Transient Changes in the Plasma of Astrocytic and Neuronal Injury Biomarkers in COVID-19 Patients without Neurological Syndromes.

The levels of several glial and neuronal plasma biomarkers have been found to increase during the acute phase in COVID-19 patients with neurological symptoms. However, replications in patients with minor or non-neurological symptoms are needed to understand their potential as indicators of CNS injury or vulnerability. Plasma levels of glial fibrillary acidic protein (GFAP), neurofilament light chain protein (NfL), and total Tau (T-tau) were determined by Single molecule array (Simoa) immunoassays in 45 samples from COVID-19 patients in the acute phase of infection [moderate (n = 35), or severe (n = 10)] with minor or non-neurological symptoms; in 26 samples from fully recovered patients after ~2 months of clinical follow-up [moderate (n = 23), or severe (n = 3)]; and in 14 non-infected controls. Plasma levels of the SARS-CoV-2 receptor, angiotensin-converting enzyme 2 (ACE2), were also determined by Western blot. Patients with COVID-19 without substantial neurological symptoms had significantly higher plasma concentrations of GFAP, a marker of astrocytic activation/injury, and of NfL and T-tau, markers of axonal damage and neuronal degeneration, compared with controls. All these biomarkers were correlated in COVID-19 patients at the acute phase. Plasma GFAP, NfL and T-tau levels were all normalized after recovery. Recovery was also observed in the return to normal values of the quotient between the ACE2 fragment and circulating full-length species, following the change noticed in the acute phase of infection. None of these biomarkers displayed differences in plasma samples at the acute phase or recovery when the COVID-19 subjects were sub-grouped according to occurrence of minor symptoms at re-evaluation 3 months after the acute episode (so called post-COVID or "long COVID"), such as asthenia, myalgia/arthralgia, anosmia/ageusia, vision impairment, headache or memory loss. Our study demonstrated altered plasma GFAP, NfL and T-tau levels in COVID-19 patients without substantial neurological manifestation at the acute phase of the disease, providing a suitable indication of CNS vulnerability; but these biomarkers fail to predict the occurrence of delayed minor neurological symptoms.

First and second waves of coronavirus disease-19: A comparative study in hospitalized patients in Reus, Spain.

Many countries have seen a two-wave pattern in reported cases of coronavirus disease-19 during the 2020 pandemic, with a first wave during spring followed by the current second wave in late summer and autumn. Empirical data show that the characteristics of the effects of the virus do vary between the two periods. Differences in age range and severity of the disease have been reported, although the comparative characteristics of the two waves still remain largely unknown. Those characteristics are compared in this study using data from two equal periods of 3 and a half months. The first period, between 15th March and 30th June, corresponding to the entire first wave, and the second, between 1st July and 15th October, corresponding to part of the second wave, still present at the time of writing this article. Two hundred and four patients were hospitalized during the first period, and 264 during the second period. Patients in the second wave were younger and the duration of hospitalization and case fatality rate were lower than those in the first wave. In the second wave, there were more children, and pregnant and post-partum women. The most frequent signs and symptoms in both waves were fever, dyspnea, pneumonia, and cough, and the most relevant comorbidities were cardiovascular diseases, type 2 diabetes mellitus, and chronic neurological diseases. Patients from the second wave more frequently presented renal and gastrointestinal symptoms, were more often treated with non-invasive mechanical ventilation and corticoids, and less often with invasive mechanical ventilation, conventional oxygen therapy and anticoagulants. Several differences in mortality risk factors were also observed. These results might help to understand the characteristics of the second wave and the behaviour and danger of SARS-CoV-2 in the Mediterranean area and in Western Europe. Further studies are needed to confirm our findings.

Therapeutic Potential of Emerging NAD+-Increasing Strategies for Cardiovascular Diseases.

Cardiovascular diseases are the leading cause of death worldwide. Aging and/or metabolic stress directly impact the cardiovascular system. Over the last few years, the contributions of altered nicotinamide adenine dinucleotide (NAD+) metabolism to aging and other pathological conditions closely related to cardiovascular diseases have been intensively investigated. NAD+ bioavailability decreases with age and cardiometabolic conditions in several mammalian tissues. Compelling data suggest that declining tissue NAD+ is commonly related to mitochondrial dysfunction and might be considered as a therapeutic target. Thus, NAD+ replenishment by either genetic or natural dietary NAD+-increasing strategies has been recently demonstrated to be effective for improving the pathophysiology of cardiac and vascular health in different experimental models, as well as human health, to a lesser extent. Here, we review and discuss recent experimental evidence illustrating that increasing NAD+ bioavailability, particularly by the use of natural NAD+ precursors, may offer hope for new therapeutic strategies to prevent and treat cardiovascular diseases.

Latin American Origin Is Not Associated with Worse Outcomes among Hospitalized Patients with COVID-19 in a Public Healthcare System.

Exploring differences in clinical outcomes based on race and origin among patients hospitalized for COVID-19 is a controversial issue. The ALC COVID-19 Registry includes all confirmed COVID-19 patients admitted to hospital from 3 March 2020 to 17 December 2020. The data were obtained from electronic health records in order to evaluate the differences in the clinical features and outcomes among European and Latin American patients. The follow-ups occurred after 156 days. A propensity score weighting (PSW) logistic regression model was used to estimate the odds ratio (OR, 95% CI) for Latin American origin and outcome associations. Of the 696 patients included, 46.7% were women, with a median age of 65 (IQR 53-67) years, 614 (88.2%) were European, and 82 (11.8%) were Latin American. Latin American patients were younger, with fewer comorbidities, and a higher incidence of extensive pneumonia. After adjusting for residual confounders, Latin American origin was not associated with an increased risk of death (PSW OR 0.85 (0.23-3.14)) or with the need for invasive mechanical ventilation (PSW OR 0.35 (0.12-1.03)). Latin American origin was associated with a shorter hospital stay, but without differences in how long the patient remained on mechanical ventilation. In a public healthcare system, the rates of death or mechanical ventilation in severe COVID-19 cases were found to be comparable between patients of European and Latin American origins.

Clinical Frailty Score vs Hospital Frailty Risk Score for predicting mortality and other adverse outcome in hospitalised patients with COVID-19: Spanish case series.

OBJECTIVES: Frailty can be used as a predictor of adverse outcomes in people with coronavirus disease 2019 (COVID-19). The aim of the study was to analyse the prognostic value of two different frailty scores in patients hospitalised for COVID-19. MATERIAL AND METHODS: This retrospective cohort study included adult (≥18 years) inpatients with COVID-19 and took place from 3 March to 2 May 2020. Patients were categorised by Clinical Frailty Score (CFS) and Hospital Frailty Risk Score (HFRS). The primary outcome was in-hospital mortality, and secondary outcomes were tocilizumab treatment, length of hospital stay, admission in intensive care unit (ICU) and need for invasive mechanical ventilation. Results were analysed by multivariable logistic regression and expressed as odds ratios (ORs), adjusting for age, sex, kidney function and comorbidity. RESULTS: Of the 290 included patients, 54 were frail according to the CFS (≥5 points; prevalence 18.6%, 95% confidence interval [CI]: 14.4-23.7) vs 65 by HFRS (≥5 points; prevalence: 22.4%, 95% CI 17.8-27.7). Prevalence of frailty increased with age according to both measures: 50-64 years, CFS 1.9% vs HFRS 12.3%; 65-79 years, CFS 31.5% vs HFRS 40.0%; and ≥80 years, CFS 66.7% vs HFRS 40.0% (P < .001). CFS-defined frailty was independently associated with risk of death (OR 3.67, 95% CI 1.49-9.04) and less treatment with tocilizumab (OR 0.28, 95% CI 0.08-0.93). HFRS-defined frailty was independently associated with length of hospital stay over 10 days (OR 2.89, 95% CI 1.53-5.44), ICU admission (OR 4.18, 95% CI 1.84-9.52) and invasive mechanical ventilation (OR 5.93, 95% CI 2.33-15.10). CONCLUSION: In the spring 2020 wave of the COVID-19 pandemic in Spain, CFS-defined frailty was an independent predictor for death, while frailty as measured by the HFRS was associated with length of hospital stay over 10 days, ICU admission and use of invasive mechanical ventilation.

Plasma ACE2 species are differentially altered in COVID-19 patients.

Studies are needed to identify useful biomarkers to assess the severity and prognosis of COVID-19 disease, caused by severe acute respiratory syndrome coronavirus (SARS-CoV-2) virus. Here, we examine the levels of various plasma species of the SARS-CoV-2 host receptor, the angiotensin-converting enzyme 2 (ACE2), in patients at different phases of the infection. Human plasma ACE2 species were characterized by immunoprecipitation and western blotting employing antibodies against the ectodomain and the C-terminal domain, using a recombinant human ACE2 protein as control. In addition, changes in the cleaved and full-length ACE2 species were also examined in serum samples derived from humanized K18-hACE2 mice challenged with a lethal dose of SARS-CoV-2. ACE2 immunoreactivity was present in human plasma as several molecular mass species that probably comprise truncated (70 and 75 kDa) and full-length forms (95, 100, 130, and 170 kDa). COVID-19 patients in the acute phase of infection (n = 46) had significantly decreased levels of ACE2 full-length species, while a truncated 70-kDa form was marginally higher compared with non-disease controls (n = 26). Levels of ACE2 full-length species were in the normal range in patients after a recovery period with an interval of 58-70 days (n = 29), while the 70-kDa species decreased. Levels of the truncated ACE2 species served to discriminate between individuals infected by SARS-CoV-2 and those infected with influenza A virus (n = 17). In conclusion, specific plasma ACE2 species are altered in patients with COVID-19 and these changes normalize during the recovery phase. Alterations in ACE2 species following SARS-CoV-2 infection warrant further investigation regarding their potential usefulness as biomarkers for the disease process and to asses efficacy during vaccination.

Male pituitary-gonadal axis dysfunction in post-acute COVID-19 syndrome-Prevalence and associated factors: A Mediterranean case series.

OBJECTIVE: Severe acute respiratory syndrome coronavirus 2 through angiotensin-converting enzyme 2 receptor can harm testes function. The objectives were to analyse the prevalence of low serum testosterone (LT) and impaired fertility potential (Leydig and Sertoli cells dysfunction, respectively) in coronavirus disease 2019 (COVID-19) male survivors and to evaluate acute infection-related associated factors. Also, we explore its association with post-acute COVID-19 syndrome (PCS) and quality of life (QOL). MATERIALS AND METHODS: Male adults recovered from polymerase chain reaction-confirmed COVID-19 were offered a structured evaluation 8-12 weeks after recovery. The main outcome measure(s) were as follows: LT, defined as total testosterone (TT) < 2 ng/ml or if TT levels 2-4 ng/ml as calculated free testosterone < 6.36 ng/dl; Sertoli cell dysfunction was defined as inhibin-B < 89 pg/ml. Secondary outcome-associated factors were analysed by multiple logistic regression (odds ratio; 95% confidence interval [CI]). QOL was evaluated by SF-36 v.2. RESULTS: One hundred and forty-three patients were evaluated at a median (interquartile range) of 77 days (72-83) after disease onset; 72% of them recovered from severe pneumonia. LT was detected in 41 patients (28.7%; 95% CI: 21.8-36.5). Low levels of inhibin-B were detected in 25 patients (18.1%; 95% CI: 12.5-25.3). After multivariate adjustment, obesity and hypokalaemia were associated with LT, whereas age more than 65 was an independent predictor of Sertoli cell dysfunction. LT or Sertoli cell dysfunction was not associated with PCS. Patients with LT had a lower score in four domains of QOL. CONCLUSIONS: Prevalence of male LT and impaired fertility potential in COVID-19 survivors is high in the medium term. Traditional risk factors and severity markers for COVID-19 could be predictive.

Medium-term serostatus in Spanish case series recovered from SARS-CoV-2 infection.

The medium-term serologic response of SARS-CoV-2 infection recovered individuals is not well known. The aims were to quantify the incidence of seropositive failure in the medium term in a cohort of patients with different COVID-19 severity and to analyze its associated factors. Patients who had recovered from mild and severe forms of SARS-CoV-2 infection in an Academic Spanish hospital (March 12-May 2, 2020), were tested for total anti-SARS-CoV-2 antibodies by electrochemiluminescence immunoassay (Elecsys Anti-SARS-CoV-2 test; Roche Diagnostics GmbH). The non-seropositive status (seropositive failure) incidence (95% CI) was determined. Associations were tested by multiple logistic regression in a global cohort and severe pneumonia subpopulation. Of 435 patients with PCR-confirmed SARS-CoV-2, a serological test was carried out in 325: 210 (64.6%) had severe pneumonia (hospitalized patients), 51 (15.7%) non-severe pneumonia (managed as outpatients), and 64 (19.7%) mild cases without pneumonia. After a median (IQR) of 76 days (70-83) from symptom onset, antibody responses may not consistently develop or reach levels sufficient to be detectable by antibody tests (non-seropositive incidence) in 6.9% (95% CI, 4.4-10.6) and 20.3% (95% CI, 12.2-31.7) of patients with and without pneumonia, respectively. Baseline independent predictors of seropositive failure were higher leukocytes and fewer days of symptoms before admission, while low glomerular filtrate and fever seem associated with serologic response. Age, comorbidity or immunosuppressive therapies (corticosteroids, tocilizumab) did not influence antibody response. In the medium-term, SARS-CoV-2 seropositive failure is not infrequent in COVID-19 recovered patients. Age, comorbidity or immunosuppressive therapies did not influence antibody response.

Missing Diagnoses during the COVID-19 Pandemic: A Year in Review.

The COVID-19 pandemic has had major impacts on population health not only through COVID-positive cases, but also via the disruption of healthcare services, which in turn has impacted the diagnosis and treatment of all other diseases during this time. We study changes in all new registered diagnoses in ICD-10 groups during 2020 with respect to a 2019 baseline. We compare new diagnoses in 2019 and 2020 based on administrative records of the public primary health system in Central Catalonia, Spain, which cover over 400,000 patients and 3 million patient visits. We study the ratio of new diagnoses between 2019 and 2020 and find an average decline of 31.1% in new diagnoses, with substantial drops in April (61.1%), May (55.6%), and November (52%). Neoplasms experience the largest decline (49.7%), with heterogeneity in the magnitudes of the declines across different types of cancer diagnoses. While we find evidence of temporal variation in new diagnoses, reductions in diagnoses early in the year are not recouped by the year end. The observed decline in new diagnoses across all diagnosis groups suggest a large number of untreated and undetected cases across conditions. Our findings provide a year-end summary of the impact of the pandemic on healthcare activities and can help guide health authorities to design evidence-based plans to target under-diagnosed conditions in 2021.

Fatality and risk features for prognosis in COVID-19 according to the care approach - a retrospective cohort study.

INTRODUCTION: This study analyzed the impact of a categorized approach, based on patients' prognosis, on major outcomes and explanators in patients hospitalized for COVID-19 pneumonia in an academic center in Spain. METHODS: Retrospective cohort study (March 3 to May 2, 2020). Patients were categorized according to the followed clinical management, as maximum care or limited therapeutic effort (LTE). Main outcomes were all-cause mortality and need for invasive mechanical ventilation (IMV). Baseline factors associated with outcomes were analyzed by multiple logistic regression, estimating odds ratios (OR; 95%CI). RESULTS: Thirty-hundred and six patients were hospitalized, median age 65.0 years, 57.8% males, 53.3% Charlson index ≥3. The overall all-cause fatality rate was 15.0% (n = 46). Maximum care was provided in 238 (77.8%), IMV was used in 38 patients (16.0%), and 5.5% died. LTE was decided in 68 patients (22.2%), none received IMV and fatality was 48.5%. Independent risk factors of mortality under maximum care were lymphocytes <790/mm3, troponin T >15ng/L and hypotension. Advanced age, lymphocytes <790/mm3 and BNP >240pg/mL independently associated with IMV requirement. CONCLUSION: Overall fatality in the cohort was 15% but markedly varied regarding the decided approach (maximum care versus LTE), translating into nine-fold higher mortality and different risk factors.

An integrated emergency department/hospital at home model in mild COVID-19 pneumonia: feasibility and outcomes after discharge from the emergency department.

To evaluate the effectiveness of an integrated emergency department (ED)/hospital at home (HH) medical care model in mild COVID-19 pneumonia and evaluate baseline predictors of major outcomes and potential savings. Retrospective cohort study with patients evaluated for COVID-19 pneumonia in the ED, from March 3 to April 30, 2020. All of them were discharged home and controlled by HH. The main outcomes were ED revisit and the need for deferred hospital admission (protocol failure). Outcome predictors were analyzed by simple logistic regression model (OR; 95% CI). Potential savings of this medical care model were estimated. Of the 377 patients attended in the ED, 109 were identified as having mild pneumonia and were included in the ED/HH medical care model. Median age was 50.0 years, 52.3% were males and 57.8% had Charlson index ≥ 1. The median HH stay was 8 (IQR 3.7-11) days. COVID-19-related ED revisit was 19.2% (n = 21) within 6 days (IQR 3-12.5) after discharge from ED. Overall protocol failure (deferred hospital admission) was 6.4% (n = 7), without ICU admission. The ED/HH model provided potential cost savings of 77% compared to traditional stay, due to the costs of home care entails 23% of the expenses generated by a conventional hospital stay. 789 days of hospital stay were avoided by HH, rather than hospital admission. An innovative ED/HH model for selected patients with mild COVID-19 pneumonia is feasible, safe and effective. Less than 6.5% of patients requiring deferred hospital admission and potential savings were generated due to hospitalization.

Post-acute COVID-19 syndrome. Incidence and risk factors: A Mediterranean cohort study.

OBJECTIVES: This study aims to analyze the incidence of Post-acute COVID-19 syndrome (PCS) and its components, and to evaluate the acute infection phase associated risk factors. METHODS: A prospective cohort study of adult patients who had recovered from COVID-19 (27th February to 29th April 2020) confirmed by PCR or subsequent seroconversion, with a systematic assessment 10-14 weeks after disease onset. PCS was defined as the persistence of at least one clinically relevant symptom, or abnormalities in spirometry or chest radiology. Outcome predictors were analyzed by multiple logistic regression (OR; 95%CI). RESULTS: Two hundred seventy seven patients recovered from mild (34.3%) or severe (65.7%) forms of SARS-CoV-2 infection were evaluated 77 days (IQR 72-85) after disease onset. PCS was detected in 141 patients (50.9%; 95%CI 45.0-56.7%). Symptoms were mostly mild. Alterations in spirometry were noted in 25/269 (9.3%), while in radiographs in 51/277 (18.9%). No baseline clinical features behaved as independent predictors of PCS development. CONCLUSIONS: A Post-acute COVID-19 syndrome was detected in a half of COVID19 survivors. Radiological and spirometric changes were mild and observed in less than 25% of patients. No baseline clinical features behaved as independent predictors of Post-acute COVID-19 syndrome development.

Hypokalemia as a sensitive biomarker of disease severity and the requirement for invasive mechanical ventilation requirement in COVID-19 pneumonia: A case series of 306 Mediterranean patients.

OBJECTIVES: Serum levels of potassium (K+) appear to be significantly lower in severe cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the clinical significance of this is unknown. The objective was to investigate whether hypokalemia acts as a biomarker of severity in coronavirus disease 2019 (COVID-19) pneumonia and is associated with major clinical outcomes. METHODS: A retrospective cohort study of inpatients with COVID-19 pneumonia (March 3 to May 2, 2020) was performed. Patients were categorized according to nadir levels of K+ in the first 72 h of admission: hypokalemia (K+ ≤3.5 mmol/l) and normokalemia (K+ >3.5 mmol/l). The main outcomes were all-cause mortality and the need for invasive mechanical ventilation (IMV); these were analyzed by multiple logistic regression (odds ratio (OR), 95% confidence interval (CI)). RESULTS: Three hundred and six patients were enrolled. Ninety-four patients (30.7%) had hypokalemia and these patients showed significantly higher comorbidity (Charlson comorbidity index ≥3, 30.0% vs 16.3%; p =  0.02) and CURB65 scores (median (interquartile range): 1.5 (0.0-3.0) vs 1.0 (0.0-2.0); p =  0.04), as well as higher levels of some inflammatory parameters at baseline. After adjustment for confounders, hypokalemia was independently associated with requiring IMV during the admission (OR 8.98, 95% CI 2.54-31.74). Mortality was 15.0% (n = 46) and was not influenced by low K+. Hypokalemia was associated with longer hospital and ICU stays. CONCLUSIONS: Hypokalemia is prevalent in patients with COVID-19 pneumonia. Hypokalemia is an independent predictor of IMV requirement and seems to be a sensitive biomarker of severe progression of COVID-19.

Experience with tocilizumab in severe COVID-19 pneumonia after 80 days of follow-up: A retrospective cohort study.

OBJECTIVES: To describe the clinical characteristics and predictors of major outcomes in patients treated with tocilizumab (TCZ) for severe COVID-19 pneumonia. PATIENTS AND METHODS: Case series of all sequential patients with severe COVID-19 pneumonia treated with TCZ at an Academic Spanish hospital (March 12 - May 2, 2020). Clinical outcomes: death, length of hospital stay. An early clinical response to TCZ (48-72 h after the administration) was assessed by variations in respiratory function markers, Brescia COVID Respiratory Severity Scale (BCRSS), inflammatory parameters, and patients' and physicians' opinion. Associations were tested by multiple logistic regression. RESULTS: From a cohort of 236 patients, 77 patients treated with TCZ were included (median age 62 years (IQR 53.0-72.0), 64.9% were males), 42.9% had Charlson index ≥3; hypertension (41.6%), obesity (34.7%), and diabetes (20.8%). Median follow-up was 83.0 days (78.0-86.5), no patient was readmitted. ICU admission was required for 42 (54.5%), invasive mechanical ventilation in 38 (49.4%) and 10 patients died (12.9% global, 23.8% at ICU admitted). After multivariate adjustment, TCZ response by BCRSS (OR 0.03 (0.01-0.68), p = 0.028), and Charlson index (OR 3.54 (1.20-10.44), p = 0.022) has been identified as independent factors associated with mortality. Median of hospital stay was 16.0 days (11.0-23.0); BCRSS, physician subjective and D-dimer response were associated with shorter hospitalization stay. CONCLUSIONS: In a Mediterranean cohort, use of tocilizumab for severe COVID-19 show 12.9% of mortality. Early TCZ-response by BCRSS and low comorbidity were associated with increased survival. Early TCZ-response was related to shorter median hospital stay.