BACKGROUND

There is disagreement about the level of asymptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We conducted a living systematic review and meta-analysis to address three questions: (1) Amongst people who become infected with SARS-CoV-2, what proportion does not experience symptoms at all during their infection? (2) Amongst people with SARS-CoV-2 infection who are asymptomatic when diagnosed, what proportion will develop symptoms later? (3) What proportion of SARS-CoV-2 transmission is accounted for by people who are either asymptomatic throughout infection or presymptomatic?

METHODS AND FINDINGS

We searched PubMed, Embase, bioRxiv, and medRxiv using a database of SARS-CoV-2 literature that is updated daily, on 25 March 2020, 20 April 2020, and 10 June 2020. Studies of people with SARS-CoV-2 diagnosed by reverse transcriptase PCR (RT-PCR) that documented follow-up and symptom status at the beginning and end of follow-up or modelling studies were included. One reviewer extracted data and a second verified the extraction, with disagreement resolved by discussion or a third reviewer. Risk of bias in empirical studies was assessed with an adapted checklist for case series, and the relevance and credibility of modelling studies were assessed using a published checklist. We included a total of 94 studies. The overall estimate of the proportion of people who become infected with SARS-CoV-2 and remain asymptomatic throughout infection was 20% (95% confidence interval [CI] 17-25) with a prediction interval of 3%-67% in 79 studies that addressed this review question. There was some evidence that biases in the selection of participants influence the estimate. In seven studies of defined populations screened for SARS-CoV-2 and then followed, 31% (95% CI 26%-37%, prediction interval 24%-38%) remained asymptomatic. The proportion of people that is presymptomatic could not be summarised, owing to heterogeneity. The secondary attack rate was lower in contacts of people with asymptomatic infection than those with symptomatic infection (relative risk 0.35, 95% CI 0.10-1.27). Modelling studies fit to data found a higher proportion of all SARS-CoV-2 infections resulting from transmission from presymptomatic individuals than from asymptomatic individuals. Limitations of the review include that most included studies were not designed to estimate the proportion of asymptomatic SARS-CoV-2 infections and were at risk of selection biases; we did not consider the possible impact of false negative RT-PCR results, which would underestimate the proportion of asymptomatic infections; and the database does not include all sources.

CONCLUSIONS

The findings of this living systematic review suggest that most people who become infected with SARS-CoV-2 will not remain asymptomatic throughout the course of the infection. The contribution of presymptomatic and asymptomatic infections to overall SARS-CoV-2 transmission means that combination prevention measures, with enhanced hand hygiene, masks, testing tracing, and isolation strategies and social distancing, will continue to be needed.

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Occurrence and transmission potential of asymptomatic and presymptomatic SARS-CoV-2 infections: A living systematic review and meta-analysis.

Fatigue is a common symptom in those presenting with symptomatic COVID-19 infection. However, it is unknown if COVID-19 results in persistent fatigue in those recovered from acute infection. We examined the prevalence of fatigue in individuals recovered from the acute phase of COVID-19 illness using the Chalder Fatigue Score (CFQ-11). We further examined potential predictors of fatigue following COVID-19 infection, evaluating indicators of COVID-19 severity, markers of peripheral immune activation and circulating pro-inflammatory cytokines. Of 128 participants (49.5 ± 15 years; 54% female), more than half reported persistent fatigue (67/128; 52.3%) at median of 10 weeks after initial COVID-19 symptoms. There was no association between COVID-19 severity (need for inpatient admission, supplemental oxygen or critical care) and fatigue following COVID-19. Additionally, there was no association between routine laboratory markers of inflammation and cell turnover (leukocyte, neutrophil or lymphocyte counts, neutrophil-to-lymphocyte ratio, lactate dehydrogenase, C-reactive protein) or pro-inflammatory molecules (IL-6 or sCD25) and fatigue post COVID-19. Female gender and those with a pre-existing diagnosis of depression/anxiety were over-represented in those with fatigue. Our findings demonstrate a significant burden of post-viral fatigue in individuals with previous SARS-CoV-2 infection after the acute phase of COVID-19 illness. This study highlights the importance of assessing those recovering from COVID-19 for symptoms of severe fatigue, irrespective of severity of initial illness, and may identify a group worthy of further study and early intervention.

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Persistent fatigue following SARS-CoV-2 infection is common and independent of severity of initial infection.

Although COVID-19 presents primarily as a lower respiratory tract infection transmitted via air droplets, increasing data suggest multiorgan involvement in patients that are infected. This systemic involvement is postulated to be mainly related to the SARS-CoV-2 virus binding on angiotensin-converting enzyme 2 (ACE2) receptors located on several different human cells. Lung involvement is the most common serious manifestation of the disease, ranging from asymptomatic disease or mild pneumonia, to severe disease associated with hypoxia, critical disease associated with shock, respiratory failure and multiorgan failure or death. Among patients with COVID-19, underlying cardiovascular comorbidities including hypertension, diabetes and especially cardiovascular disease, has been associated with adverse outcomes, whereas the emergence of cardiovascular complications, including myocardial injury, heart failure and arrhythmias, has been associated with poor survival. Gastrointestinal symptoms are also frequently encountered and may persist for several days. Haematological complications are frequent as well and have been associated with poor prognosis. Furthermore, recent studies have reported that over a third of infected patients develop a broad spectrum of neurological symptoms affecting the central nervous system, peripheral nervous system and skeletal muscles, including anosmia and ageusia. The skin, the kidneys, the liver, the endocrine organs and the eyes are also affected by the systemic COVID-19 disease. Herein, we provide a comprehensive overview of the organ-specific systemic manifestations of COVID-19.

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Organ-specific manifestations of COVID-19 infection.

Anosmia, stroke, paralysis, cranial nerve deficits, encephalopathy, delirium, meningitis, and seizures are some of the neurological complications in patients with coronavirus disease-19 (COVID-19) which is caused by acute respiratory syndrome coronavirus 2 (SARS-Cov2). There remains a challenge to determine the extent to which neurological abnormalities in COVID-19 are caused by SARS-Cov2 itself, the exaggerated cytokine response it triggers, and/or the resulting hypercoagulapathy and formation of blood clots in blood vessels throughout the body and the brain. In this article, we review the reports that address neurological manifestations in patients with COVID-19 who may present with acute neurological symptoms (e.g., stroke), even without typical respiratory symptoms such as fever, cough, or shortness of breath. Next, we discuss the different neurobiological processes and mechanisms that may underlie the link between SARS-Cov2 and COVID-19 in the brain, cranial nerves, peripheral nerves, and muscles. Finally, we propose a basic "NeuroCovid" classification scheme that integrates these concepts and highlights some of the short-term challenges for the practice of neurology today and the long-term sequalae of COVID-19 such as depression, OCD, insomnia, cognitive decline, accelerated aging, Parkinson's disease, or Alzheimer's disease in the future. In doing so, we intend to provide a basis from which to build on future hypotheses and investigations regarding SARS-Cov2 and the nervous system.

Neurobiology of COVID-19.

AIM: COVID-19 clinical presentation is heterogeneous, ranging from asymptomatic to severe cases. While there are a number of early publications relating to risk factors for COVID-19 infection, low sample size and heterogeneity in study design impacted consolidation of early findings. There is a pressing need to identify the factors which predispose patients to severe cases of COVID-19. For rapid and widespread risk stratification, these factors should be easily obtainable, inexpensive, and avoid invasive clinical procedures. The aim of our study is to fill this knowledge gap by systematically mapping all the available evidence on the association of various clinical, demographic, and lifestyle variables with the risk of specific adverse outcomes in patients with COVID-19. METHODS: The systematic review was conducted using standardized methodology, searching two electronic databases (PubMed and SCOPUS) for relevant literature published between 1st January 2020 and 9th July 2020. Included studies reported characteristics of patients with COVID-19 while reporting outcomes relating to disease severity. In the case of sufficient comparable data, meta-analyses were conducted to estimate risk of each variable. RESULTS: Seventy-six studies were identified, with a total of 17,860,001 patients across 14 countries. The studies were highly heterogeneous in terms of the sample under study, outcomes, and risk measures reported. A large number of risk factors were presented for COVID-19. Commonly reported variables for adverse outcome from COVID-19 comprised patient characteristics, including age >75 (OR: 2.65, 95% CI: 1.81-3.90), male sex (OR: 2.05, 95% CI: 1.39-3.04) and severe obesity (OR: 2.57, 95% CI: 1.31-5.05). Active cancer (OR: 1.46, 95% CI: 1.04-2.04) was associated with increased risk of severe outcome. A number of common symptoms and vital measures (respiratory rate and SpO2) also suggested elevated risk profiles. CONCLUSIONS: Based on the findings of this study, a range of easily assessed parameters are valuable to predict elevated risk of severe illness and mortality as a result of COVID-19, including patient characteristics and detailed comorbidities, alongside the novel inclusion of real-time symptoms and vital measurements.

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Population risk factors for severe disease and mortality in COVID-19: A global systematic review and meta-analysis.

BACKGROUND: Objective data on chemosensitive disorders during COVID-19 are lacking in the Literature. METHODS: Multicenter cohort study that involved four Italian hospitals. Three hundred and forty-five COVID-19 patients underwent objective chemosensitive evaluation. RESULTS: Chemosensitive disorders self-reported by 256 patients (74.2%) but the 30.1% of the 89 patients who did not report dysfunctions proved objectively hyposmic. Twenty-five percentage of patients were seen serious long-lasting complaints. All asymptomatic patients had a slight lowering of the olfactory threshold. No significant correlations were found between the presence and severity of chemosensitive disorders and the severity of the clinical course. On the contrary, there is a significant correlation between the duration of the olfactory and gustatory symptoms and the development of severe COVID-19. CONCLUSIONS: Patients under-report the frequency of chemosensitive disorders. Contrary to recent reports, such objective testing refutes the proposal that the presence of olfactory and gustatory dysfunction may predict a milder course, but instead suggests that those with more severe disease neglect such symptoms in the setting of severe respiratory disease.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/hed.26269

Olfactory and gustatory function impairment in COVID-19 patients: Italian objective multicenter-study.

Nasopharyngeal swab collection in the suspicion of Covid-19.

Background Benign paroxysmal positional vertigo (BPPV) has a reported recurrence ranging from 26.8 to 50%. Osteoporosis and Vitamin D deficiency seems to have an impact on recurrence of BPPV. Objective to evaluate the impact of osteoporosis and Vitamin D deficiency on recurrence of BPPV. Methods 73 consecutive patients were divided in two groups according to the presence (group 1) or absence (group 0) of a recurrent episode. BMD, femoral and lumbar T-scores and Vitamin D levels were recorded. Statistical analysis was performed to investigate correlations. Results patients in group 1 had statistically significant lower values of both femoral (-1,62±1,06 vs. -0,53±1,51; p = 0,001), lumbar T-score (-2,10±1,19 vs -0, 53±1.51, p = 0.001) and Vitamin D (19.53±15.33). The values of femoral T-score and Vitamin D could be combined in a model able to properly classify 65.8% of the cases (p = 0.002) as isolated or recurrent BPPV, with high accuracy (AUC 0.710 [0.590 -0.830]). Conclusion present data show a probable correlation between osteoporosis and Vitamin D with recurrent BPPV.

Relationship between calcium metabolism and benign paroxysmal positional vertigo in north Sardinia population

(1) Background: Endoscopy and morphological imaging are the mainstay of the diagnostic work up of laryngeal squamous cell carcinomas (LSCCs), which can be integrated in a multidisciplinary discussion to obtain a shared pretreatment staging. (2) Methods: A retrospective evaluation of patients, managed at a tertiary university hospital in Italy and submitted to major laryngeal surgery, has been performed. Four different stagings have been defined and compared: epTN (based on endoscopy and physical ENT examination); radTN (based on CT scan); cTN (based on multidisciplinary integration of the two above); pTN based on pathology on surgical samples. Oncological outcomes have been assessed. (3) Results: Three-year relapse free and disease specific survival were 88% and 92.5%, respectively, without significant differences between partial surgeries (n = 13) and total laryngectomies (n = 32). As for the pretreatment staging, and in particular the T classification, the cTN has been revealed as more reliable than epTN and radTN alone in predicting the final pT (Cohen kappa coefficient: 0.7 for cT, 0.44 for radT, 0.32 for epT). In the partial surgery group, we did not record any positive margin nor local recurrence, with a 100% overall and disease-specific survival. (4) Conclusions: The multidisciplinary approach is fundamental in the definition of the primary lesion in LSCC, in particular in order to safely perform surgical preservation of laryngeal function, which is associated with a higher laryngectomy-free survival than irradiation but to a lower salvageability in case of recurrence.

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Reliability of a Multidisciplinary Multiparametric Approach in the Surgical Planning of Laryngeal Squamous Cell Carcinomas: A Retrospective Observational Study

Nicola Turra

Papers

Olfactory and gustatory function impairment in COVID-19 patients: Italian objective multicenter-study.

Nasopharyngeal swab collection in the suspicion of Covid-19.

Relationship between calcium metabolism and benign paroxysmal positional vertigo in north Sardinia population

Reliability of a Multidisciplinary Multiparametric Approach in the Surgical Planning of Laryngeal Squamous Cell Carcinomas: A Retrospective Observational Study