L.G. Tereshchenko et al.

Risk of Cardiovascular Events after Covid-19: a double-cohort study

medRxiv, December 2021; doi.org/10.1101/2021.12.27.21268448

Abstract

Objective To determine absolute and relative risks of either symptomatic or asymptomatic SARS-CoV-2 infection for late cardiovascular events and all-cause mortality.

Methods We conducted a retrospective double-cohort study of patients with either symptomatic or asymptomatic SARS-CoV-2 infection [COVID-19(+) cohort] and its documented absence [COVID-19(-) cohort]. The study investigators drew a simple random sample of records from all Oregon Health & Science University (OHSU) Healthcare patients (N=65,585) with available COVID-19 test results, performed 03.01.2020 - 09.13.2020. Exclusion criteria were age < 18y and no established OHSU care. The primary outcome was a composite of cardiovascular morbidity and mortality. All-cause mortality was the secondary outcome.

Results The study population included 1355 patients (mean age 48.7±20.5 y; 770(57%) female, 977(72%) white non-Hispanic; 1072(79%) insured; 563(42%) with cardiovascular disease (CVD) history). During a median 6 months at risk, the primary composite outcome was observed in 38/319 (12%) COVID-19(+) and 65/1036 (6%) COVID-19(-) patients (p=0.001). In Cox regression adjusted for demographics, health insurance, and reason for COVID-19 testing, SARS-CoV-2 infection was associated with the risk of the primary composite outcome (HR 1.71; 95%CI 1.06-2.78; p=0.029). Inverse-probability-weighted estimation, conditioned for 31 covariates, showed that for every COVID-19(+) patient, the average time to all-cause death was 65.5 days less than when all these patients were COVID-19(-): average treatment effect on the treated -65.5 (95%CI -125.4 to -5.61) days; p=0.032.

Conclusions Either symptomatic or asymptomatic SARS-CoV-2 infection is associated with increased risk of late cardiovascular outcomes and has causal effect on all-cause mortality in a late post-COVID-19 period.

M. Wadman

Covid-19 takes serious toll on heart health—a full year after recovery

Science, February 2022; doi: 10.1126/science.ada1117

Abstract

From very early in the pandemic, it was clear that SARS-CoV-2 can damage the heart and blood vessels while people are acutely ill. Patients developed clots, heart inflammation, arrhythmias, and heart failure.

S.V. Sylvester et al.

Sex differences in sequelae from COVID-19 infection and in long COVID syndrome: a review

Current Medical Research and Opinion, June 2022;  doi.org/10.1080/03007995.2022.2081454

Abstract

Objective

We conducted literature reviews to uncover differential effects of sex on sequelae from coronavirus disease 2019 (COVID-19) and on long COVID syndrome.

Methods

Two authors independently searched OvidSP in Embase, Medline, Biosis, and Derwent Drug File. Publications reporting original, sex-disaggregated data for sequelae of COVID-19 (published before August 2020) and long COVID syndrome (published before June 2021) were included in the reviews. The association between COVID-19 sequelae (i.e. lasting <4 weeks after symptom onset) and sex, and between long COVID syndrome (i.e. lasting >4 weeks after symptom onset) and sex, was determined by odds ratio (OR) and 95% confidence interval (CI) (statistical significance defined by 95% CI not including 1).

Results

Of 4346 publications identified, 23 and 12 met eligibility criteria for COVID-19 sequelae and long COVID syndrome, respectively. COVID-19 sequelae in the categories of psychiatric/mood (OR = 1.80; 95% CI: 1.35–2.41), ENT (OR = 1.42; 95% CI: 1.39–1.46), musculoskeletal (OR = 1.15; 95% CI: 1.14–1.16), and respiratory (OR = 1.09; 95% CI: 1.08–1.11) were significantly more likely among females (vs. males), whereas renal sequelae (OR = 0.83; 95% CI: 0.75–0.93) were significantly more likely among males. The likelihood of having long COVID syndrome was significantly greater among females (OR = 1.22; 95% CI: 1.13–1.32), with the odds of ENT (OR = 2.28; 95% CI: 1.94–2.67), GI (OR = 1.60; 95% CI: 1.04–2.44), psychiatric/mood (OR = 1.58; 95% CI: 1.37–1.82), neurological (OR = 1.30; 95% CI: 1.03–1.63), dermatological (OR = 1.29; 95% CI: 1.05–1.58), and other (OR = 1.36; 95% CI: 1.25–1.49) disorders significantly higher among females and the odds of endocrine (OR = 0.75; 95% CI: 0.69–0.81) and renal disorders (OR = 0.74; 95% CI: 0.64–0.86) significantly higher among males.

Conclusions

Sex-disaggregated differences for COVID-19 sequelae and long COVID syndrome were observed. Few COVID-19 studies report sex-disaggregated data, underscoring the need for further sex-based research/reporting of COVID-19 disease.

M. Antonelli et al.

Risk of long COVID associated with delta versus omicron variants of SARS-CoV-2

Thelancet.com, June 2022; doi.org/10.1016/S0140-6736(22)00941-2

Abstract

The omicron variant of SARS-CoV-2 (PANGO B.1.1.529) spread rapidly across the world, out-competing former variants soon after it was first detected in November, 2021. According to the Our World in Data COVID-19 database, In Europe, the number of confirmed cases reported between December, 2021, and March, 2022 (omicron period) has exceeded all previously reported cases. Omicron appears to cause less severe acute illness than previous variants, at least in vaccinated populations. However, the potential for large numbers of people to experience longterm symptoms is a major concern, and health and workforce planners need information urgently to appropriately scale resource allocation.

Z. Al-Aly et al.   

Long COVID after breakthrough SARS-CoV-2 infection

Nature Medicine, May 2022; doi.org/10.1038/s41591-022-01840-0

Abstract

The post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection—also referred to as Long COVID—have been described, but whether breakthrough SARS-CoV-2 infection (BTI) in vaccinated people results in post-acute sequelae is not clear. In this study, we used the US Department of Veterans Affairs national healthcare databases to build a cohort of 33,940 individuals with BTI and several controls of people without evidence of SARS-CoV-2 infection, including contemporary (n = 4,983,491), historical (n = 5,785,273) and vaccinated (n = 2,566,369) controls. At 6 months after infection, we show that, beyond the first 30 days of illness, compared to contemporary controls, people with BTI exhibited a higher risk of death (hazard ratio (HR) = 1.75, 95% confidence interval (CI): 1.59, 1.93) and incident post-acute sequelae (HR = 1.50, 95% CI: 1.46, 1.54), including cardiovascular, coagulation and hematologic, gastrointestinal, kidney, mental health, metabolic, musculoskeletal and neurologic disorders. The results were consistent in comparisons versus the historical and vaccinated controls. Compared to people with SARS-CoV-2 infection who were not previously vaccinated (n = 113,474), people with BTI exhibited lower risks of death (HR = 0.66, 95% CI: 0.58, 0.74) and incident post-acute sequelae (HR = 0.85, 95% CI: 0.82, 0.89). Altogether, the findings suggest that vaccination before infection confers only partial protection in the post-acute phase of the disease; hence, reliance on it as a sole mitigation strategy may not optimally reduce long-term health consequences of SARS-CoV-2 infection. The findings emphasize the need for continued optimization of strategies for primary prevention of BTI and will guide development of post-acute care pathways for people with BTI.

S. Morioka et al.

Post COVID-19 condition of the Omicron variant of SARS-CoV-2

medRxiv, May 2022; doi.org/10.1101/2022.05.12.22274990

Abstract

Background No epidemiological data on post coronavirus disease (COVID-19) condition due to Omicron variant has been reported yet.

Methods This was as a single-center, cross-sectional study, that interviewed via telephone the patients who recovered from Omicron COVID-19 infection (Omicron group), and surveyed via self-reporting questionnaire those patients infected with other strains (control group). Data on patients’ characteristics, information regarding the acute-phase COVID-19, as well as presence and duration of COVID-19-related symptoms were obtained. Post COVID-19 condition in this study was defined as a symptom that lasted at least 2 months within 3 months since the onset of COVID-19. We investigated and compared the prevalence of post COVID-19 condition in both groups after performing propensity score matching.

Results We conducted interviews for 53 out of 128 patients with Omicron, and obtained 502 responses in the control group. After matching, 18 patients each in Omicron and control group had improved covariate balance of the older adult, female sex, obese patients, and vaccination status. There were no significant differences in the prevalence of each post-acute COVID-19 symptoms between the two groups. The numbers of patients with at least one post-acute COVID-19 symptom in the Omicron and the control group were 1 (5.6%) and 10 (55.6%) (p=0.003), respectively.

Conclusion The prevalence of post Omicron COVID-19 conditions was less than that of the other strains. Further research with more participants is needed to investigate the precise epidemiology of post COVID-19 condition of Omicron, and its impact on health-related quality of life and social productivity.

A. J. Morrow et al.

A multisystem, cardio-renal investigation of post-COVID-19 illness

Nature Medicine, May 2022; doi.org/10.1038/s41591-022-01837-9

Abstract

The pathophysiology and trajectory of post-Coronavirus Disease 2019 (COVID-19) syndrome is uncertain. To clarify multisystem involvement, we undertook a prospective cohort study including patients who had been hospitalized with COVID-19 (ClinicalTrials.gov ID NCT04403607). Serial blood biomarkers, digital electrocardiography and patient-reported outcome measures were obtained in-hospital and at 28–60 days post-discharge when multisystem imaging using chest computed tomography with pulmonary and coronary angiography and cardio-renal magnetic resonance imaging was also obtained. Longer-term clinical outcomes were assessed using electronic health records. Compared to controls (n = 29), at 28–60 days post-discharge, people with COVID-19 (n = 159; mean age, 55 years; 43% female) had persisting evidence of cardio-renal involvement and hemostasis pathway activation. The adjudicated likelihood of myocarditis was ‘very likely’ in 21 (13%) patients, ‘probable’ in 65 (41%) patients, ‘unlikely’ in 56 (35%) patients and ‘not present’ in 17 (11%) patients. At 28–60 days post-discharge, COVID-19 was associated with worse health-related quality of life (EQ-5D-5L score 0.77 (0.23) versus 0.87 (0.20)), anxiety and depression (PHQ-4 total score 3.59 (3.71) versus 1.28 (2.67)) and aerobic exercise capacity reflected by predicted maximal oxygen utilization (20.0 (7.6) versus 29.5 (8.0) ml/kg/min) (all P < 0.01). During follow-up (mean, 450 days), 24 (15%) patients and two (7%) controls died or were rehospitalized, and 108 (68%) patients and seven (26%) controls received outpatient secondary care (P = 0.017). The illness trajectory of patients after hospitalization with COVID-19 includes persisting multisystem abnormalities and health impairments that could lead to substantial demand on healthcare services in the future.

Al-Aly Z. et al.

Long COVID dopo l'infezione da SARS-CoV-2 rivoluzionaria

Nature Medicine, May 2022; doi.org/10.1038/s41591-022-01840-0

Abstract

The post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection—also referred to as Long COVID—have been described, but whether breakthrough SARS-CoV-2 infection (BTI) in vaccinated people results in post-acute sequelae is not clear. In this study, we used the US Department of Veterans Affairs national healthcare databases to build a cohort of 33,940 individuals with BTI and several controls of people without evidence of SARS-CoV-2 infection, including contemporary (n = 4,983,491), historical (n = 5,785,273) and vaccinated (n = 2,566,369) controls. At 6 months after infection, we show that, beyond the first 30 days of illness, compared to contemporary controls, people with BTI exhibited a higher risk of death (hazard ratio (HR) = 1.75, 95% confidence interval (CI): 1.59, 1.93) and incident post-acute sequelae (HR = 1.50, 95% CI: 1.46, 1.54), including cardiovascular, coagulation and hematologic, gastrointestinal, kidney, mental health, metabolic, musculoskeletal and neurologic disorders. The results were consistent in comparisons versus the historical and vaccinated controls. Compared to people with SARS-CoV-2 infection who were not previously vaccinated (n = 113,474), people with BTI exhibited lower risks of death (HR = 0.66, 95% CI: 0.58, 0.74) and incident post-acute sequelae (HR = 0.85, 95% CI: 0.82, 0.89). Altogether, the findings suggest that vaccination before infection confers only partial protection in the post-acute phase of the disease; hence, reliance on it as a sole mitigation strategy may not optimally reduce long-term health consequences of SARS-CoV-2 infection. The findings emphasize the need for continued optimization of strategies for primary prevention of BTI and will guide development of post-acute care pathways for people with BTI.

C. Barry e K. Mangion

Multisystem involvement is common in post-COVID-19 syndrome

Nature Medicine, May 2022; doi.org/10.1038/s41591-022-01838-8

Abstract

A prospective clinical study evaluating patients 28–60 days after hospitalization for COVID-19 reveals increased cardio-renal inflammation, reduced lung function and poorer self-reported clinical outcomes in patients relative to that in control participants.

The problem

Self-reporting and population studies of the post-COVID-19 illness trajectory have found that residual signs and symptoms, such as fatigue, breathlessness, exercise intolerance, and adverse cardiovascular events leading to hospitalization and death, are common. However, prospective evaluations of disease pathogenesis and health status conducted at the outset of the COVID-19 pandemic are lacking, and clinical studies generally rely on the selective recall of patients — which potentially introduces selection bias. Some early studies lacked contemporary control participants matched for age, sex, ethnicity and comorbidity. Furthermore, disease classification is susceptible to ascertainment bias, as the COVID-19 illness trajectory may differ between hospitalized patients and community-based patients. Accordingly, the pathological basis of post-COVID-19 syndrome (also known as long COVID) has not been elucidated objectively, which has led to an information gap that has underpinned uncertainty in management guidelines.

S. Reardon

Long COVID risk falls only slightly after vaccination, huge study shows

Nature New, May 2022; doi.org/10.1038/d41586-022-01453-0

Abstract

Vaccination against SARS-CoV-2 lowers the risk of long COVID after infection by only about 15%, according to a study of more than 13 million people. That’s the largest cohort that has yet been used to examine how much vaccines protect against the condition, but it is unlikely to end the uncertainty.

Long COVID — illness that persists for weeks or months after infection with SARS-CoV-2 — has proved difficult to study, not least because the array of symptoms makes it hard to define. Even finding out how common it is has been challenging. Some studies have suggested that it occurs in as many as 30% of people infected with the virus. But a November study of about 4.5 million people treated at US Department of Veterans Affairs (VA) hospitals suggests that the number is 7% overall and lower than that for those who were not hospitalized.

S.M. Yoo et al.

Factors Associated with Post-Acute Sequelae of SARS-CoV-2 (PASC) After Diagnosis of Symptomatic COVID-19 in the Inpatient and Outpatient Setting in a Diverse Cohort

J. Gen. Internal Medicine, May 2022; doi.org/10.1007/s11606-022-07523-3

Abstract

BackgroundThe incidence of persistent clinical symptoms and risk factors in Post-Acute Sequelae of SARS-CoV-2 (PASC) in diverse US cohorts is unclear. While there are a disproportionate share of COVID-19 deaths in older patients, ethnic minorities, and socially disadvantaged populations in the USA, little information is available on the association of these factors and PASC.

ObjectiveTo evaluate the association of demographic and clinical characteristics with development of PASC.

DesignProspective observational cohort of hospitalized and high-risk outpatients, April 2020 to February 2021.

ParticipantsOne thousand thirty-eight adults with laboratory-confirmed symptomatic COVID-19 infection.

Main MeasuresDevelopment of PASC determined by patient report of persistent symptoms on questionnaires conducted 60 or 90 days after COVID-19 infection or hospital discharge. Demographic and clinical factors associated with PASC.

Key ResultsOf 1,038 patients with longitudinal follow-up, 309 patients (29.8%) developed PASC. The most common persistent symptom was fatigue (31.4%) followed by shortness of breath (15.4%) in hospitalized patients and anosmia (15.9%) in outpatients. Hospitalization for COVID-19 (odds ratio [OR] 1.49, 95% [CI] 1.04–2.14), having diabetes (OR, 1.39; 95% CI 1.02–1.88), and higher BMI (OR, 1.02; 95% CI 1–1.04) were independently associated with PASC. Medicaid compared to commercial insurance (OR, 0.49; 95% CI 0.31–0.77) and having had an organ transplant (OR 0.44, 95% CI, 0.26–0.76) were inversely associated with PASC. Age, race/ethnicity, Social Vulnerability Index, and baseline functional status were not associated with developing PASC.

ConclusionsThree in ten survivors with COVID-19 developed a subset of symptoms associated with PASC in our cohort. While ethnic minorities, older age, and social disadvantage are associated with worse acute COVID-19 infection and greater risk of death, our study found no association between these factors and PASC.

T. Stephenson et al.

Long COVID - the physical and mental health of children and non-hospitalised young people 3 months after SARS-CoV-2 infection; a national matched cohort study (The CLoCk) Study.

Research Square, August 2021; doi.org/10.21203/rs.3.rs-798316/v1

Abstract

Introduction: We describe post-COVID symptomatology in a national sample of 11-17-year-old children and young people (CYP) with PCR-confirmed SARS-CoV-2 infection compared to test-negative controls.

Methods and analysis: A cohort study of test-positive (n=3,065) and age-, sex- and geographically-matched test-negative CYP (n=3,739) completed detailed questionnaires 3 months post-test.

Results: At PCR-testing, 35.4% of test-positives and 8.3% of test-negatives had any symptoms whilst 30.6% and 6.2%, respectively, had 3+ symptoms. At 3 months post-testing, 66.5% of test-positives and 53.3% of test-negatives had any symptoms, whilst 30.3% and 16.2%, respectively, had 3+ symptoms. Latent class analysis identified two classes, characterised by “few” or “multiple” symptoms. This latter class was more frequent among test-positives, females, older CYP and those with worse pre-test physical and mental health.

Discussion: Test-positive CYP had a similar symptom profile to test-negative CYP but with higher prevalence of single and, particularly, multiple symptoms at PCR-testing and 3 months later.

R. Rubin

SARS-CoV-2 RNA Can Persist in Stool Months After Respiratory Tract Clears Virus

Jama, May 2022; doi:10.1001/jama.2022.7892

Abstract

SARS-CoV-2, or at least pieces of it, sticks around longer in some infected individuals than respiratory sample testing would suggest, a recent study found.

After respiratory samples tested negative, a small proportion of the 113 study participants continued to shed SARS-CoV-2 RNA in their feces—about 4% of them for at least 7 months—and those people were more likely to report ongoing gastrointestinal (GI) symptoms, researchers reported in the journal Med.

The findings provide more evidence that SARS-CoV-2 infects the gut as well as the lungs and could help explain why some people with “long COVID” have persistent abdominal pain, nausea, and other GI symptoms, according to the authors.

D. Goh et al.

Persistence of residual SARS-CoV-2 viral antigen and RNA in tissues of patients with long COVID-19

Research Square, February 2022; doi.org/10.21203/rs.3.rs-1379777/v1

Abstract

The World Health Organization has defined long COVID-19 (LC) as a condition where patients exhibit persistent symptoms over time after its acute phase, which cannot be explained by alternative diagnosis. Since we have previously reported residual viral antigens in tissues of convalescent patients, we now aim to assess the presence of such antigens in post-convalescent tissues. Here, we established the presence of residual virus within the appendix and breast tissue of 2 patients who exhibited LC symptoms, 175 to 462 days upon positive diagnosis, using immunohistological techniques. We observed positive staining for viral nucleocapsid protein (NP) in the appendix, and tumour-adjacent region of the breast, but not within the tumour via multiplex immunohistochemistry. Notably, with RNAscope, both positive-sense and negative-sense (replicative intermediate) viral RNA were detected. As a single-stranded virus, SARS-CoV-2, have to produce a replicative intermediate as a template to synthesize new genomic RNAs. Thus, the detection of negative-sense viral RNA suggests ongoing viral replication. While viral RNA and antigen from gastrointestinal and stool samples of convalescent patients has been extensively reported, we believe this is the first study to detect viable virus. Furthermore, our positive finding in the breast tissue also corroborated with recent reports that immunocompromised patients had also experienced LC symptoms and persistent viral replication. Overall, our findings, along with emerging LC studies, question the possibility of the gastrointestinal tract functioning as a reservoir.

A. Zollner et al.

Postacute COVID-19 is Characterized by Gut Viral Antigen Persistence in Inflammatory Bowel Diseases

Gastroenterology, 2022 – article in press

Abstract

BACKGROUND & AIMS: The coronavirus disease 2019 Q4 (COVID-19) pandemic has affected populations, societies, and lives for more than 2 years. Long-term sequelae of COVID-19, collectively termed the postacute COVID-19 syndrome, are rapidly emerging across the globe. Here, we investigated whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigen persistence underlies the postacute COVID-19 syndrome.

METHODS: We performed an endoscopy study with 46 patients with inflammatory bowel disease (IBD) 219 days (range, 94–257) after a confirmed COVID-19 infection. SARS-CoV-2 antigen persistence was assessed in the small and large intestine using quantitative polymerase chain reaction of 4 viral transcripts, immunofluorescence of viral nucleocapsid, and virus cultivation from biopsy tissue. Postacute COVID-19 was assessed using a standardized questionnaire, and a systemic SARS-CoV-2 immune response was evaluated using flow cytometry and Q5 enzyme-linked immunosorbent assay at endoscopy. IBD activity was evaluated using clinical, biochemical, and endoscopic means.

RESULTS: We report expression of SARSCoV-2 RNA in the gut mucosa w7 months after mild acute COVID-19 in 32 of 46 patients with IBD. Viral nucleocapsid protein persisted in 24 of 46 patients in gut epithelium and CD8þ T cells. Expression of SARS-CoV-2 antigens was not detectable in stool and viral antigen persistence was unrelated to severity of acute COVID-19, immunosuppressive therapy, and gut inflammation. We were unable to culture SARS-CoV-2 from gut tissue of patients with viral antigen persistence. Postacute sequelae of COVID-19 were reported from the majority of patients with viral antigen persistence, but not from patients without viral antigen persistence.

CONCLUSION: Our results indicate that SARS-CoV-2 antigen persistence in infected tissues serves as a basis for postacute COVID-19. The concept that viral antigen persistence instigates immune perturbation and postacute COVID-19 requires validation in controlled clinical trials.

Prasannan et al.

Impaired exercise capacity in oost-COVID syndrome: the role of VWF-ADAMTS13 axis

Blood Advances, May 2022 ;doi.org/10.1182/bloodadvances.2021006944

Abstract

Post-COVID syndrome (PCS) or Long-COVID is an increasingly recognised complication of acute SARS-CoV-2 infection, characterised by persistent fatigue, reduced exercise tolerance chest pain, shortness of breath and cognitive slowing. Acute COVID-19 is strongly linked with increased risk of thrombosis; a prothrombotic state, quantified by elevated Von Willebrand Factor (VWF) Antigen (Ag):ADAMTS13 ratio, and is associated with severity of acute COVID-19 infection. We investigated if patients with PCS also had evidence of a pro-thrombotic state associating with symptom severity. In a large cohort of patients referred to a dedicated post-COVID-19 clinic, thrombotic risk including VWF(Ag):ADAMTS13 ratio, was investigated. An elevated VWF(Ag):ADAMTS13 ratio (≥1.5) was raised in nearly one-third of the cohort and four times more likely in patients with impaired exercise capacity as evidenced by desaturation ≥3% and/or rise in lactate level more than 1 from baseline on 1-minute sit to stand test and/or 6-minute walk test (p<0.0001). 20% (56/276) had impaired exercise capacity, of which 55% (31/56) had a raised VWF(Ag):ADAMTS13 ratio ≥1.5 (p<0.0001). FVIII and VWF(Ag) were elevated in 26% and 18% respectively and support a hypercoagulable state in some patients with PCS. These findings suggest possible ongoing microvascular/endothelial dysfunction in the pathogenesis of PCS and highlight a potential role for antithrombotic therapy in the management of these patients.

The PHOSP-COVID Collaborative Group

Clinical characteristics with inflammation profiling of long COVID and association with 1-year recovery following hospitalisation in the UK: a prospective observational study

Lancet Respir Medicine, April 2022; doi.org/10.1016/ S2213-2600(22)00127-8

Abstract

Background No effective pharmacological or non-pharmacological interventions exist for patients with long COVID. We aimed to describe recovery 1 year after hospital discharge for COVID-19, identify factors associated with patientperceived recovery, and identify potential therapeutic targets by describing the underlying inflammatory profiles of the previously described recovery clusters at 5 months after hospital discharge.

Methods The Post-hospitalisation COVID-19 study (PHOSP-COVID) is a prospective, longitudinal cohort study recruiting adults (aged ≥18 years) discharged from hospital with COVID-19 across the UK. Recovery was assessed using patient-reported outcome measures, physical performance, and organ function at 5 months and 1 year after hospital discharge, and stratified by both patient-perceived recovery and recovery cluster. Hierarchical logistic regression modelling was performed for patient-perceived recovery at 1 year. Cluster analysis was done using the clustering large applications k-medoids approach using clinical outcomes at 5 months. Inflammatory protein profiling was analysed from plasma at the 5-month visit. This study is registered on the ISRCTN Registry, ISRCTN10980107, and recruitment is ongoing.

Findings 2320 participants discharged from hospital between March 7, 2020, and April 18, 2021, were assessed at 5 months after discharge and 807 (32·7%) participants completed both the 5-month and 1-year visits. 279 (35·6%) of these 807 patients were women and 505 (64·4%) were men, with a mean age of 58·7 (SD 12·5) years, and 224 (27·8%) had received invasive mechanical ventilation (WHO class 7–9). The proportion of patients reporting full recovery was unchanged between 5 months (501 [25·5%] of 1965) and 1 year (232 [28·9%] of 804). Factors associated with being less likely to report full recovery at 1 year were female sex (odds ratio 0·68 [95% CI 0·46–0·99]), obesity (0·50 [0·34–0·74]) and invasive mechanical ventilation (0·42 [0·23–0·76]). Cluster analysis (n=1636) corroborated the previously reported four clusters: very severe, severe, moderate with cognitive impairment, and mild, relating to the severity of physical health, mental health, and cognitive impairment at 5 months. We found increased inflammatory mediators of tissue damage and repair in both the very severe and the moderate with cognitive impairment clusters compared with the mild cluster, including IL-6 concentration, which was increased in both comparisons (n=626 participants). We found a substantial deficit in median EQ-5D-5L utility index from before COVID-19 (retrospective assessment; 0·88 [IQR 0·74–1·00]), at 5 months (0·74 [0·64–0·88]) to 1 year (0·75 [0·62–0·88]), with minimal improvements across all outcome measures at 1 year after discharge in the whole cohort and within each of the four clusters.

Interpretation The sequelae of a hospital admission with COVID-19 were substantial 1 year after discharge across a range of health domains, with the minority in our cohort feeling fully recovered. Patient-perceived health-related quality of life was reduced at 1 year compared with before hospital admission. Systematic inflammation and obesity are potential treatable traits that warrant further investigation in clinical trials.

Huang et al.

1-year outcomes in hospital survivors with COVID-19: a longitudinal cohort study

Lancet, August 2021 ;doi: 10.1016/S0140-6736(21)01755-4

Abstract

Background: The full range of long-term health consequences of COVID-19 in patients who are discharged from hospital is largely unclear. The aim of our study was to comprehensively compare consequences between 6 months and 12 months after symptom onset among hospital survivors with COVID-19.

Methods: We undertook an ambidirectional cohort study of COVID-19 survivors who had been discharged from Jin Yin-tan Hospital (Wuhan, China) between Jan 7 and May 29, 2020. At 6-month and 12-month follow-up visit, survivors were interviewed with questionnaires on symptoms and health-related quality of life (HRQoL), and received a physical examination, a 6-min walking test, and laboratory tests. They were required to report their health-care use after discharge and work status at the 12-month visit. Survivors who had completed pulmonary function tests or had lung radiographic abnormality at 6 months were given the corresponding tests at 12 months. Non-COVID-19 participants (controls) matched for age, sex, and comorbidities were interviewed and completed questionnaires to assess prevalent symptoms and HRQoL. The primary outcomes were symptoms, modified British Medical Research Council (mMRC) score, HRQoL, and distance walked in 6 min (6MWD). Multivariable adjusted logistic regression models were used to evaluate the risk factors of 12-month outcomes.

Findings: 1276 COVID-19 survivors completed both visits. The median age of patients was 59·0 years (IQR 49·0-67·0) and 681 (53%) were men. The median follow-up time was 185·0 days (IQR 175·0-198·0) for the 6-month visit and 349·0 days (337·0-361·0) for the 12-month visit after symptom onset. The proportion of patients with at least one sequelae symptom decreased from 68% (831/1227) at 6 months to 49% (620/1272) at 12 months (p<0·0001). The proportion of patients with dyspnoea, characterised by mMRC score of 1 or more, slightly increased from 26% (313/1185) at 6-month visit to 30% (380/1271) at 12-month visit (p=0·014). Additionally, more patients had anxiety or depression at 12-month visit (26% [331/1271] at 12-month visit vs 23% [274/1187] at 6-month visit; p=0·015). No significant difference on 6MWD was observed between 6 months and 12 months. 88% (422/479) of patients who were employed before COVID-19 had returned to their original work at 12 months. Compared with men, women had an odds ratio of 1·43 (95% CI 1·04-1·96) for fatigue or muscle weakness, 2·00 (1·48-2·69) for anxiety or depression, and 2·97 (1·50-5·88) for diffusion impairment. Matched COVID-19 survivors at 12 months had more problems with mobility, pain or discomfort, and anxiety or depression, and had more prevalent symptoms than did controls.

Interpretation: Most COVID-19 survivors had a good physical and functional recovery during 1-year follow-up, and had returned to their original work and life. The health status in our cohort of COVID-19 survivors at 12 months was still lower than that in the control population.

 

Di Gennaro et al.

Long COVID: a systematic review and meta-analysis of 120.970 patients

The Lancet, May 2022; preprints

Abstract

Background: The long-term consequences of the coronavirus disease 19 (COVID-19) are likely to be frequent but results hitherto are inconclusive. Therefore, we aimed to summarize the state-of-the-art literature in relation to long COVID symptomatology, using a systematic review and meta-analysis of observational studies.

Methods: A systematic search in several databases was carried out up to 12 January 2022 for observational studies reporting the incidence rate of long COVID signs and symptoms divided according to body systems affected and defined using the World Health Organization criteria. Data are reported as incidence and 95% confidence intervals (CIs). Several sensitivity and meta-regression analyses were moreover performed.

Findings: Among 11,162 papers initially screened, 196 studies were included, consisting of 120,970 participants (mean age: 52.3 years; 48.8% females) who were followed-up for a median of six months. The incidence of any long COVID symptomatology was 56.9% (95%CI: 52.2-61.6). General long COVID signs and symptoms were the most frequent (incidence of 31%), digestive issues the less frequent (7.7%). Higher percentage of females moderated the onset of any, neurological, general and cardiovascular long COVID symptomatology, whilst higher mean age was associated with higher incidence of psychiatric, respiratory, general, digestive and skin conditions. The incidence of long COVID symptomatology was different according to continent, age and follow-up length.

Interpretation: Long COVID is a common condition in patients who have been infected with SARS-CoV-2, whether symptomatically or asymptomatically, and often regardless of the severity of the acute illness indicating the need for more cohort studies on this topic.

M. Whitaker et al.

Persistent COVID-19 symptoms in a community study of 606,434 people in England

Nature Communications, April 2022 ;doi.org/10.1038/s41467-022-29521-z

Abstract

Long COVID remains a broadly defined syndrome, with estimates of prevalence and duration varying widely. We use data from rounds 3–5 of the REACT-2 study (n= 508,707; September 2020 – February 2021), a representative community survey of adults in England, and replication data from round 6 (n= 97,717; May 2021) to estimate the prevalence and identify predictors of persistent symptoms lasting 12 weeks or more; and unsupervised learning to cluster individuals by reported symptoms. At 12 weeks in rounds 3–5, 37.7% experienced at least one symptom, falling to 21.6% in round 6. Female sex, increasing age, obesity, smoking, vaping, hospitalisation with COVID-19, deprivation, and being a healthcare worker are associated with higher probability of persistent symptoms in rounds 3–5, and Asian ethnicity with lower probability. Clustering analysis identifies a subset of participants with predominantly respiratory symptoms. Managing the long-term sequelae of COVID-19 will remain a major challenge for affected individuals and their families and for health services.

S. Staffolani et al.

Infezioni in Medicina, 2022; doi: 10.53854/liim-3001-3

Long COVID-19 syndrome as a fourth phase of SARS-CoV-2 infection

Abstract

The SARS-CoV-2 pandemic has affected in the last two years a large number of subjects, with a high cost in terms of morbidity and mortality. The scientific community made progress in understanding risk factors, pathophysiology, clinical manifestations, diagnosis and treatment of acute SARS-CoV-2 infection. In the last months, another condition has become evident and caught the attention of the scientific community: the so-called long COVID syndrome. The pathophysiology of this condition is not known, even if some hypothesis have been made but not demonstrated yet. Long COVID is characterized by a very heterogeneous group of subacute and/or chronic symptoms and signs that follow the acute phase of SARS-CoV-2 infection and have a very variable duration. The presence of this syndrome in an individual is not dependent from the severity of the acute SARS-CoV-2 infection. Because of the extreme clinical heterogeneity, and also due to the lack of a shared and specific definition of the disease, it is very difficult to know the real prevalence and incidence of this condition. Some risk factors for the development of the disease have been identified: advanced age, elevated body mass index, comorbidities, specific symptoms of acute COVID-19 (in particular dyspnea), number of symptoms in the acute phase and female sex.

The number of individuals affected by long COVID is high, even if it occurs only in a part of the subjects who had COVID-19. Therefore, long COVID constitutes now a major health issue and has to be managed in order to ensure an adequate access to care for all the people that need it.

“Post COVID” clinics have been created in various countries, especially in Europe, for the management of people affected by long COVID syndrome. Guidelines have been written to help clinicians. An important role in the management of long COVID patients is played by the general practitioner, directly or indirectly linked to post COVID hospital clinics. The extreme heterogeneity of clinical presentation needs a patient-tailored, multidisciplinary approach. As NHS guidelines say, the three principal of care for long COVID patients are personalized care, multidisciplinary support and rehabilitation.

More studies are needed in order to know better the pathophysiology of the disease. It is also necessary to create standardized and shared definitions of the disease, in order to better understand the epidemiology, the diagnostic criteria and to offer the right treatment to all the individuals who need it, without social or economic differences.

Clare Watson

Nature NEWS, March 2022

Diabetes risk rises after COVID, massive study finds

Even mild SARS-CoV-2 infections can amplify a person’s chance of developing diabetes, especially for those already susceptible to the disease.

Yan Xie et al.

Risks and burdens of incident diabetes in long COVID: a cohort study

The Lancet , https://www.thelancet.com/action/showPdf?pii=S2213-8587%2822%2900044-4

CONTENUTO E COMMENTO: Studio di coorte condotto negli USA su 181.280 pazienti guariti dal COVID-19 e circa 8 milioni di controlli, con l’obiettivo di esaminare il rischio post-acuto di insorgenza di diabete nei primi 30 giorni dopo la guarigione dall’infezione da SARS-CoV-2.

I risultati suggeriscono che vi è un maggior rischio di diabete incidente e di utilizzo di farmaci ipoglicemizzanti. Pertanto il diabete dovrebbe essere considerato come un aspetto della sindrome Long COVID. Le strategie di cura dei pazienti post-COVID dovrebbero integrare lo screening e la gestione del diabete.

Peghin M et al

Post-COVID-19 syndrome and humoral response association after one year in vaccinated and unvaccinated patients

Clinical Microbiology and Infection,

https://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(22)00155-0/fulltext

CONTENUTO E COMMENTO: Studio prospettico su 479 individui con infezione da SARS-CoV-2 sia ospedalizzati che non, intervistati a 6 e 12 mesi dopo l’infezione acuta, con l’obiettivo di valutare l’impatto della vaccinazione e il ruolo della risposta umorale sulla sindrome post-COVID-19.

Gli autori dimostrano che la vaccinazione da SARS-CoV-2 non è associata ad un aumento dei sintomi post-COVID-19 a un anno dall’infezione acuta, mentre la persistenza di alti titoli di anticorpi indotti dall’infezione naturale (non-RBD-SARS-CoV-2 IgG) potrebbe giocare un ruolo nel long-COVID-19.

Sandmann FG et al

Long-term health-related quality of life in non-hospitalised COVID-19 cases with confirmed SARS-CoV-2 infection in England: Longitudinal analysis and cross-sectional comparison with controls

Clinical Infectious Diseases

https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciac151/6542727  

CONTENUTO E COMMENTO : Studio di coorte prospettico condotto in Inghilterra su 548 adulti con storia di infezione da SAR-SCoV-2 ma non ospedalizzati, seguiti a partire dal 1 dicembre 2020 per sei mesi. Lo studio della qualità di vita in termini di QALDs (quality-adjusted life days), dei sintomi residui dopo la fase acuta e delle spese mediche restituisce un quadro di significative conseguenze sulla salute, soprattutto negli anziani, con un paziente su sei che lamenta sintomi persistenti a sei mesi dall’esordio e uno su dieci che riferisce un generico peggioramento del proprio stato di salute dopo la malattia.

Pérez-González A et al

Long COVID in hospitalized and non-hospitalized patients in a large cohort in Northwest Spain, a prospective cohort study

Scientific Reports, https://www.nature.com/articles/s41598-022-07414-x#auth-Alexandre-P_rez_Gonz_lez

CONTENUTO E COMMENTO : Studio prospettico di coorte condotto nel nord-ovest della Spagna con l’obiettivo di descrivere i sintomi persistenti 6 mesi dopo la diagnosi di COVID-19, generalmente definiti come « long COVID » o « persistent COVID ».

Lo studio include 248 pazienti che hanno completato il follow-up a 6 mesi, di cui il 48% ha riportato uno o più sintomi persistenti a 6 mesi, tra cui sintomi toracici, extra-toracici, dispnea e astenia. Questi sintomi erano più comuni nei pazienti ospedalizzati e nelle donne. L’analisi multivariata ha identificato la broncopneumopatia cronica ostruttiva, il genere femminile e il consumo di tabacco come fattori di rischio per il long COVID, suggerendo la necessità di proseguire un follow-up clinico dopo la dimissione in queste categorie di pazienti.

Nalbandian A et al

Post-acute COVID-19 syndrome

Nature Medicine, https://www.nature.com/articles/s41591-021-01283-z

CONTENUTO E COMMENTO : Revisione delle caratteristiche cliniche, della fisiopatologia e dei fattori di rischio del cosiddetto « long COVID », qui definita come COVID-19 « post acuta ».

SelinaKikkenborg Berg et al.

Long COVID symptoms in SARS-CoV-2-positive adolescents and matched controls (LongCOVIDKidsDK): a national, cross-sectional study

The Lancet Child Adolesc Health, https://www.thelancet.com/action/showPdf?pii=S2352-4642%2822%2900004-9

CONTENUTO E COMMENTO: Studio trasversale condotto in Danimarca (LongCOVIDKidsDK) in cui è stata indagata la persistenza di sintomi e la qualità della vita dopo l’infezione da Sars-CoV-2 negli adolescenti (15-18 anni) rispetto a un gruppo di controllo. Questo studio ha il più lungo tempo di follow-up (oltre 12 mesi) e la coorte più numerosa (6630 nel gruppo di casi e 21640 nel gruppo di controllo).

Gli adolescenti che hanno avuto un’infezione da Sars-CoV2 avevano maggiori probabilità di avere sintomi di lunga durata, ma riportavano migliori punteggi in termini di qualità della vita. Inoltre, il gruppo degli adolescenti con Long Covid ha registrato un numero maggiore di giorni di malattia e di assenze scolastiche rispetto al gruppo di controllo.

Yan Xie et al

Long-term cardiovascular outcomes of COVID-19

Nature Medicine, https://www.nature.com/articles/s41591-022-01689-3

CONTENUTO E COMMENTO : In questo studio retrospettivo caso controllo, gli autori mettono a confronto 153,760 individui con COVID-19, con due coorti di pazienti, una coorte contemporanea (5,637,647 pazienti) e una coorte storica (5,859,411 pazienti), con l’obiettivo di stimare il rischio di eventi cardiovascolari a 1 anno. I risultati mostrano che, oltre i 30 giorni dall’infezione acuta, gli individui con COVID-19 sono ad aumentato rischio di eventi cardiovascolari, inclusi malattie cerebrovascolari, disritmie, patologie cardiache ischemiche e non ischemiche, pericardite, miocardite, scompenso cardiaco e malattie tromboemboliche. Questi rischi si sono dimostrati inoltre evidenti anche tra i pazienti non ospedalizzati nella fase acuta di malattia.

Righi E et al

Determinants of Persistence of Symptoms and Impact on Physical and Mental Wellbeing in Long COVID: A Prospective Cohort Study

Journal of Infection, https://www.journalofinfection.com/article/S0163-4453(22)00065-2/fulltext

CONTENUTO E COMMENTO : Studio prospettico su una coorte di 465 pazienti con COVID-19 seguiti per 9 mesi, con l’obiettivo di valutare la durata e i predittori della persistenza di sintomi.

A 9 mesi dall’infezione acuta, il 20% dei pazienti era ancora sintomatico, presentando principalmente astenia e fatica respiratoria. L’età >50 anni, la degenza in Terapia Intensiva e l’esordio con 4 o più sintomi sono risultati essere fattori predittivi indipendenti della persistenza di sintomi a 9 mesi. La persistenza di sintomi a 9 mesi a sua volta ha dimostrto avere un impatto negativo sul benessere fisico e mentale dei partecipanti.

Yapeng Su et al.

Multiple Early Factors Anticipate Post-Acute COVID-19 Sequelae

Cell, https://www.cell.com/action/showPdf?pii=S0092-8674%2822%2900072-1

CONTENUTO E COMMENTO: Studio longitudinale condotto su circa 300 pazienti con l’obiettivo di comprendere l’eterogeneicità che caratterizza le sequele post-acute da COVID-19 (PASC). Lo studio ha identificato quattro fattori di rischio associati a PASC al momento della diagnosi di COVID-19: diabete di tipo 2, SARS-Cov-2 RNAemia, viremia del virus di Epstein-Barr e autoanticorpi specifici.

La rilevabilità dei fattori associati a PASC alla diagnosi di COVID-19 permette il monitoraggio clinico e può guidare le sperimentazioni interventistiche per trattare e prevenire la sindrome long-COVID.

Hidde Heesakkers et al.

Clinical Outcomes Among Patients With 1-Year Survival Following Intensive Care Unit Treatment for COVID-19

JAMA, https://jamanetwork.com/journals/jama/fullarticle/2788504#:~:text=Findings%20In%20this%20exploratory%20multicenter,and%2016.2%25%20reported%20cognitive%20symptoms.

CONTENUTO E COMMENTO: Studio esplorativo multicentrico di coorte prospettico che ha incluso 246 pazienti guariti da COVID-19 1 anno dopo il ricovero in terapia intensiva. Il 74,3% ha riferito la persistenza di sintomi fisici (i più frequenti erano dolore e rigidità articolare, debolezza e mialgie), 26,2% ha riferito sintomi psichiatrici (fra cui stato di ansia, depressione e sindrome post-traumatica da stress), e 16,2% ha riferito sintomi cognitivi.

La comprensione degli outcomes a lungo termine tra i pazienti con COVID-19 che sono stati ricoverati in ICU è importante per fornire le cure adeguate alle esigenze cliniche dei pazienti durante e dopo l’infezione da Sars-CoV-2.

Phetsouphanh C et al.

Immunological dysfunction persists for 8 months following initial mild-to-moderate SARS-CoV-2 infection

Nat Immunol., https://www.nature.com/articles/s41590-021-01113-x.pdf

CONTENUTO E COMMENTO : Studio che mira a valutare la funzionalità del sistema immunitario nel pazienti con sintomi fisici e neuropsichiatrici persistenti dopo l’infezione acuta da SARS-CoV-2 (il cosiddetto long COVID), nei pazienti senza sintomatologia compatbile con long COVID e nei pazienti con infezione da altri coronavirus. Rispetto alle altre categorie, i paziente affetti da long COVID hanno una persistente attivazione dell’immunità innata, un deficit della risposta T e B-mediata e un’elevata espressione di IFN-b e IFN-l1.
Da questo studio sembra emergere come questo virus abbia una peculiare capacità di modificare per lungo tempo la rispost immunitaria innata ed adattativa. Tale prolungata risposta infiammatoria potrebbe essere scatenata da antigeni persistenti, da una risposta autoimmune o da un lungo processo riparativo e sembrerebbe rappresentare il substrato scientifico del long COVID.

Petersen EL et al

Multi-organ assessment in mainly non-hospitalized individuals after SARS-CoV-2 infection: The Hamburg City Health Study COVID programme

European Heart Journal, https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehab914/6499078

CONTENUTO E COMMENTO : Studio volto a valutare lo status polmonare, cardiaco, vascolare, renale e neurologico dopo una media di 9 mesi dall’infezione da SARS-CoV-2, in pazienti con forme da lievi a moderate di infezione e prevalentemente non ospedalizzati.

Gli autori dimostrano che soggetti apparentementi guariti riportano comunque sequele multi-organo a lungo termine, quali lieve riduzione del volume polmonare totale e aumento delle resistenze delle vie aeree, misure di funzione ventricolare destra e sinistra lievemente più basse e aumento delle concentrazioni di biomarkers cardiaci, maggiore incidenza di trombosi venosa profonda e riduzione della capacità di filtrazione glomerulare.

Serviente C et al

From heart to muscle: Pathophysiological mechanisms underlying long-term physical sequelae from SARS-CoV-2 infection

J Appl Physiol , https://doi.org/10.1152/japplphysiol.00734.2021

CONTENUTO E COMMENTO : Disamina delle manifestazioni a lungo di termine dell’infezione da SARS-CoV-2 (cosiddetto « long COVID »), che possono essere giustificati da una disfunzione endoteliale persistente che potrebbe determinare in particolare malessere e ridotta tolleranza all’esercizio per ridotta perfusione periferica e per peggioramento degli scambi gassosi a livello polmonare.

Fang X et al

Post-sequelae one year after hospital discharge among older COVID-19 patients: a multi-center prospective cohort study

Journal of Infection,

https://www.journalofinfection.com/action/showPdf?pii=S0163-4453%2821%2900596-X

CONTENUTO : Studio prospettico multicentrico di coorte su 1233 pazienti con COVID-19 con un’età maggiore di 60 anni con l’obiettivo di valutare la prevalenza di sequele e di sintomi post-COVID (valutati tramite CAT-scoring) dopo un anno dalla dimissione.La gravità della malattia durante il ricovero e l’età contribuiscono ad aumentare il rischio di sequele post-COVID ed il numero di sintomi riportati a un anno dalla dimissione (CAT scores ≥10), mentre viene dimostrata una riduzione del tasso di prevalenza dei sintomi nella durata del follow-up.

COMMENTO: Il long COVID con tutte le sue multiformi manifestazioni cliniche, rappresenta una realtà con la quale i clinici si debbono quotidianamente confrontare. Questo studio multicentrico significativo per numerosità e durata dell’osservazione (1 anno dall’evento acuto) permette di stabilire che gravità di malattia, età, numero di sintomi al momento della diagnosi (con uno score >10) aumentavano il rischio della dutrata dei sintomi causando il Long-COVID.

Pin Li et al

Factors Associated With Risk of PostdischargeThrombosis in Patients With COVID-19

JAMA Network Open, https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2786413

CONTENUTO : Il COVID-19 si è dimostrato associato ad un’alta incidenza di eventi trombotici. Tuttavia rimane da chiarire la necessità di proseguire terapia anticoagulante nei pazienti dopo la dimissione.

Gli autori hanno quindi condotto questo studio di coorte su pazienti adulti ospedalizzati con COVID-19 con l’obiettivo di quantificare il tasso di tromboembolismo arterioso e venoso post-dimissione e di valutare l’associazione tra utilizzo di anticoagulanti dopo la dimissione e incidenza di tromboembolismo.

I risultati mostrano che il rischio di tromboembolismo venoso post-dimissione diminuisce con il passare del tempo, mentre non c’è nessun cambiamento nel rischio di tromboembolismo arterioso con il tempo. Inoltre, il rischio di tromboembolismo venoso dopo la dimissione risulta associato con una storia di precedente tromboembolismo venoso, D-dimero >3 μg/mL, Proteina C Reattiva >10 mg/dl. La prescrizione di anticoagulanti in dimissione risulta essere associata ad una ridotta incidenza di tromboembolismo venoso post-dimissione.

COMMENTO: Questa analisi retrospettiva multicentrica considera i pazienti dimessi a domicilio dopo COVID-19 per valutare quali siano i fattori di rischio per eventi tromboembolici (TE), inoltre si ricerca una potenzialità preventiva della terapia anticoagulante in un gruppo di soggetti caratterizzati da un alto rischio clinico.

Lo studio può vantare una casistica ampia che consente un’analisi su un numero relativamente elevato di TE. Di 2832 pazienti 36 (1.3%) sono andati in contro a tromboembolismo venoso a 90 giorni dalla dimissione, di questi 16 hanno sviluppato embolia polmonare, 18 trombosi venosa profonda e due trombosi della vena porta. 15 pazienti (0.5%) hanno sperimentato tromboembolismo arterioso (un attacco ischemico transitorio e 14 sindrome coronarica acuta). Dei 108 pazienti andati in contro ad exitus nei 90 giorni seguenti la dimissione, sei sono deceduti per TE (quattro arteriosi e due venosi). La mortalità per TE comunque decresce nel tempo ed il numero maggiore di eventi si sono osservati tra il nono ed il 37° giorno dalla dimissione. I fattori associati con un elevato rischio di TE che emergono da questa analisi erano: anamnesi positiva per TE e livelli di proteina c-reattiva (PCR) e D-dimero alla dimissione rispettivamente maggiori di 10 mg/dL e 3 μg/mL. Alla dimissione a 682 pazienti (24.1%) è stata indicata terapia anticoagulante, di questi 188 (6.6%) hanno ricevuto il dosaggio profilattico e 494 (17.4%) quello terapeutico: solo per quest’ultimi è dimostrato un rischio sensibilmente minore di incorrere in eventi tromboembolici, mentre per i primi non si raggiunge la significatività statistica.

Né l’Agenzia Italiana del Farmaco (AIFA), né le più recenti linee guida del National Institutes of Health (NIH) consigliano di proseguire terapia anticoagulante a domicilio se non indicata per condizioni pre-esistenti diverse da COVID-19, ma è noto che le sequele dell’infezione da SARS-CoV-2 possono persistere per un periodo di tempo non ancora ben definito anche dopo la negativizzazione del tampone naso-faringeo. Questo studio apre la possibilità di proseguire terapia anticoagulante a domicilio in alcuni pazienti considerati ad alto rischio di eventi tromboembolici ma ha il grosso limite di non riportare il numero di eventi di sanguinamenti maggiori nei pazienti ai quali si era prescritto di proseguire terapia anticoagulante dopo la dimissione. Occorrono studi longitudinali randomizzati e controllati per definire in modo più riproducibile il ruolo della terapia anticoagulante e il rapporto rischio/beneficio nella coorte di soggetti ad alto rischio per TE.

Pinato DJ et al

Prevalence and impact of COVID-19 sequelae on treatment and survival of patients with cancer who recovered from SARS-CoV-2 infection: evidence from the OnCovid retrospective, multicentre registry study

The Lancet Oncology, https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(21)00573-8/fulltext

CONTENTUO : Studio retrospettivo multicentrico basato sul registro europeo OnCovid che include pazienti con età maggiore di 18 anni, storia di neoplasia di organo solido o ematologica e diagnosi di infezione da SARS-CoV-2 confermata all’esame RT-PCR, con l’obiettivo di descrivere l’impatto a medio e lungo termine del COVID-19 sulla sopravvivenza e sul trattamento dei pazienti oncologici. Su 2634 pazienti rivalutati post-COVID-19, il 15% ha riferito sequele COVID-relate, quali sintomi respiratori e astenia. Le sequele da COVID-19 sono inoltre risultate associate al rischio di mortalità ad un’analisi corretta per vari fattori tra cui sesso, età, comorbidità, caratteristiche del tumore, terapia antineoplastica e gravità del COVID-19 all’esordio. Tra i 466 pazienti in terapia antineoplastica sistemica, il 15% ha sospeso definitivamente il trattamento ed il 38% lo ha ripreso con necessità di aggiustamento della dose o del regime terapeutico. La sospensione permanente del trattamento è risultata associata ad un maggior rischio di mortalità, ma non l’aggiustamento di dose o regime terapeutico.

In conclusione, le sequele da COVID-19 riguardano il 15% dei pazienti con cancro ed impattano in maniera negativa sull’outcome oncologico e sulla sopravvivenza.

COMMENTO: Fin da subito si sono cercati di identificare delle popolazioni particolari nelle quali COVID-19 poteva avere un decorso differente e che per questo motivo necessitavano di particolare attenzione. In questo studio retrospettivo multicentrico basato sul Registro Europeo OnCovid, 2634 pazienti con storia di neoplasia, sia da organo solido o ematologica, sono stati rivalutati a distanza. E’ interessante notare che il 15% di sequele COVID relate, quali sintomi respiratori e astenia, sono percentualmente non differenti da quelli della popolazione generale. Queste sequele però sono state associate ad un rischio di mortalità più elevata. Significativo è il rilievo che una quota parte importante di pazienti in terapia antineoplastica (466), ha sospeso nel 15% in maniera definitiva il trattamento e nel 38% con la necessità con un aggiustamento della dose o cambio di regime terapeutico. Questi dati confermano che una quota parte di pazienti affetti da tumore o patologia neoplastica o ematologica hanno una prognosi più grave dopo COVID-19.

Dudouet P et al

Clinical Microbiology and Infection

Aortic 18F-FDG PET/CT hypermetabolism in patients with long COVID: a retrospective study

Clinical Microbiology and Infection, https://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(21)00542-5/pdf

CONTENUTO : Studio retrospettivo su 47 pazienti con sintomi compatibili con long COVID (>4 settimane dopo il primo test RT-PCR positivo per SARS-COV-2) che sono stati sottoposti a 18F-FDG PET-TC come parte della normale pratica clinica. 10 pazienti avevano un ipermetabolismo aortico con coinvolgimento del segmento toracico, in 3 pazienti era presente anche un coinvolgimento dell’aorta addominale. Il dolore toracico era un sintomo presente in maniera significativamente maggiore nel gruppo dei pazienti con ipermetabolismo aortico (60% vs 19%, p=0,017). Gli autori hanno poi confrontato questo gruppo di 47 pazienti long COVID con un gruppo di controllo di 20 pazienti negativi per SARS-CoV-2 selezionati in maniera random che erano stati sottoposti a 18F-FDG PET-TC per motivi oncologici. In nessun paziente nel gruppo di controllo è stato riscontrato un ipermetabolismo dell’aorta. Nonostante i limiti legati alla natura retrospettiva, questo studio supporta l’ipotesi fisiopatologica di un danno tissutale vascolare probabilmente mediato dall’ingresso di SARS-CoV-2 nelle cellule endoteliali tramite i recettori ACE2. Tuttavia non è ancora chiaro se il danno infiammatorio sia dovuto ad una replicazione virale attiva nell’endotelio o a un meccanismo infiammatorio post-infettivo. 

COMMENTO: Long COVID-19 rappresenta una realtà con la quale bisognerà fare i conti anche quando la pandemia sarà scomparsa. Questo studio retrospettivo, ma non per questo meno importante, sottolinea che il danno endoteliale dovuto a SARS-CoV-2 potrebbe essere la conseguenza della replicazione virale conseguente danno infiammatorio. Quando questo danno endoteliale coinvolge i grossi vasi (es. aorta) potrebbe spiegare per esempio il dolore toracico persistente pro-COVID-19.

Perez-Garcia F et al

Age-Adjusted Endothelial Activation and Stress Index for Coronavirus Disease 2019 at Admission Is a Reliable Predictor for 28-Day Mortality in Hospitalized Patients With Coronavirus Disease 2019

Frontiers in Medicine, https://www.frontiersin.org/articles/10.3389/fmed.2021.736028/full

CONTENUTO : Studio retrospettivo su pazienti affetti da COVID-19, con l’obiettivo di valutare l’efficacia predittiva in termini di mortalità dell’ Endothelial Activation and Stress Index (EASIX), un indice già utilizzato come predittore di mortalità nei pazienti trapiantati di midollo osseo che sviluppano danno endoteliale, e dell’EASIX-COVID (stesso indice corretto per età). Entrambi gli indici sono risultati significativamente associati alla mortalità a 28 giorni nei pazienti ricoverati con COVID-19, anche se l’EASIX-COVID ha mostrato un miglior valore predittivo negativo, ovvero una migliore capacità di individuare i pazienti che non andranno incontro all’evento morte. L’EASIX-COVID potrebbe pertanto risultare di utilità nella gestione dei pazienti con COVID-19.

COMMENTO: questo studio che valutaEASIX applicato a COVID-19, così come altri studi che utilizzano metodologie diverse, hanno l’obiettivo di identificare parametri sicuri che indicano il rischio di sviluppare forme gravi in soggetti osservati precocemente. Oggi l’affidabilità di questi metodi riveste ancor più valore poiché esistono gli anticorpi monoclonali e sempre più esisteranno farmaci (antivirali) in grado di favorevolmente influenzare la prognosi.

Blixt L et al

Covid-19 in patients with chronic lymphocytic leukemia: clinical outcome and B- and T-cell immunity during 13 months in consecutive patients

Leukemia, https://www.nature.com/articles/s41375-021-01424-w.pdf

CONTENUTO : Studio retrospettivo sugli outcome clinici e immunologici su 60 pazienti affetti da leucemia linfatica cronica (CLL) e COVID-19 in 3 centri ematologici a Stoccolma (Svezia) durante i primi 13 mesi di pandemia. Le forme gravi di COVID-19 si sono verificate indipendentemente da età, genere, BMI e CLL status. Un’età >75 anni è risultato essere l’unico fattore di rischio per mortalità. Nel corso della pandemia si è ridotto il numero di decessi e di ricoveri in terapia intensiva, mentre il numero di ricoveri ospedalieri si è mantenuto elevato. Nella maggior parte dei pazienti si è osservata una risposta immunitaria B e T cellulare robusta e stabile.

COMMENTO: Ancora una volta si conferma in una popolazione particolare (pazienti con leucemia linfatica cronica) che l’età avanzata (>75 anni) è un importante fattore di rischio per la mortalità. E’ giusto quindi vaccinare, anche effettuando uno o più (?) richiami, i soggetti più anziani al fine di proteggerli al meglio.

Ullrich A., et al. Robert Koch’s Infectious Disease Surveillance Group.

Impact of the COVID-19 pandemic and associated non-pharmaceuticalinterventions on other notifiable infectious diseases in Germany:An analysis of national surveillance data during week 1-2016—week32-2020

The Lancet Regional Health – Europe,

https://reader.elsevier.com/reader/sd/pii/S2666776221000806?token=BD572F29CB41C7D017B51E1F56B5C579143E4CAC7CC62AD29C47AAED12488621615A66E4096CE3EB2409B78062F1CAF7&originRegion=eu-west-1&originCreation=20210927164654

CONTENUTO: L’Istituto Roberto Koch tedesco fornisce regolarmente una panoramica dell' epidemiologia di tutte le malattie infettive soggette a notifica in Germania. Questo studio evidenzia come le principali misure di salute pubblica per COVID-19 in Germania, ovvero il distanziamento sociale, l'igiene delle mani, le mascherine, ecc. hanno ridotto drasticamente la trasmissione di molte malattie infettive, in particolare le infezioni respiratorie. Le ragioni alla base di questo cambiamento sono multifattoriali.

COMMENTO : questo lavoro molto interessante ci da un’idea di come il covid sia stato indirettamente responsabile del decremento della trasmissione di molte malattie infettive.

Il lavoro raccoglie 32 tipi di malattie notificate ed analizzate utilizzando il modello di regressione di poisson.

Crook H et al

Long covid—mechanisms, risk factors, and management

BMJ, July 2021 ; doi.org/10.1136/bmj.n1648 

COMMENTO : Since its emergence in Wuhan, China, covid-19 has spread and had a profound effect on the lives and health of people around the globe. As of 4 July 2021, more than 183 million confirmed cases of covid-19 had been recorded worldwide, and 3.97 million deaths. Recent evidence has shown that a range of persistent symptoms can remain long after the acute SARS-CoV-2 infection, and this condition is now coined long covid by recognized research institutes. Studies have shown that long covid can affect the whole spectrum of people with covid-19, from those with very mild acute disease to the most severe forms. Like acute covid-19, long covid can involve multiple organs and can affect many systems including, but not limited to, the respiratory, cardiovascular, neurological, gastrointestinal, and musculoskeletal systems. The symptoms of long covid include fatigue, dyspnea, cardiac abnormalities, cognitive impairment, sleep disturbances, symptoms of post-traumatic stress disorder, muscle pain, concentration problems, and headache. This review summarizes studies of the long term effects of covid-19 in hospitalized and non-hospitalized patients and describes the persistent symptoms they endure. Risk factors for acute covid-19 and long covid and possible therapeutic options are also discussed.

Barizien N et al

Clinical characterization of dysautonomia in long COVID-19 patients

Scientific Reports, July 2021 ; doi.org/10.1038/s41598-021-93546-5

COMMENTO : Increasing numbers of COVID-19 patients, continue to experience symptoms months after recovering from mild cases of COVID-19. Amongst these symptoms, several are related to neurological manifestations, including fatigue, anosmia, hypogeusia, headaches and hypoxia. However, the involvement of the autonomic nervous system, expressed by a dysautonomia, which can aggregate all these neurological symptoms has not been prominently reported. Here, we hypothesize that dysautonomia, could occur in secondary COVID-19 infection, also referred to as “long COVID” infection. 39 participants were included from December 2020 to January 2021 for assessment by the Department of physical medicine to enhance their physical capabilities: 12 participants with COVID-19 diagnosis and fatigue, 15 participants with COVID-19 diagnosis without fatigue and 12 control participants without COVID-19 diagnosis and without fatigue. Heart rate variability (HRV) during a change in position is commonly measured to diagnose autonomic dysregulation. In this cohort, to reflect HRV, parasympathetic/sympathetic balance was estimated using the NOL index, a multiparameter artificial intelligence-driven index calculated from extracted physiological signals by the PMD-200 pain monitoring system. Repeated-measures mixed-models testing group effect were performed to analyze NOL index changes over time between groups. A significant NOL index dissociation over time between long COVID-19 participants with fatigue and control participants was observed (p = 0.046). A trend towards significant NOL index dissociation over time was observed between long COVID-19 participants without fatigue and control participants (p = 0.109). No difference over time was observed between the two groups of long COVID-19 participants (p = 0.904). Long COVID-19 participants with fatigue may exhibit a dysautonomia characterized by dysregulation of the HRV, that is reflected by the NOL index measurements, compared to control participants. Dysautonomia may explain the persistent symptoms observed in long COVID-19 patients, such as fatigue and hypoxia.

SeeBle J et al

Persistent symptoms in adult patients one year after COVID-19: a prospective cohort study

CID, July 2021 ; DOI: 10.1093/cid/ciab611

COMMENTO: Background : Long COVID is defined as the persistence of symptoms beyond 3 months after SARS-CoV-2 infection. To better understand the long-term course and etiology of symptoms we analyzed a cohort of COVID-19 patients prospectively.

Methods : Patients were included at 5 months after acute COVID-19 in this prospective, non-interventional follow-up study. Patients followed until 12 months after COVID-19 symptom onset (n=96, 32.3% hospitalised, 55.2% females) were included in this analysis of symptoms, quality of life (based on a SF-12 survey), laboratory parameters including antinuclear antibodies (ANA), and SARS-CoV-2 antibody levels.

Results : At month 12, only 22.9% of patients were completely free of symptoms and the most frequent symptoms were reduced exercise capacity (56.3%), fatigue (53.1%), dyspnoea (37.5%), concentration problems (39.6%), problems finding words (32.3%), and sleeping problems (26.0%). Females showed significantly more neurocognitive symptoms than males.

ANA titres were ≥1:160 in 43.6% of patients at 12 months post COVID-19 symptom onset, and neurocognitive symptom frequency was significantly higher in the group with an ANA titre ≥1:160 compared to <1:160. Compared to patients without symptoms, patients with at least one long COVID symptom at 12 months did not differ significantly with respect to their SARS-CoV-2-antibody levels, but had a significantly reduced physical and mental life quality compared to patients without symptoms.

Conclusions : Neurocognitive long COVID symptoms can persist at least for one year after COVID-19 symptom onset, and reduce life quality significantly. Several neurocognitive symptoms were associated with ANA titre elevations. This may indicate autoimmunity as cofactor in aetiology of long COVID.

Radin JL et al

Assessment of Prolonged Physiological and Behavioral Changes Associated With COVID-19 Infection

JAMA, July 2021; doi:10.1001/jamanetworkopen.2021.15959

COMMENTO: To our knowledge, this is the first study to examine longer duration wearable sensor data. We found a prolonged physiological impact of COVID-19 infection, lasting approximately 2 to 3 months, on average, but with substantial intraindividual variability, which may reflect various levels of autonomic nervous system dysfunction or potentially ongoing inflammation. Transient bradycardia has been noted in a case study6 approximately 9 to 15 days after symptom onset, which was also seen in our population. Our data suggest that early symptoms and larger initial RHR response to COVID-19 infection may be associated with the physiological length of recovery from this virus.

Burke M et al

Long COVID has exposed medicine's blind-spot

The Lancet, June 2021; doi.org/10.1016/S1473-3099(21)00333-9

COMMENTO: Indeed, one of the most concerning stories emerging out of the COVID-19 pandemic is the quandary of long COVID. Long COVID, or post-acute sequelae of SARS-CoV-2 infection, is being seen in a growing number of patients reporting a constellation of symptoms after SARS-CoV-2 infection that are persistent, debilitating, and have yet to be fully explained by known or measurable mechanisms.

De Giorgi V et al

Naturally acquired SARS-CoV-2 immunity persists for up to 11 months following infection

The Journal of Infectious Diseases, June 2021;  DOI: 10.1093/infdis/jiab295

COMMENTO: Background : Characterizing the kinetics of the antibody response to SARS‐CoV‐2 is of critical importance to developing strategies that may mitigate the public health burden of COVID-19. We conducted a prospective, longitudinal analysis of COVID-19 convalescent plasma (CCP) donors at multiple time points over an 11-month period in order to determine how circulating antibody levels change over time following natural infection.

Methods : From April 2020 to February 2021, we enrolled 228 donors. At each study visit, subjects either donated plasma or had study samples drawn only. Anti-SARS-CoV-2 donor testing was performed using the VITROS® Anti-SARS-CoV-2 Total and IgG assays, and an in-house fluorescence reduction neutralization assay (FRNA).

Results : Anti-SARS-CoV-2 antibodies were identified in 97% of COVID-19 convalescent donors at initial presentation. In follow up analyses, of the 116 donors presenting for repeat timepoints, 91.4% of donors had detectable IgG levels up to 11 months post-symptom recovery, while 63% had detectable neutralizing titers, however, we observed that 25% of donors had neutralizing levels that dropped to an undetectable titer over time.

Conclusion : Our data suggest that immunological memory is acquired in most individuals infected with SARS-CoV-2 and is sustained in a majority of patients for up to 11 months after recovery.

Verna EC et al

Factors Associated with Readmission in the US Following Hospitalization with COVID-19

CID, May 2021 ; doi.org/10.1093/cid/ciab464

COMMENTO: Background : Patients hospitalized for COVID-19 may experience complications following hospitalization and require readmission. This analysis estimates the rate and risk factors associated with COVID-19-related readmission and inpatient mortality.

Methods : This is a retrospective cohort study utilizing deidentified chargemaster data from 297 hospitals across 40 US states on patients hospitalized with COVID-19 February 15-June 09, 2020. Demographics, comorbidities, acute conditions, and clinical characteristics of first hospitalization are summarized. Mulitvariable logistic regression was used to measure risk factor associations with 30-day readmission and in-hospital mortality.

Results : Among 29,659 patients, 1,070 (3.6%) were readmitted. Readmitted patients were more likely to have diabetes, hypertension, cardiovascular disease (CVD), chronic kidney disease (CKD) vs those not readmitted (p<0.0001) and to present on first admission with acute kidney injury (15.6% vs. 9.2%), congestive heart failure (6.4% vs. 2.4%), and cardiomyopathy (2.1% vs. 0.8%) (p<0.0001). Higher odds of readmission were observed in patients age >60 vs. 1840 (odds ratio [OR]=1.92, 95% confidence interval [CI]=1.48, 2.50), and admitted in the Northeast vs. West (OR=1.43, 95% CI=1.14, 1.79) or South (OR=1.28, 95% CI=1.11, 1.49). Comorbidities including diabetes (OR=1.34, 95% CI=1.12, 1.60), CVD (OR=1.46, 95% CI=1.23, 1.72), CKD stage 1-5 (OR=1.51, 95% CI=1.25,1.81) and stage 5 (OR=2.27, 95% CI=1.81, 2.86) were associated with higher odds of readmission. 12.3% of readmitted patients died during second hospitalization.

Conclusions : Among this large US population of patients hospitalized with COVID-19, readmission was associated with certain comorbidities and acute conditions during first hospitalization. These findings may inform strategies to mitigate risks of readmission due to COVID-19 complications.

Istituto Superiore di Sanità

Prevalenza e distribuzione delle varianti del virus SARS-CoV-2 di interesse per la sanità pubblica in Italia

https://www.iss.it/news/-/asset_publisher/gJ3hFqMQsykM/content/id/5746202

COMMENTO: La variante del virus SARS-CoV-2 prevalentemente circolante in Italia è la variante VOC-202012/01 (cosiddetta variante UK) - lignaggio B.1.1.7, caratterizzata da una elevata trasmissibilità.

Il lignaggio P.1 (cosiddetta variante brasiliana) ha una diffusione maggiore in alcune Regioni italiane.

La prevalenza di altre varianti del virus SARS-CoV-2 di interesse per la sanità pubblica è <1% nel nostro paese, ad eccezione della cosiddetta variante nigeriana (1,17%).

È necessario continuare a monitorare con grande attenzione la circolazione delle varianti del virus SARS-CoV-2 ed in particolare la presenza di mutazioni riconducibili ad una maggiore trasmissibilità e/o associate ad un potenziale immune escape.

Lund LC et al

Post-acute effects of SARS-CoV-2 infection in individuals not requiring hospital admission: a Danish population-based cohort study

The Lancet, May 2021; doi.org/10.1016/S1473-3099(21)00211-5

COMMENTO : Background :Individuals admitted to hospital for COVID-19 might have persisting symptoms (so-called long COVID) and delayed complications afterdischarge. However, little is known regarding the risk for those not admitted to hospital. We there fore examined prescription drug and health-care use after SARS-CoV-2 infection not requiring hospital admission.

Methods : This was a population-basedcohortstudyusing the Danish prescription, patient, and healthinsuranceregistries. All individualswith a positive or negative RT-PCR test for SARS-CoV-2 in Denmark between Feb 27 and May 31, 2020, wereeligible for inclusion. Outcomes of interestweredelayed acute complications, chronicdisease, hospitalvisits due to persistingsymptoms, and prescription drug use. Weused data from non-hospitalised SARS-CoV-2-positive and matched SARS-CoV-2-negative individualsfrom 2 weeks to 6 monthsafter a SARS-CoV-2 test to obtainpropensity score-weightedriskdifferences (RDs) and risk ratios (RRs) for initiation of 14 drug groups and 27 hospital diagnoses indicative of potential post-acute effects. We also calculated priorevent rate ratio-adjusted rate ratios of over allhealth-care use.

Findings : 10 498 eligible individuals tested positive for SARS-CoV-2 in Denmark from Feb 27 to May 31, 2020, of whom 8983 (85·6%) were alive and not admitted to hospital 2 weeks after their positive test. The matched SARS-CoV-2-negative reference population not admitted to hospital consisted of 80 894 individuals. Compared with SARS-CoV-2-negative individuals, SARS-CoV-2-positive individuals were not at an increased risk of initiating new drugs (RD <0·1%) except bronchodilating agents, specifically short-acting β2-agonists (117 [1·7%] of 6935 positive individuals vs 743 [1·3%] of 57 206 negative individuals; RD +0·4% [95% CI 0·1–0·7]; RR 1·32 [1·09–1·60]) and triptans (33 [0·4%] of 8292 vs 198 [0·3%] of 72 828; RD +0·1% [0·0–0·3]; RR 1·55 [1·07–2·25]). There was an increased risk of receiving hospital diagnoses of dyspnoea (103 [1·2%] of 8676 vs 499 [0·7%] of 76 728; RD +0·6% [0·4–0·8]; RR 2·00 [1·62–2·48]) and venous thromboembolism (20 [0·2%] of 8785 vs 110 [0·1%] of 78 872; RD +0·1% [0·0–0·2]; RR 1·77 [1·09–2·86]) for SARS-CoV-2-positive individuals compared with negative individuals, but no increased risk of other diagnoses. Prior event rate ratio-adjusted rate ratios of over al lgeneral practitioner visits (1·18 [95% CI 1·15–1·22]) and out patient hospital visits (1·10 [1·05–1·16]), but not hospital admission, showed increasesamong SARS-CoV-2-positive individual scompared with SARS-CoV-2-negative individuals.

Interpretation : The absolute risk of severe post-acute complications after SARS-CoV-2 infection not requiring hospital admission is low. However, increases in visits to general practitioners and out patient hospital visits could indicate COVID-19 sequelae.

Huang L et al

Post-acute conditions of patients with COVID-19 not requiring hospital admission

The Lancet, May 2021; doi.org/10.1016/S1473-3099(21)00225-5

COMMENTO : In the study, the authors only investigated six persisting symptoms, which did not cover the whole potential clinical spectrum. In addition, the prevalence of the persistent symptoms in patients with COVID-19 was about 1%, which was lower than that in a previous study, which showed a rate of 5–15%.5 Given the inherent nature of this type of registration study, thereis the possibility of greatly underestimating the actual prevalence, because there are many reasons that patients with persistent symptoms might not visit the health-care service, such as symptoms be ingmild, not havinghe alth insurance or access to health care, and the risk of reinfection when visiting a health-care facility during the COVID-19 pandemic. Although the number might be undere stimated, SARS-CoV-2-positive individuals still more frequently developed dyspnoea than SARS-CoV-2-negative individuals, supporting the finding of greater prescription of bronchodilating agents in SARS-CoV-2-positive individuals. These find ingswill prompt health-care workers to focus on those patients who have recovered from COVID-19 whoalready have potential risk factors for dyspnoea, such as chronic pulmonary disease, heart failure, and pulmonary hypertension. Monitoring respiratory rate and oxygen saturation at home were simple and practicleways for these patients to assess their respiratory function and health status.

Gautam N et al

Medium-term outcome of severe to critically ill patients with SARS-CoV-2 infection

Clinical Infectious Diseases, April 2021; DOI: 10.1093/cid/ciab341

COMMENTO: BACKGROUND: The medium and long-term effects of severe SARS-CoV-2 infection on survivors are unknown. Here we studied the medium term effects of COVID-19 on survivors of severe disease. METHODS: This is a retrospective, case series of 200 patients hospitalised across three large Birmingham hospitals with severe-to-critical COVID-19 infection 4-7 months from disease-onset. Patients underwent comprehensive clinical, laboratory, imaging, lung function test, quality of life and cognitive assessments. RESULTS: At 4-7 months from disease-onset, 63.2% of patients experienced persistent breathlessness, 53.5% complained of significant fatigue, 37.5% reduced mobility and 36.8% pain. Serum markers of inflammation and organ injuries that persisted at hospital discharge had normalised on follow-up indicating no sustained immune response causing chronic maladaptive inflammation. Chest radiographs showed a complete resolution in 82.8%; and significantly improved or no change in 17.2%. Lung function test (LFT) revealed gas transfer abnormalities in 80.0% and spirometry in 37.6% patients. Patients with breathlessness had significantly high incidence of comorbidities, abnormal residual chest X-ray and LFT (p<0.01 to all). In all parameters assessed and persisting symptoms there was no statically significant difference between patients managed on hospital wards and on ITU groups. All patients reported a significantly reduced quality of life in all domains of the EQ-5D-5L quality of life measures. CONCLUSIONS AND RELEVANCE: A significant proportion of COVID-19 with severe illness experience ongoing symptoms of breathlessness, fatigue, pain, reduced mobility, depression and reduced quality of life at 4-7 months from disease-onset. Symptomatic patients tend to have more residual CXR and LFT abnormalities.

Santhosh L et al

“How I Do It: Rapid Design & Implementation of Post-COVID Clinics”

Chest, March 2021; doi.org/10.1016/j.chest.2021.03.044

COMMENTO: Survivors of COVID-19 are a vulnerable population, withcomplexneedsowing to lingeringsymptoms and complications across multiple organsystems. Thosewhorequiredhospitalization or intensive care are also at risk for post-hospital syndrome and post-ICU syndromes, with attendant cognitive, psychological, and physicalimpairments, and high levels of healthcareutilization. Effective ambulatory care for COVID-19 survivorsrequires coordination across multiple subspecialties, which can beburdensome if not well-coordinated. Withgrowing recognition of theseneeds, post-COVID-19 clinics are beingcreatedacross the country. Wedescribe the design and implementation of multidisciplinary post-COVID-19 clinics at twoacademichealthsystems, Johns Hopkins and the University of California-San Francisco. We highlight components of the model whichshouldbereplicatedacross sites, whileacknowledgingopportunities to tailorofferings to the local institutionalcontext. Our goal is to provide a replicableframework for others to createthesemuch-needed care deliverymodels for survivors of COVID-19.

Taquet M et al

6-month neurological and psychiatric outcomes in 236 379 survivors of COVID-19: a retrospective cohort study using electronic health records

The Lancet, April 2021; doi.org/10.1016/S2215-0366(21)00084-5

COMMENTO: Background : Neurological and psychiatricsequelae of COVID-19 have been reported, but more data are needed to adequatelyassess the effects of COVID-19 on brainhealth. Weaimed to providerobustestimates of incidence rates and relative risks of neurological and psychiatric diagnoses in patients in the 6 monthsfollowing a COVID-19 diagnosis.

Methods : For this retrospective cohort study and time-to-event analysis, we used data obtained from the TriNetX electronic health records network (with over 81 million patients). Our primary cohort comprised patients who had a COVID-19 diagnosis; one matched control cohort included patients diagnosed with influenza, and the other matched control cohort included patients diagnosed with any respiratory tract infection including influenza in the same period. Patients with a diagnosis of COVID-19 or a positive test for SARS-CoV-2 were excluded from the control cohorts. All cohorts included patients older than 10 years who had an index event on or after Jan 20, 2020, and who were still alive on Dec 13, 2020. We estimated the incidence of 14 neurological and psychiatric outcomes in the 6 months after a confirmed diagnosis of COVID-19: intracranial haemorrhage; ischaemic stroke; parkinsonism; Guillain-Barré syndrome; nerve, nerve root, and plexus disorders; myoneural junction and muscle disease; encephalitis; dementia; psychotic, mood, and anxiety disorders (grouped and separately); substance use disorder; and insomnia. Using a Cox model, we compared incidences with those in propensity score-matched cohorts of patients with influenza or other respiratory tract infections. We investigated how these estimates were affected by COVID-19 severity, as proxied by hospitalisation, intensive therapy unit (ITU) admission, and encephalopathy (delirium and related disorders). We assessed the robustness of the differences in outcomes between cohorts by repeating the analysis in different scenarios. To provide benchmarking for the incidence and risk of neurological and psychiatric sequelae, we compared our primary cohort with four cohorts of patients diagnosed in the same period with additional index events: skin infection, urolithiasis, fracture of a large bone, and pulmonary embolism.

Findings : Among 236 379 patients diagnosed with COVID-19, the estimated incidence of a neurological or psychiatric diagnosis in the following 6 months was 33·62% (95% CI 33·17–34·07), with 12·84% (12·36–13·33) receiving their first such diagnosis. For patients who had been admitted to an ITU, the estimated incidence of a diagnosis was 46·42% (44·78–48·09) and for a first diagnosis was 25·79% (23·50–28·25). Regarding individual diagnoses of the study outcomes, the whole COVID-19 cohort had estimated incidences of 0·56% (0·50–0·63) for intracranial haemorrhage, 2·10% (1·97–2·23) for ischaemic stroke, 0·11% (0·08–0·14) for parkinsonism, 0·67% (0·59–0·75) for dementia, 17·39% (17·04–17·74) for anxiety disorder, and 1·40% (1·30–1·51) for psychotic disorder, among others. In the group with ITU admission, estimated incidences were 2·66% (2·24–3·16) for intracranial haemorrhage, 6·92% (6·17–7·76) for ischaemic stroke, 0·26% (0·15–0·45) for parkinsonism, 1·74% (1·31–2·30) for dementia, 19·15% (17·90–20·48) for anxiety disorder, and 2·77% (2·31–3·33) for psychotic disorder. Most diagnostic categories were more common in patients who had COVID-19 than in those who had influenza (hazard ratio [HR] 1·44, 95% CI 1·40–1·47, for any diagnosis; 1·78, 1·68–1·89, for any first diagnosis) and those who had other respiratory tract infections (1·16, 1·14–1·17, for any diagnosis; 1·32, 1·27–1·36, for any first diagnosis). As with incidences, HRs were higher in patients who had more severe COVID-19 (eg, those admitted to ITU compared with those who were not: 1·58, 1·50–1·67, for any diagnosis; 2·87, 2·45–3·35, for any first diagnosis). Resultswererobust to varioussensitivity analyses and benchmarking against the four additional index healthevents.

Interpretation : Our studyprovidesevidence for substantialneurological and psychiatricmorbidity in the 6 monthsafter COVID-19 infection. Risks weregreatest in, but not limited to, patients whohadsevere COVID-19. This information could help in service planning and identification of researchpriorities. Complementarystudy designs, including prospective cohorts, are needed to corroborate and explainthesefindings.

Havervall S et al

Symptoms and Functional Impairment Assessed 8 Months After Mild COVID-19 Among Health Care Workers

JAMA, April 2021; doi:10.1001/jama.2021.5612

COMMENTO : Approximately 80% of hospitalized patients with COVID-19 report persistent symptoms several months after infection onset.1,2 However, knowledge of long-term outcomes among individuals with mild COVID-19 is scarce, and prevalence data are hampered by selection bias and suboptimal control groups.3,4 This cohort study investigated COVID-19–related long-term symptoms in health care professionals.Symptoms and Functional Impairment Assessed 8 Months After Mild COVID-19 Among Health Care Workers.

Nalbandian A et al

Post-acute COVID-19 syndrome

Nature, March 2021; doi.org/10.1038/s41591-021-01283-z

COMMENTO : Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the pathogen responsible for the coronavirus disease 2019 (COVID-19) pandemic, which has resulted in global healthcare crises and strained health resources. As the population of patients recovering from COVID-19 grows, it is paramount to establish an understanding of the healthcare issues surrounding them. COVID-19 is now recognized as a multi-organ disease with a broad spectrum of manifestations. Similarly to post-acute viral syndromes described in survivors of other virulent coronavirus epidemics, there are increasing reports of persistent and prolonged effects after acute COVID-19. Patient advocacy groups, many members of which identify themselves as long haulers, have helped contribute to the recognition of post-acute COVID-19, a syndrome characterized by persistent symptoms and/or delayed or long-term complications beyond 4 weeks from the onset of symptoms. Here, we provide a comprehensive review of the current literature on post-acute COVID-19, its pathophysiology and its organ-specific sequelae. Finally, we discuss relevant considerations for the multidisciplinary care of COVID-19 survivors and propose a framework for the identification of those at high risk for post-acute COVID-19 and their coordinated management through dedicated COVID-19 clinics.

The Writing Committee for the COMEBAC Study Group

Four-Month Clinical Status of a Cohort of Patients After Hospitalization for COVID-19

JAMA, March 2021; DOI: 10.1001/jama.2021.3331

COMMENTO : Importance  Little is known about long-term sequelae of COVID-19.

Objective  To describe the consequences at 4 months in patients hospitalized for COVID-19.

Design, Setting, and Participants  In a prospective uncontrolled cohort study, survivors of COVID-19 who had been hospitalized in a university hospital in France between March 1 and May 29, 2020, underwent a telephone assessment 4 months after discharge, between July 15 and September 18, 2020. Patients with relevant symptoms and all patients hospitalized in an intensive care unit (ICU) were invited for further assessment at an ambulatory care visit.

Exposures  Survival of hospitalization for COVID-19.

Main Outcomes and Measures  Respiratory, cognitive, and functional symptoms were assessed by telephone with the Q3PC cognitive screening questionnaire and a checklist of symptoms. At the ambulatory care visit, patients underwent pulmonary function tests, lung computed tomographic scan, psychometric and cognitive tests (including the 36-Item Short-Form Health Survey and 20-item Multidimensional Fatigue Inventory), and, for patients who had been hospitalized in the ICU or reported ongoing symptoms, echocardiography.

Results  Among 834 eligible patients, 478 were evaluated by telephone (mean age, 61 years [SD, 16 years]; 201 men, 277 women). During the telephone interview, 244 patients (51%) declared at least 1 symptom that did not exist before COVID-19: fatigue in 31%, cognitive symptoms in 21%, and new-onset dyspnea in 16%. There was further evaluation in 177 patients (37%), including 97 of 142 former ICU patients. The median 20-item Multidimensional Fatigue Inventory score (n = 130) was 4.5 (interquartile range, 3.0-5.0) for reduced motivation and 3.7 (interquartile range, 3.0-4.5) for mental fatigue (possible range, 1 [best] to 5 [worst]). The median 36-Item Short-Form Health Survey score (n = 145) was 25 (interquartile range, 25.0-75.0) for the subscale “role limited owing to physical problems” (possible range, 0 [best] to 100 [worst]). Computed tomographic lung-scan abnormalities were found in 108 of 171 patients (63%), mainly subtle ground-glass opacities. Fibrotic lesions were observed in 33 of 171 patients (19%), involving less than 25% of parenchyma in all but 1 patient. Fibrotic lesions were observed in 19 of 49 survivors (39%) with acute respiratory distress syndrome. Among 94 former ICU patients, anxiety, depression, and posttraumatic symptoms were observed in 23%, 18%, and 7%, respectively. The left ventricular ejection fraction was less than 50% in 8 of 83 ICU patients (10%). New-onset chronic kidney disease was observed in 2 ICU patients. Serology was positive in 172 of 177 outpatients (97%).

Conclusions and Relevance  Four months after hospitalization for COVID-19, a cohort of patients frequently reported symptoms not previously present, and lung-scan abnormalities were common among those who were tested. These findings are limited by the absence of a control group and of pre-COVID assessments in this cohort. Further research is needed to understand longer-term outcomes and whether these findings reflect associations with the disease.

Logue JK et al

Sequelae in Adults at 6 Months After COVID-19 Infection

JAMA, February 2021; doi:10.1001/jamanetworkopen.2021.0830

COMMENTO: Many individuals experience persistent symptoms and a decline in health-related quality of life (HRQoL) after coronavirus disease 2019 (COVID-19) illness. Existing studies have focused on hospitalized individuals 30 to 90 days after illness onsetand have reported symptoms up to 110 days after illness. Longer-term sequelae in outpatients have not been well characterized.

Bellan Mattia et al

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

JAMA, January 2021; doi:10.1001/jamanetworkopen.2020.36142

COMMENTO : 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 wasconfirmed via reverse transcription–polymerasechainreactiontesting, bronchial swab, serologicaltesting, or suggestive computedtomographyresults.

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 symptomswerereported 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.

Huang C et al

6-month consequences of COVID-19 in patients discharged from hospital: a cohort study

The Lancet, January 2021 ; doi.org/10.1016/S0140-6736(20)32656-8

COMMENTO : Background : The long-term health consequences of COVID-19 remain largely unclear. The aim of this study was to describe the long-term health consequences of patients with COVID-19 who have been discharged from hospital and investigate the associated risk factors, in particular disease severity.

Methods : We did an ambidirectional cohort study of patients with confirmed COVID-19 who had been discharged from Jin Yin-tan Hospital (Wuhan, China) between Jan 7, 2020, and May 29, 2020. Patients who died before follow-up, patients for whom follow-up would be difficult because of psychotic disorders, dementia, or re-admission to hospital, those who were unable to move freely due to concomitant osteoarthropathy or immobile before or after discharge due to diseases such as stroke or pulmonary embolism, those who declined to participate, those who could not be contacted, and those living outside of Wuhan or in nursing or welfare homes were all excluded. All patients were interviewed with a series of questionnaires for evaluation of symptoms and health-related quality of life, underwent physical examinations and a 6-min walking test, and received blood tests. A stratified sampling procedure was used to sample patients according to their highest seven-category scale during their hospital stay as 3, 4, and 5–6, to receive pulmonary function test, high resolution CT of the chest, and ultrasonography. Enrolled patients who had participated in the Lopinavir Trial for Suppression of SARS-CoV-2 in China received severe acute respiratory syndrome coronavirus 2 antibody tests. Multivariable adjusted linear or logistic regression models were used to evaluate the association between disease severity and long-term health consequences.

Findings : In total, 1733 of 2469 discharged patients with COVID-19 were enrolled after 736 were excluded. Patients had a median age of 57·0 (IQR 47·0–65·0) years and 897 (52%) were men. The follow-up study was done from June 16, to Sept 3, 2020, and the median follow-up time after symptom onset was 186·0 (175·0–199·0) days. Fatigue or muscle weakness (63%, 1038 of 1655) and sleep difficulties (26%, 437 of 1655) were the most common symptoms. Anxiety or depression was reported among 23% (367 of 1617) of patients. The proportions of median 6-min walking distance less than the lower limit of the normal range were 24% for those at severity scale 3, 22% for severity scale 4, and 29% for severity scale 5–6. The corresponding proportions of patients with diffusion impairment were 22% for severity scale 3, 29% for scale 4, and 56% for scale 5–6, and median CT scores were 3·0 (IQR 2·0–5·0) for severity scale 3, 4·0 (3·0–5·0) for scale 4, and 5·0 (4·0–6·0) for scale 5–6. After multivariable adjustment, patients showed an odds ratio (OR) 1·61 (95% CI 0·80–3·25) for scale 4 versus scale 3 and 4·60 (1·85–11·48) for scale 5–6 versus scale 3 for diffusion impairment; OR 0·88 (0·66–1·17) for scale 4 versus scale 3 and OR 1·77 (1·05–2·97) for scale 5–6 versus scale 3 for anxiety or depression, and OR 0·74 (0·58–0·96) for scale 4 versus scale 3 and 2·69 (1·46–4·96) for scale 5–6 versus scale 3 for fatigue or muscle weakness. Of 94 patients with blood antibodies tested at follow-up, the seropositivity (96·2% vs 58·5%) and median titres (19·0 vs 10·0) of the neutralising antibodies were significantly lower compared with at the acute phase. 107 of 822 participants without acute kidney injury and with estimated glomerular filtration rate (eGFR) 90 mL/min per 1·73 m2 or more at acute phase had eGFR less than 90 mL/min per 1·73 m2 at follow-up.

Interpretation : At 6 months after acute infection, COVID-19 survivors were mainly troubled with fatigue or muscle weakness, sleep difficulties, and anxiety or depression. Patients who were more severely ill during their hospital stay had more severe impaired pulmonary diffusion capacities and abnormal chest imaging manifestations, and are the main target population for intervention of long-term recovery.

Salman D et al

Returning to physical activity after covid-19

BMJ, JANUARY 2021 ; doi.org/10.1136/bmj.m4721

COMMENTO: What you need to know

Risk stratify patients before recommending a return to physical activity in people who have had covid-19. Patients with ongoing symptoms or who had severe covid-19 or a history suggestive of cardiac involvement need further clinical assessment

Only return to exercise after at least seven days free of symptoms, and begin with at least two weeks of minimal exertion

Use daily self monitoring to track progress, including when to seek further help

Mahase E

Covid-19: Past infection provides 83% protection for five months but may not stop transmission, study finds

BMJ, January 2021; doi.org/10.1136/bmj.n124

COMMENTO: People who have previously been infected with covid-19 are likely to be protected against reinfection for several months, but could still carry the virus in their nose and throat and transmit it to others, according to a study which regularly tested thousands of healthcare workers.

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