-reactive protein. In experimental settings, peroxynitrite incubation of serum samples and isolated purified ceruloplasmin reduced FeOxI activity while increasing ceruloplasmin tyrosine nitration and cysteine thiol oxidation. Reduced glutathione prevented peroxynitrite-induced FeOxI drop, tyrosine nitration, and cysteine oxidation; flavonoid(-)-epicatechin, which prevented ceruloplasmin tyrosine nitration but not cysteine oxidation, partially impeded peroxynitrite-induced FeOxI drop. CONCLUSIONS: Reduced activity of serum FeOxI is associated with ceruloplasmin nitration and reduced survival in patients with HF. Both ceruloplasmin tyrosine nitration and cysteine thiol oxidation may be operant in vivo in peroxynitrite-induced FeOxI activity inhibition.

Prealbumin improves death risk prediction of BNP-added Seattle Heart Failure Model: results from a pilot study in elderly chronic heart failure patients.

BACKGROUND: An accurate prognosis prediction represents a key element in chronic heart failure (CHF) management. Seattle Heart Failure Model (SHFM) prognostic power, a validated risk score for predicting mortality in CHF, is improved by adding B-type natriuretic peptide (BNP). We evaluated in a prospective study the incremental value of several biomarkers, linked to different biological domains, on death risk prediction of BNP-added SHFM. METHODS: Troponin I (cTnI), norepinephrine, plasma renin activity, aldosterone, high sensitivity-C reactive protein (hs-CRP), tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), interleukin 2 soluble receptor, leptin, prealbumin, free malondialdehyde, and 15-F2t-isoprostane were measured in plasma from 142 consecutive ambulatory, non-diabetic stable CHF (mean NYHA-class 2.6) patients (mean age 75±8years). Calibration, discrimination, and risk reclassification of BNP-added SHFM were evaluated after individual biomarker addition. RESULTS: Individual addition of biomarkers to BNP-added SHFM did not improve death prediction, except for prealbumin (HR 0.49 CI: (0.31-0.76) p=0.002) and cTnI (HR 2.03 CI: (1.20-3.45) p=0.009). In fact, with respect to BNP-added SHFM (Harrell's C-statistic 0.702), prealbumin emerged as a stronger predictor of death showing the highest improvement in model discrimination (+0.021, p=0.033) and only a trend was observed for cTn I (+0.023, p=0.063). These biomarkers showed also the best reclassification statistic (Integrated Discrimination Improvement-IDI) at 1-year (IDI: cTnI, p=0.002; prealbumin, p=0.020), 2-years (IDI: cTnI, p=0.018; prealbumin: p=0.006) and 3-years of follow-up (IDI: cTnI p=0.024; prealbumin: p=0.012). CONCLUSIONS: Individual addition of prealbumin allows a more accurate prediction of mortality of BNP enriched SHFM in ambulatory elderly CHF suggesting its potential use in identifying those at high-risk that need nutritional surveillance.