Trends and symptoms of SARS-CoV-2 infection: a longitudinal study on an Alpine population representative sample.

OBJECTIVES: The continuous monitoring of SARS-CoV-2 infection waves and the emergence of novel pathogens pose a challenge for effective public health surveillance strategies based on diagnostics. Longitudinal population representative studies on incident events and symptoms of SARS-CoV-2 infection are scarce. We aimed at describing the evolution of the COVID-19 pandemic during 2020 and 2021 through regular monitoring of self-reported symptoms in an Alpine community sample. DESIGN: To this purpose, we designed a longitudinal population representative study, the Cooperative Health Research in South Tyrol COVID-19 study. PARTICIPANTS AND OUTCOME MEASURES: A sample of 845 participants was retrospectively investigated for active and past infections with swab and blood tests, by August 2020, allowing adjusted cumulative incidence estimation. Of them, 700 participants without previous infection or vaccination were followed up monthly until July 2021 for first-time infection and symptom self-reporting: COVID-19 anamnesis, social contacts, lifestyle and sociodemographic data were assessed remotely through digital questionnaires. Temporal symptom trajectories and infection rates were modelled through longitudinal clustering and dynamic correlation analysis. Negative binomial regression and random forest analysis assessed the relative importance of symptoms. RESULTS: At baseline, the cumulative incidence of SARS-CoV-2 infection was 1.10% (95% CI 0.51%, 2.10%). Symptom trajectories mimicked both self-reported and confirmed cases of incident infections. Cluster analysis identified two groups of high-frequency and low-frequency symptoms. Symptoms like fever and loss of smell fell in the low-frequency cluster. Symptoms most discriminative of test positivity (loss of smell, fatigue and joint-muscle aches) confirmed prior evidence. CONCLUSIONS: Regular symptom tracking from population representative samples is an effective screening tool auxiliary to laboratory diagnostics for novel pathogens at critical times, as manifested in this study of COVID-19 patterns. Integrated surveillance systems might benefit from more direct involvement of citizens' active symptom tracking.

Structural equation modeling (SEM) of kidney function markers and longitudinal CVD risk assessment.

Lower kidney function is known to enhance cardiovascular disease (CVD) risk. It is unclear which estimated glomerular filtration rate (eGFR) equation best predict an increased CVD risk and if prediction can be improved by integration of multiple kidney function markers. We performed structural equation modeling (SEM) of kidney markers and compared the performance of the resulting pooled indexes with established eGFR equations to predict CVD risk in a 10-year longitudinal population-based design. We split the study sample into a set of participants with only baseline data (n = 647; model-building set) and a set with longitudinal data (n = 670; longitudinal set). In the model-building set, we fitted five SEM models based on serum creatinine or creatinine-based eGFR (eGFRcre), cystatin C or cystatin-based eGFR (eGFRcys), uric acid (UA), and blood urea nitrogen (BUN). In the longitudinal set, 10-year incident CVD risk was defined as a Framingham risk score (FRS)>5% and a pooled cohort equation (PCE)>5%. Predictive performances of the different kidney function indexes were compared using the C-statistic and the DeLong test. In the longitudinal set, a SEM-based estimate of latent kidney function based on eGFRcre, eGFRcys, UA, and BUN showed better prediction performance for both FRS>5% (C-statistic: 0.70; 95% CI: 0.65-0.74) and PCE>5% (C-statistic: 0.75; 95%CI: 0.71-0.79) than other SEM models and different eGFR formulas (DeLong test p-values<3.21×10-6 for FRS>5% and <1.49×10-9 for PCE>5%, respectively). However, the new derived marker could not outperform eGFRcys (DeLong test p-values = 0.88 for FRS>5% and 0.20 for PCE>5%, respectively). SEM is a promising approach to identify latent kidney function signatures. However, for incident CVD risk prediction, eGFRcys could still be preferrable given its simpler derivation.

Determinants of SARS-CoV-2 nasopharyngeal testing in a rural community sample susceptible of first infection: the CHRIS COVID-19 study.

To characterize COVID-19 epidemiology, numerous population-based studies have been undertaken to model the risk of SARS-CoV-2 infection. Less is known about what may drive the probability to undergo testing. Understanding how much testing is driven by contextual or individual conditions is important to delineate the role of individual behavior and to shape public health interventions and resource allocation. In the Val Venosta/Vinschgau district (South Tyrol, Italy), we conducted a population-representative longitudinal study on 697 individuals susceptible to first infection who completed 4,512 repeated online questionnaires at four-week intervals between September 2020 and May 2021. Mixed-effects logistic regression models were fitted to investigate associations of self-reported SARS-CoV-2 testing with individual characteristics (social, demographic, and biological) and contextual determinants. Testing was associated with month of reporting, reflecting the timing of both the pandemic intensity and public health interventions, COVID-19-related symptoms (odds ratio, OR:8.26; 95% confidence interval, CI:6.04-11.31), contacts with infected individuals within home (OR:7.47, 95%CI:3.81-14.62) or outside home (OR:9.87, 95%CI:5.78-16.85), and being retired (OR:0.50, 95%CI:0.34-0.73). Symptoms and next within- and outside-home contacts were the leading determinants of swab testing predisposition in the most acute phase of the pandemics. Testing was not associated with age, sex, education, comorbidities, or lifestyle factors. In the study area, contextual determinants reflecting the course of the pandemic were predominant compared to individual sociodemographic characteristics in explaining the SARS-CoV-2 probability of testing. Decision makers should evaluate whether the intended target groups were correctly prioritized by the testing campaign.

Long-term worsening of different body functions in persons with progressive multiple sclerosis.

BACKGROUND: It is unclear whether EDSS is responsive to disability worsening in advanced MS. OBJECTIVE: To explore the dynamics of disability worsening in persons with advanced-stage MS (EDSS ≥5.5) using three disability worsening definitions (EDSS, Rivermead Mobility Index (RMI), 9-Hole Peg Test (9-HPT)). METHODS: EDSS-, RMI- and 9-HPT-based disability worsening were assessed over a minimum of two years in a cohort of 286 persons with advanced MS attending inpatient rehabilitation using Kaplan-Meier Curves and multivariable Cox regression. Furthermore, the correspondence between EDSS-, RMI- and 9-HPT-based disability worsening was analyzed. RESULTS: Disability progression was observed in 49% (9-HPT), 52% (EDSS) and 53% (RMI), with 9-HPT-based worsening slightly lagging behind. The Multiple Sclerosis Severity Score (MSSS) was the only consistent factor predicting disability worsening based on all three definitions (EDSS: hazard ratio 1.48 [1.30;1.68]; RMI: 1.12 [0.99;1.27]; 9-HPT: 1.36 [1.18;1.57]). Correspondence between EDSS and the other definitions (9-HPT and RMI) was 44.3% and 55.7% at time of EDSS progression and 65.1% and 72.5% overall, respectively. CONCLUSION: In persons with advanced-stage MS, half still developed disability worsening in different functional systems over a median of 6 years. MSSS seems a valid predictor for disability worsening in all three outcome measures in advanced MS.

Development and validation of the self-reported disability status scale (SRDSS) to estimate EDSS-categories.

BACKGROUND: Clinician-assessed Expanded Disease Status Scale (EDSS) is gold standard in clinical investigations but normally unavailable in population-based, patient-centred MS-studies. Our objective was to develop a self-reported gait measure reflecting EDSS-categories. METHODS: We developed the self-reported disability status scale (SRDSS) with three categories (≤3.5, 4-6.5, ≥7) based on three mobility-related questions. The SRDSS was determined for 173 persons with MS and validated against clinical EDSS to calculate sensitivity and specificity. RESULTS: Accuracy was 88.4% (153 correctly classified) and weighted kappa 0.73 (0.62-0.84). Sensitivity/specificity-pairs were 94.5%/77.8%, 69.0%/94.7% and 100%/98.2% for SRDSS ≤3.5, 4-6.5 and ≥7, respectively. CONCLUSIONS: Self-reported SRDSS approximates EDSS-categories well and fosters comparability between clinical and population-based studies.

How do patients enter the healthcare system after the first onset of multiple sclerosis symptoms? The influence of setting and physician specialty on speed of diagnosis.

BACKGROUND: Diagnosing multiple sclerosis (MS) early is crucial to avoid future disability. However, potentially preventable delays in the diagnostic cascade from contact with a physician to definite diagnosis still occur and their causes are still unclear. OBJECTIVE: To identify the possible causes of delays in the diagnostic process. METHODS: We analyzed the data of the Swiss MS Registry. With logistic regression, we modeled the time from the first contact to the first consultation (contact-to-evaluation time, ⩽1 month/>1 month) and the evaluation-to-diagnosis time (⩽6 months/>6 months). Potential factors were health system characteristics, sociodemographic variables, first symptoms, and MS type. RESULTS: We included 522 participants. Mostly, general practitioners (67%) were contacted first, without delaying the diagnosis. In contrast, first symptoms and MS type were the major contributors to delays: gait problems were associated with longer contact-to-evaluation times, depression as a concomitant symptom with longer evaluation-to-diagnosis times, and having primary progressive MS prolonged both phases. In addition, living in mountainous areas was associated with longer contact-to-evaluation times, whereas diagnosis after 2000 was associated with faster diagnoses. CONCLUSION: For a quicker diagnosis, awareness of MS as a differential diagnosis of gait disorders and the co-occurrence of depression at onset should be raised, and these symptoms should be attentively followed.

Patterns of care for Multiple Sclerosis in a setting of universal care access: A cross-sectional study.

BACKGROUND: Current guidelines recommend regular neurological MS care in persons diagnosed with MS, but little is known about implementation of this recommendation or potential access barriers. This study examined disease-specific and sociodemographic differences between MS patients in Neurological Care (NeC), General Practitioner Care (GPC), or no Physician Care (NoPC) to identify group differences and characteristics that may suggest care access barriers. METHODS: Patient-reported data were analyzed from 1038 Swiss Multiple Sclerosis Registry participants by means of multivariable regression to identify systematic differences across the three care groups. Assessments included comprehensive data on clinical, sociodemographic, and geographic factors. RESULTS: 89% reported being in regular care by a neurologist (56% in private practices, 44% in hospitals), 5% were in GPC, and 6% reported No Physician Care (NoPC). Compared with the NeC group, patients not seeing a neurologist included two subgroups, one consisting of persons with a primary progressive MS (PPMS) and/or an extended MS history. The second subgroup included persons with a recent MS diagnosis within the last 2 years. Within the NeC group, the patients seen in private practices were of older age and more frequently female compared to those at clinics, but no differences were detected with regard to disability status, MS type, or treatment patterns. CONCLUSIONS: Access to neurological care is high in Switzerland. Given the emerging paradigm for early treatment and new drugs for progressive MS, regular neurology visits should be promoted among patient groups currently less in neurological care such as persons with PPMS or recently diagnosed.

The disease burden of Multiple Sclerosis from the individual and population perspective: Which symptoms matter most?

BACKGROUND: MS symptoms affect many functional domains. Knowing the specific impact of symptoms on health-related quality of life (HRQoL) is vital for successful disease and symptom management in MS. We aimed at investigating how specific MS symptoms contribute to the disease burden in individuals and from a population perspective. METHODS: We included 855 Swiss Multiple Sclerosis Registry participants with a relapsing-remitting form (RRMS) or a progressive form (PMS). HRQoL was measured with the EuroQol 5-Dimension EQ-5D-index and EQ-Visual Analogue Scale (EQ-VAS) on 0-100% scales. Their associations with 20 symptoms, socio-demographic and clinical information were explored in median regression models, stratified by RRMS and PMS. RESULTS: We included 611 participants with RRMS and 244 with PMS. In RRMS, gait (-6.5%) and balance problems (-5.1%) had the largest EQ-5D-index reductions, and were also important at the population level (frequencies 45% and 52%). Fatigue, depression, and spasticity (frequencies 74.1%, 31%, 38%) also contributed to the population disease burden. In PMS, spasticity, paralysis, and bowel problems had the largest impact on EQ-5D-index, both at the individual and population levels. The largest impact on EQ-VAS at population level was associated in RRMS with balance problems, depression, dizziness, and spasticity, while in PMS with weakness, pain, and paralysis. CONCLUSIONS: While HRQoL at population level is most affected by balance problems, spasticity, and depression in RRMS, the biggest HRQoL losses in PMS are caused by spasticity, paralysis, weakness, and pain. Many symptoms with the largest effects in individuals substantially contribute to the population disease burden.

Recommended outcome measures for inpatient rehabilitation of multiple sclerosis are not appropriate for the patients with substantially impaired mobility.

BACKGROUND: In multiple sclerosis (MS) rehabilitation, most currently used outcome measures were validated in patients with a relapsing remitting MS and mild to moderate impairments. We aimed to assess whether these measures were also adequate in more impaired patients, frequently encountered in those with progressive MS (PMS). METHODS: Outcome measurements were extracted from medical records of 229 patients with PMS undergoing 3 weeks of routine inpatient rehabilitation between 2011 and 2015. We assessed the acceptability of Nine-Hole Peg Test (9HPT), Timed 25-Foot Walk (T25FW), 2-Minute Walk Test (2MWT), Rivermead Mobility Index (RMI) and the Functional Independence Measure (FIM) by analysing their statistical distributions, concurrent validity by comparing Spearman correlations with pre-specified hypotheses, and responsiveness across impairment status by calculating standardized response means. RESULTS: Our concurrent validity hypotheses were mainly satisfied. However, all outcome measures had skewed distributions, showed low variability, and thus were inadequately discriminative. Moreover, 9HPT was never responsive across the impairment states, whereas the T25FW was responsive for mildly impaired patients, and the 2MWT for mild to moderate MS, respectively. Generic multi-items measures such as RMI and FIM-motor were adequately responsive for all severity levels. CONCLUSIONS: Currently used outcome measures are inadequate for patients with impaired mobility, and there is a dire need of specifically designed outcome measures for routine care that are less burdensome and short-term responsive.