Decreased Gas6 and sAxl Plasma Levels Are Associated with Hair Loss in COVID-19 Survivors.

Post-acute conditions after coronavirus disease 2019 (COVID-19) are quite common, although the underlying pathogenetic mechanisms leading to these conditions are not yet completely understood. In this prospective observational study, we aimed to test the hypothesis that Growth Arrest-Specific 6 (Gas6) and its soluble receptors, Axl (sAxl) and MerTK (sMer), might be implicated. A total of 263 subjects underwent a structured clinical evaluation one year after their hospital discharge for COVID-19, and they consented to donate a blood sample to measure their circulating Gas6, sAxl, and sMer levels. A total of 98 (37.3%) post-COVID-19 subjects complained of at least one residual physical symptom one year after their hospital discharge. Univariate analysis revealed that sAxl was marginally associated with residual symptoms, but at the level of logistic regression analysis, only the diffusing capacity of the lungs for carbon monoxide (DLCO) (OR 0.98, CI 95%: 0.96-0.99; p = 0.007) and the female sex (OR 2.49, CI 95%: 1.45-4.28; p = 0.001) were independently associated with long-lasting symptoms. A total of 69 (26.2%) subjects had hair loss. At the level of univariate analysis, Gas6, sAxl, DLCO, and the female gender were associated with its development. In a logistic regression analysis model, Gas6 (OR 0.96, CI 95%: 0.92-0.99; p = 0.015) and sAxl (OR 0.98, CI 95%; 0.97-1.0; p = 0.014), along with the female sex (OR 6.58, CI 95%: 3.39-12.78; p = 0.0001), were independent predictors of hair loss. Decreased levels of Gas6 and sAxl were associated with a history of hair loss following COVID-19. This was resolved spontaneously in most patients, although 23.7% complained of persistent hair loss one year after hospital discharge.

Determinants of long COVID among adults hospitalized for SARS-CoV-2 infection: A prospective cohort study.

Rationale: Factors associated with long-term sequelae emerging after the acute phase of COVID-19 (so called "long COVID") are unclear. Here, we aimed to identify risk factors for the development of COVID-19 sequelae in a prospective cohort of subjects hospitalized for SARS-CoV-2 infection and followed up one year after discharge. Methods: A total of 324 subjects underwent a comprehensive and multidisciplinary evaluation one year after hospital discharge for COVID-19. A subgroup of 247/324 who consented to donate a blood sample were tested for a panel of circulating cytokines. Results: In 122 patients (37.8%) there was evidence of at least one persisting physical symptom. After correcting for comorbidities and COVID-19 severity, the risk of developing long COVID was lower in the 109 subjects admitted to the hospital in the third wave of the pandemic than in the 215 admitted during the first wave, (OR 0.69, 95%CI 0.51-0.93, p=0.01). Univariable analysis revealed female sex, diffusing capacity of the lungs for carbon monoxide (DLCO) value, body mass index, anxiety and depressive symptoms to be positively associated with COVID-19 sequelae at 1 year. Following logistic regression analysis, DLCO was the only independent predictor of residual symptoms (OR 0.98 CI 95% (0.96-0.99), p=0.01). In the subgroup of subjects with normal DLCO (> 80%), for whom residual lung damage was an unlikely explanation for long COVID, the presence of anxiety and depressive symptoms was significantly associated to persistent symptoms, together with increased levels of a set of pro-inflammatory cytokines: interferon-gamma, tumor necrosis factor-alpha, interleukin (IL)-2, IL-12, IL-1ß, IL-17. In logistic regression analysis, depressive symptoms (p=0.02, OR 4.57 [1.21-17.21]) and IL-12 levels (p=0.03, OR 1.06 [1.00-1.11]) 1-year after hospital discharge were independently associated with persistence of symptoms. Conclusions: Long COVID appears mainly related to respiratory sequelae, prevalently observed during the first pandemic wave. Among patients with little or no residual lung damage, a cytokine pattern consistent with systemic inflammation is in place.

Anxiety, Stress and Depression in COVID-19 Survivors From an Italian Cohort of Hospitalized Patients: Results From a 1-Year Follow-Up

Background Mental health-related symptoms can persist over time beyond the most common respiratory clinical features of COVID-19. A recent meta-analysis underlined that mental health sequalae may be relevant for COVID-19 survivors and reported the following prevalence rates: 20% for post-traumatic stress disorder, 22% for anxiety, 36% for psychological distress, and 21% for depression. In the context of a multi-disciplinary follow-up project, we already investigated the mid-term (4 months) psychiatric outcomes in a sample of COVID-19 survivors. Patients were re-assessed after 1-year since hospital discharge. Methods Follow-up conducted after 1 year involved 196 individuals recovered from COVID-19. Patients were assessed with a multi-disciplinary approach;including both a clinical interview performed by an experienced psychiatrist, trained in the use of the Mini-International Neuropsychiatric Interview (MINI) to assess the presence of anxiety, stress, and depressive symptoms and the following self-administered questionnaires: Beck Anxiety Inventory, Beck Depression Inventory-II, Resilience Scale for Adults, Impact of Event Scale, and COVID-19 Peritraumatic Distress Index (CPDI). Results Anxiety (p < 0.0001) and depressive (p < 0.0003) symptoms registered at the clinical interview showed a significant improvement from the 4 to 12-months follow-up. Logistic regression model showed that female gender (p = 0.006), arterial hypertension (p = 0.01), obesity (0.04), anxiety (p < 0.0001), and depressive (p = 0.02) symptoms at 4-months follow-up were associated with persistence of anxiety symptoms at 12 months. At logistic regression analysis female gender (p = 0.02) and depressive symptoms at 4-months follow-up (p = 0.01) were associated with depressive symptoms after 12 months. Conclusion Severity of the disease in the acute phase, in this study, was not a determining factor in identifying subjects at risk of developing clinically relevant anxiety and depression as a consequence of COVID-19 disease. Findings from the logistic regressions suggest that the factors most affecting depression and anxiety in COVID survivors after 12 months were female gender, the presence of anxiety and depression after 4 months and some physical symptoms, not necessarily COVID-related. Impact of infection and consequent hospitalization for COVID-19 did no longer represent a relevant issue for depressive symptoms, compared to other general factors.

Long-lasting consequences of coronavirus disease 19 pneumonia: a systematic review.

INTRODUCTION: Coronavirus disease 19 (COVID-19) is an infectious disease caused by the newly discovered severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We have plenty of data about the clinical features of the disease's acute phase, while little is known about the long-term consequences on survivors. EVIDENCE ACQUISITION: We aimed to review systematically emerging evidence about clinical and functional consequences of COVID-19 pneumonia months after hospital discharge. EVIDENCE SYNTHESIS: Current evidence supports the idea that a high proportion of COVID-19 survivors complain of symptoms months after the acute illness phase, being fatigue and reduced tolerance to physical effort the most frequently reported symptom. The strongest association for these symptoms is with the female gender, while disease severity seems less relevant. Respiratory symptoms are associated with a decline in respiratory function and, conversely, seem to be more frequent in those who experienced a more severe acute pneumonia. Current evidence highlighted a persistent motor impairment which is, again, more prevalent among those survivors who experienced a more severe acute phase of the disease. Additionally, the persistence of symptoms is a primary determinant of mental health outcome, with anxiety, depression, sleep disturbances, and post-traumatic stress symptoms being commonly reported in COVID-19 survivors. CONCLUSIONS: Current literature highlights the importance of a multidisciplinary approach to Coronavirus Disease 19 since the sequelae appear to involve different organs and systems. Given the pandemic outbreak's size, this is a critical public health issue: a better insight on this topic should inform clinical decisions about the modalities of follow-up for COVID-19 survivors.

Long-term sequelae are highly prevalent one year after hospitalization for severe COVID-19.

Many coronavirus disease 2019 (Covid-19) survivors show symptoms months after acute illness. The aim of this work is to describe the clinical evolution of Covid-19, one year after discharge. We performed a prospective cohort study on 238 patients previously hospitalized for Covid-19 pneumonia in 2020 who already underwent clinical follow-up 4 months post-Covid-19. 200 consented to participate to a 12-months clinical assessment, including: pulmonary function tests with diffusing lung capacity for carbon monoxide (DLCO); post-traumatic stress (PTS) symptoms evaluation by the Impact of Event Scale (IES); motor function evaluation (by Short Physical Performance Battery and 2 min walking test); chest Computed Tomography (CT). After 366 [363-369] days, 79 patients (39.5%) reported at least one symptom. A DLCO < 80% was observed in 96 patients (49.0%). Severe DLCO impairment (< 60%) was reported in 20 patients (10.2%), related to extent of CT scan abnormalities. Some degree of motor impairment was observed in 25.8% of subjects. 37/200 patients (18.5%) showed moderate-to-severe PTS symptoms. In the time elapsed from 4 to 12 months after hospital discharge, motor function improves, while respiratory function does not, being accompanied by evidence of lung structural damage. Symptoms remain highly prevalent one year after acute illness.

Mid-term Psychiatric Outcomes of Patients Recovered From COVID-19 From an Italian Cohort of Hospitalized Patients.

Background: Although the usual primary clinical manifestation of Coronavirus disease (COVID-19) is respiratory, several non-respiratory symptoms have been described, including neuropsychiatric ones. The aim of this study was to investigate the mid-term mental health outcomes in patients recovered from COVID-19, 3-4 months after discharge from the University Hospital Maggiore della Carità, Novara, Italy. Furthermore, we investigated the possible association of the mid-term mental health consequences of the COVID-19 infection with patients' clinical current status, persistent physical impairment and severity of acute phase of the disease. Methods: Prospective study involving 238 individuals recovered from COVID-19. In the context of a multi-disciplinary approach, patients' assessment included both a clinical interview performed by an experienced psychiatrist, trained in the use of the Mini-International Neuropsychiatric Interview to assess the presence of anxiety and depressive symptoms and self-administered questionnaires: Beck Anxiety Inventory (BAI), Beck Depression Inventory-II (BDI-II), Resilience Scale for Adults (RSA), Impact of Event Scale (IES). Results: At the psychiatric assessment 32.9 and 29.5% of participants showed anxiety and depressive symptoms, respectively. Changes in appetite and sleep patterns emerged for 15.6 and 31.2% of patients. According to the self-administered questionnaires, 7.1% of participants had moderate-severe anxiety levels (BAI), while 10.5% had mild to severe depression (BDI-II). Twenty-six (11%) participants were referred to further psychiatric consultation. Psychiatric symptoms showed no correlation with acute COVID-19 severity; in our sample patients with depressive symptoms at the clinical interview, as well as those with mild to severe levels of depression according to BDI-II scores, had lower forced expiratory volume in the 1st second (FEV1) values than those without and greater odds for persistent, poor tolerance for physical efforts. Conclusions: As could be expected, an approach including both a psychiatric interview and the use of self-administered questionnaires is likely to capture the psychiatric outcome of patients recovered from COVID-19 better than questionnaires alone. Anxiety and depressive symptoms at follow-up had no correlation with the severity of COVID acute manifestations, but rather with ongoing and persistent physical symptoms. Further studies and longer follow-up duration will allow a better understanding of the complex relationship between residual physical symptoms, quality of life and psychological health.

Simple Parameters from Complete Blood Count Predict In-Hospital Mortality in COVID-19.

INTRODUCTION: The clinical course of Coronavirus Disease 2019 (COVID-19) is highly heterogenous, ranging from asymptomatic to fatal forms. The identification of clinical and laboratory predictors of poor prognosis may assist clinicians in monitoring strategies and therapeutic decisions. MATERIALS AND METHODS: In this study, we retrospectively assessed the prognostic value of a simple tool, the complete blood count, on a cohort of 664 patients (F 260; 39%, median age 70 (56-81) years) hospitalized for COVID-19 in Northern Italy. We collected demographic data along with complete blood cell count; moreover, the outcome of the hospital in-stay was recorded. RESULTS: At data cut-off, 221/664 patients (33.3%) had died and 453/664 (66.7%) had been discharged. Red cell distribution width (RDW) (χ 2 10.4; p < 0.001), neutrophil-to-lymphocyte (NL) ratio (χ 2 7.6; p = 0.006), and platelet count (χ 2 5.39; p = 0.02), along with age (χ 2 87.6; p < 0.001) and gender (χ 2 17.3; p < 0.001), accurately predicted in-hospital mortality. Hemoglobin levels were not associated with mortality. We also identified the best cut-off for mortality prediction: a NL ratio > 4.68 was characterized by an odds ratio for in-hospital mortality (OR) = 3.40 (2.40-4.82), while the OR for a RDW > 13.7% was 4.09 (2.87-5.83); a platelet count > 166,000/µL was, conversely, protective (OR: 0.45 (0.32-0.63)). CONCLUSION: Our findings arise the opportunity of stratifying COVID-19 severity according to simple lab parameters, which may drive clinical decisions about monitoring and treatment.

Midterm functional sequelae and implications in rehabilitation after COVID-19: a cross-sectional study.

BACKGROUND: COVID-19 has been mainly investigated concerning the acute and subacute phase implications and management. Meanwhile, few studies focused on the midterm sequelae, which still remain largely unknown. AIM: To assess the physical performance of COVID-19 survivors at 3 to 6 months from Hospital discharge. DESIGN: A cross-sectional study focused on mid-term functional outcomes evaluation in COVID-19 survivors. SETTING: Outpatients who had been previously hospitalized due to COVID-19 from March to May 2020 at the University Hospital of Novara, Italy. POPULATION: We enrolled 204 patients, of which 60% were men, with the mean age of 57.9 years. METHODS: Patients firstly underwent the short physical performance battery test (SPPB), which is composed of a series of physical tests assessing the lower limb function and the functional status of the subjects. Subsequently, based on SPPB results, patients' cardiorespiratory fitness performance was further investigated. Patients with normal SPPB score (SPPB>10) underwent the 2-minute walking test (2MWT) whereas, in order to safely test the cardiorespiratory function, in patients with abnormal SPPB score (SPPB≤10) the 1-minute sit-to-stand test (1MSTST) was performed. It should be noted that the 1MSTST can be safely performed even by subjects with compromised walking ability. RESULTS: Overall, 66 patients (32% of our sample) showed an impaired physical performance at 3 to 6 months after hospital discharge. In particular, 29 patients presented an SPPB score ≤10, and the 1MSTST confirmed this status in the whole group (100%) compared to the reference values for age and sex. Besides, among patients with a normal SPPB score, 37 showed a lower sex- and age-matched 2MWT score. Finally, a significant association between Intensive Care Unit hospitalization or mechanical ventilation and physical impairment was observed together with a significant association between the walking ability (measured with SPPB and 2MWT) and the number of comorbidities. CONCLUSIONS: A residual physical and functional impairment was observed in COVID-19 survivors at mid-term evaluation after hospitalization. CLINICAL REHABILITATION IMPACT: Considering the current COVID-19 epidemiology, we might expect a tremendous burden of disability in the next future. Thus, an appropriate clinical rehabilitation pathway must be implemented.

Respiratory and Psychophysical Sequelae Among Patients With COVID-19 Four Months After Hospital Discharge.

Importance: Although plenty of data exist regarding clinical manifestations, course, case fatality rate, and risk factors associated with mortality in severe coronavirus disease 2019 (COVID-19), long-term respiratory and functional sequelae in survivors of COVID-19 are unknown. Objective: To evaluate the prevalence of lung function anomalies, exercise function impairment, and psychological sequelae among patients hospitalized for COVID-19, 4 months after discharge. Design, Setting, and Participants: This prospective cohort study at an academic hospital in Northern Italy was conducted among a consecutive series of patients aged 18 years and older (or their caregivers) who had received a confirmed diagnosis of severe acute respiratory coronavirus 2 (SARS-CoV-2) infection severe enough to require hospital admission from March 1 to June 29, 2020. SARS-CoV-2 infection was confirmed via reverse transcription-polymerase chain reaction testing, bronchial swab, serological testing, or suggestive computed tomography results. Exposure: Severe COVID-19 requiring hospitalization. Main Outcomes and Measures: The primary outcome of the study was to describe the proportion of patients with a diffusing lung capacity for carbon monoxide (Dlco) less than 80% of expected value. Secondary outcomes included proportion of patients with severe lung function impairment (defined as Dlco <60% expected value); proportion of patients with posttraumatic stress symptoms (measured using the Impact of Event Scale-Revised total score); proportion of patients with functional impairment (assessed using the Short Physical Performance Battery [SPPB] score and 2-minute walking test); and identification of factors associated with Dlco reduction and psychological or functional sequelae. Results: Among 767 patients hospitalized for severe COVID-19, 494 (64.4%) refused to participate, and 35 (4.6%) died during follow-up. A total of 238 patients (31.0%) (median [interquartile range] age, 61 [50-71] years; 142 [59.7%] men; median [interquartile range] comorbidities, 2 [1-3]) consented to participate to the study. Of these, 219 patients were able to complete both pulmonary function tests and Dlco measurement. Dlco was reduced to less than 80% of the estimated value in 113 patients (51.6%) and less than 60% in 34 patients (15.5%). The SPPB score was suggested limited mobility (score <11) in 53 patients (22.3%). Patients with SPPB scores within reference range underwent a 2-minute walk test, which was outside reference ranges of expected performance for age and sex in 75 patients (40.5%); thus, a total of 128 patients (53.8%) had functional impairment. Posttraumatic stress symptoms were reported in a total of 41 patients (17.2%). Conclusions and Relevance: These findings suggest that at 4 months after discharge, respiratory, physical, and psychological sequelae were common among patients who had been hospitalized for COVID-19.

Discontinuation of botulinum neurotoxin type-A treatment during COVID-19 pandemic: an Italian survey in post stroke and traumatic brain injury patients living with spasticity.

BACKGROUND: The COVID-19 pandemic has affected health-care systems worldwide, including the outpatient spasticity care with botulinum neurotoxin toxin type A (BoNT-A). AIM: The aim of this study was to investigate the impact of discontinuation of BoNT-A treatment on patients living with spasticity during the COVID-19 quarantine. DESIGN: A multicentric cross-sectional study. SETTING: Outpatients setting. POPULATION: Patients with spasticity after stroke and traumatic brain injury treated with BoNT-A. METHODS: A phone-based survey was conducted from March to May, 2020. Based on the International Classification of Functioning, Disability and Health (ICF), an ad hoc questionnaire CORTOX (CORonavirus TOXin survey) was developed to investigate patients' experiences following the discontinuation of their usual treatment for spasticity due to the lockdown and its implication on their health perception. It assessed patients' condition and explored different ICF domains related to spasticity: unpleasant sensations, mobility, self-care, facilitators and psychosocial factors. The sum of those represented the CORTOX score (Max 142). The questionnaire also collected data about the impact of COVID-19 on patients' wellbeing (mood, sleep, relationships, community life, motivation). RESULTS: A total of 151 participants completed the survey. Most participants (72.2%) experienced a worsening in perceived spasticity, 53% got worse in independence and 70.9% had a negative impact on quality of life. The mean CORTOX score was 52.85±27.25, reflecting a perceived worsening in all ICF domains investigated. Moderate to strong correlations were found between different sub-scores of the questionnaire and severity of spasticity (P<0.001). COVID-19 psychosocial related factors were associated with loss of independence (P<0.05) but only mood was associated with worsening of spasticity (P<0.001). The lack of rehabilitation therapy was significantly associated with the worsening of independence but not with the worsening of spasticity. Finally, respondents reported that BoNT-A was useful to their condition and should not be discontinued. CONCLUSIONS: The discontinuation of BoNT-A treatment was associated with worsening of activities and participation and perceived spasticity. COVID-19 related problems and rehabilitation showed an association with loss of independence. CLINICAL REHABILITATION IMPACT: This study will provide useful information in the field of spasticity management using a patient's centred approach, with consistent quantitative and qualitative information.

Fatality rate and predictors of mortality in an Italian cohort of hospitalized COVID-19 patients.

Clinical features and natural history of coronavirus disease 2019 (COVID-19) differ widely among different countries and during different phases of the pandemia. Here, we aimed to evaluate the case fatality rate (CFR) and to identify predictors of mortality in a cohort of COVID-19 patients admitted to three hospitals of Northern Italy between March 1 and April 28, 2020. All these patients had a confirmed diagnosis of SARS-CoV-2 infection by molecular methods. During the study period 504/1697 patients died; thus, overall CFR was 29.7%. We looked for predictors of mortality in a subgroup of 486 patients (239 males, 59%; median age 71 years) for whom sufficient clinical data were available at data cut-off. Among the demographic and clinical variables considered, age, a diagnosis of cancer, obesity and current smoking independently predicted mortality. When laboratory data were added to the model in a further subgroup of patients, age, the diagnosis of cancer, and the baseline PaO2/FiO2 ratio were identified as independent predictors of mortality. In conclusion, the CFR of hospitalized patients in Northern Italy during the ascending phase of the COVID-19 pandemic approached 30%. The identification of mortality predictors might contribute to better stratification of individual patient risk.