Sok-Ja Janket et al
Tachykinins and the potential causal factors for post-COVID-19 condition
The Lancet, June 2023 ; doi.org/10.1016/S2666-5247(23)00111-8
Abstract
The most prevalent symptoms of post-COVID-19 condition are pulmonary dysfunction, fatigue and muscle weakness, anxiety, anosmia, dysgeusia, headaches, difficulty in concentrating, sexual dysfunction, and digestive disturbances. Hence, neurological dysfunction and autonomic impairments predominate in post-COVID-19 condition. Tachykinins including the most studied substance P are neuropeptides expressed throughout the nervous and immune systems, and contribute to many physiopathological processes in the nervous, immune, gastrointestinal, respiratory, urogenital, and dermal systems and participate in inflammation, nociception, and cell proliferation. Substance P is a key molecule in neuroimmune crosstalk; immune cells near the peripheral nerve endings can send signals to the brain with cytokines, which highlights the important role of tachykinins in neuroimmune communication. We reviewed the evidence that relates the symptoms of post-COVID-19 condition to the functions of tachykinins and propose a putative pathogenic mechanism. The antagonism of tachykinins receptors can be a potential treatment target.
Aarthi Talla et al.
Persistent serum protein signatures define an inflammatory subcategory of long COVID
Nature, June 2023; doi.org/10.1038/s41467-023-38682-4
Abstract
Long COVID or post-acute sequelae of SARS-CoV-2 (PASC) is a clinical syndrome featuring diverse symptoms that can persist for months following acute SARS-CoV-2 infection. The aetiologies may include persistent inflammation, unresolved tissue damage or delayed clearance of viral protein or RNA, but the biological differences they represent are not fully understood. Here we evaluate the serum proteome in samples, longitudinally collected from 55 PASC individuals with symptoms lasting ≥60 days after onset of acute infection, in comparison to samples from symptomatically recovered SARS-CoV-2 infected and uninfected individuals. Our analysis indicates heterogeneity in PASC and identified subsets with distinct signatures of persistent inflammation. Type II interferon signaling and canonical NF-κB signaling (particularly associated with TNF), appear to be the most differentially enriched signaling pathways, distinguishing a group of patients characterized also by a persistent neutrophil activation signature. These findings help to clarify biological diversity within PASC, identify participants with molecular evidence of persistent inflammation, and highlight dominant pathways that may have diagnostic or therapeutic relevance, including a protein panel that we propose as having diagnostic utility for differentiating inflammatory and non-inflammatory PASC.
Michael Gottlieb et al.
Severe Fatigue and Persistent Symptoms at 3 Months Following Severe Acute Respiratory Syndrome Coronavirus 2 Infections During the Pre-Delta, Delta, and Omicron Time Periods: A Multicenter Prospective Cohort Study
CID, January 2023; doi.org/10.1093/cid/ciad045
Abstract
Most research on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants focuses on initial symptomatology with limited longer-term data. We characterized prevalences of prolonged symptoms 3 months post–SARS-CoV-2 infection across 3 variant time-periods (pre-Delta, Delta, and Omicron).
Methods
This multicenter prospective cohort study of adults with acute illness tested for SARS-CoV-2 compared fatigue severity, fatigue symptoms, organ system–based symptoms, and ≥3 symptoms across variants among participants with a positive (“COVID-positive”) or negative SARS-CoV-2 test (“COVID-negative”) at 3 months after SARS-CoV-2 testing. Variant periods were defined by dates with ≥50% dominant strain. We performed multivariable logistic regression modeling to estimate independent effects of variants adjusting for sociodemographics, baseline health, and vaccine status.
Results
The study included 2402 COVID-positive and 821 COVID-negative participants. Among COVID-positives, 463 (19.3%) were pre-Delta, 1198 (49.9%) Delta, and 741 (30.8%) Omicron. The pre-Delta COVID-positive cohort exhibited more prolonged severe fatigue (16.7% vs 11.5% vs 12.3%; P = .017) and presence of ≥3 prolonged symptoms (28.4% vs 21.7% vs 16.0%; P < .001) compared with the Delta and Omicron cohorts. No differences were seen in the COVID-negatives across time-periods. In multivariable models adjusted for vaccination, severe fatigue and odds of having ≥3 symptoms were no longer significant across variants.
Conclusions
Prolonged symptoms following SARS-CoV-2 infection were more common among participants infected during pre-Delta than with Delta and Omicron; however, these differences were no longer significant after adjusting for vaccination status, suggesting a beneficial effect of vaccination on risk of long-term symptoms.
Chaolin Huang et al.
6-month consequences of COVID-19 in patients discharged from hospital: a cohort study
The Lancet, June 2023; doi.org/10.1016/S0140-6736(23)00810-3
Abstract
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 and May 29, 2020. Patients who died before follow-up; patients for whom follow-up would be difficult because of psychotic disorders, dementia, or readmission 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 SARS-CoV-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 years (IQR 47·0–65·0) and 897 (52%) were male and 836 (48%) were female. 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 days (175·0–199·0). Fatigue or muscle weakness (52%, 855 of 1654) and sleep difficulties (26%, 437 of 1655) were the most common symptoms. Anxiety or depression was reported among 23% (367 of 1616) of patients. The proportions of 6-min walking distance less than the lower limit of the normal range were 17% for those at severity scale 3, 13% for severity scale 4, and 28% 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) of 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 1·76 (1·05–2·96) for scale 5–6 versus scale 3 for anxiety or depression, and OR 0·87 (0·68–1·11) for scale 4 versus scale 3 and 2·75 (1·61–4·69) 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 an estimated glomerular filtration rate (eGFR) of 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.
Naomi Oka et al.
SARS-CoV-2 S1 protein causes brain inflammation by reducing intracerebral acetylcholine production
Cell, May 2023; doi.org/10.1016/j.isci.2023.106954
Abstract
Neurological complications that occur in SARS-CoV-2 infection, such as olfactory dysfunction, brain inflammation, malaise, and depressive symptoms, are thought to contribute to long COVID. However, in autopsies of patients who have died from COVID-19, there is normally no direct evidence that central nervous system damage is due to proliferation of SARS-CoV-2. For this reason, many aspects of the pathogenesis mechanisms of such symptoms remain unknown. Expressing SARS-CoV-2 S1 protein in the nasal cavity of mice was associated with increased apoptosis of the olfactory system and decreased intracerebral acetylcholine production. The decrease in acetylcholine production was associated with brain inflammation, malaise, depressive clinical signs, and decreased expression of the cytokine degrading factor ZFP36. Administering the cholinesterase inhibitor donepezil to the mice improved brain inflammation, malaise and depressive clinical signs. These findings could contribute to the elucidation of the pathogenesis mechanisms of neurological complications associated with COVID-19 and long COVID.
HaruyukiKinoshita et al
The impact that myocarditis for post-acute COVID-19 syndrome may be dermatomyositis-like myocarditis: A case report
Cell, May 2023; doi.org/10.1016/j.heliyon.2023.e16512
Abstract
Myocarditis is often reported as a complication of COVID-19 infection or post-vaccination, but there are few reports of “myocarditis for Post-acute COVID-19 syndrome”, and many unknowns still remain.
Apart from that, an association between COVID-19 infection and dermatomyositis has also been reported. We describe the clinical presentation of acute myocarditis in a patient who had developed COVID-19 syndrome one-month earlier. A healthy 49-year-old man experienced typical COVID-19 symptoms. Thirty-two days later, he was admitted because of fever and severe fatigue, chest pain and bradycardia. Blood tests showed major inflammation. PCR for SARS-CoV-2 on nasopharyngeal swab (ID NOW™) was positive, but diagnosed as a previous infection due to a high CT value.
Because of haemodynamic worsening with both an increase in cardiac troponin I and NT-pro BNP levels and reduced wall motion on echocardiography, acute myocarditis was suspected.
Myocardial biopsy revealed severe lymphocytic infiltration and interstitial edema between myocardial fibers. These findings led to the diagnosis of fulminant myocarditis. Interestingly, myocardium was also stained with human myxovirus resistance protein 1 (MxA).
We consider that there may be an aspect of “dermatomyositis-like myocarditis with SARS-CoV-2” in our case. This is the first case of fulminant myocarditis for Post-acute COVID-19 syndrome in which diagnosis of active myocarditis was proven by pathological examination following myocardial biopsy and strong association with dermatomyositis was suggested pathologically.
RubeshanPerumal et al
Biological mechanisms underpinning the development of Long COVID
Cell, May 2023; doi.org/10.1016/j.isci.2023.106935
Abstract
As COVID-19 evolves from a pandemic to an endemic disease, the already staggering number of people that have been or will be infected with SARS-COV-2 is only destined to increase, and the majority of humanity will be infected. It is well understood that COVID-19, like many other viral infections, leaves a significant fraction of the infected with prolonged consequences. Continued high number of SARS-CoV-2 infections, viral evolution with escape from post-infection and vaccinal immunity, and reinfections heighten the potential impact of Long COVID. Hence, the impact of COVID-19 on human health will be seen for years to come until more effective vaccines and pharmaceutical treatments become available. To that effect, it is imperative that the mechanisms underlying the clinical manifestations of Long COVID be elucidated. In this article, we provide an in-depth analysis of the evidence on several potential mechanisms of Long COVID and discuss their relevance to its pathogenesis.
M. Daniel Brannock et al
Long COVID risk and pre-COVID vaccination in an EHR-based cohort study from the RECOVER program
Nature, May 2023; doi.org/10.1038/s41467-023-38388-7
Abstract
Long COVID, or complications arising from COVID-19 weeks after infection, has become a central concern for public health experts. The United States National Institutes of Health founded the RECOVER initiative to better understand long COVID. We used electronic health records available through the National COVID Cohort Collaborative to characterize the association between SARS-CoV-2 vaccination and long COVID diagnosis. Among patients with a COVID-19 infection between August 1, 2021 and January 31, 2022, we defined two cohorts using distinct definitions of long COVID—a clinical diagnosis (n = 47,404) or a previously described computational phenotype (n = 198,514)—to compare unvaccinated individuals to those with a complete vaccine series prior to infection. Evidence of long COVID was monitored through June or July of 2022, depending on patients’ data availability. We found that vaccination was consistently associated with lower odds and rates of long COVID clinical diagnosis and high-confidence computationally derived diagnosis after adjusting for sex, demographics, and medical history.
Revital Marcus et al.
New Alzheimer Disease Drugs, Long COVID and the Central Nervous System, and a Nasal Spray for Migraines—Highlights From the 2023 American Academy of Neurology Conference
JAMA, May 2023; doi:10.1001/jama.2023.4389
Abstract
During its annual conference this April, the American Academy of Neurology (AAN) celebrated its 75th “Jubilee” anniversary. While in Boston for the conference, JAMA Fishbein Fellow and neurologist Revital Marcus, MD, sat down with AAN president-elect and the meeting’s science committee chair Natalia Rost, MD, who is chief of the stroke division in the Department of Neurology at Massachusetts General Hospital and professor of neurology at Harvard Medical School. The following is an edited version of their conversation about cutting-edge research presented at the conference.
Dr Marcus:The past couple of years we’ve seen the approval of 2 new disease-modifying therapies for Alzheimer disease—aducanumab and lecanemab. A phase 3 randomized clinical trial evaluated the potential superiority of the investigational drug donanemab vs aducanumab among patients with early symptomatic Alzheimer disease. Can you please tell us about this study?
Dr Rost:One way to look at it is that it’s not just a study, it’s the beginning of a new era in the treatment of Alzheimer disease. Aducanumab was the first monoclonal antibody approved for treatment of Alzheimer disease. It’s an amyloid β–specific monoclonal antibody that is primed for removal of this toxic protein in the brain of individuals with early Alzheimer disease. Donanemab is a next-generation drug that has been compared head-to-head with aducanumab, and it showed superiority in the way the amyloid was being removed from the brain. There is some evidence of removal, but there’s also evidence of somewhat of an improvement in function of those patients.
But I don’t think this is the end of the story. Maybe next year, or 5 years down the road, there will be another monoclonal antibody or even a more innovative treatment that is targeted specifically for Alzheimer disease. I think this was a kind of opening salvo into targeted treatment of Alzheimer disease. It’s offering hope to our patients and of course a lot of excitement to our clinicians.
There’s still a lot of work to be done. It’s not a period in a sentence, it’s more of an invitation for future innovation in this field. I think that we’re going to see a wide horizon of therapeutic options open up for Alzheimer disease.
Dr Marcus:With COVID-19, a lot of research has been focused on the neurological sequelae. Can you please discuss a study that particularly stood out for you?
Dr Rost:I would like to highlight a study that focused on what we call neuro PASC. PASC [postacute sequelae of SARS-CoV-2 infection] refers to the clinical manifestations of post-COVID infection. Neuro PASC is related to the complications associated with the central nervous system (CNS). These are individuals who unfortunately after a COVID infection continue to suffer with symptoms like dizziness, cognitive fog, neuropathy, or fatigue—it’s just functionally and cognitively disabling.
A study presented by Dr Marianna Spatola investigated the immunological profile in patients with neuro PASC compared to those who were free of neurological long-term symptoms. The reason why this study was interesting to me is because they truly looked into a mechanism of response to the viral infection in these individuals. They looked at the profile of immunological representation of infection both in serum, in blood, and also in their spinal fluid, which is helpful because they could actually assess whether the immunological response began in the blood or within the constraints of the nervous system. Are the antibodies primary to the nervous system, or were they transferred from the blood into the CSF [cerebrospinal fluid] space?
Dr Spatola and her colleagues demonstrated that both groups, those who had neuro PASC symptoms and those who didn’t, had a pretty robust immunological response to the COVID virus. Individuals who had neuro PASC or long-term complications that affected the nervous system, as compared to those who didn’t, actually had evidence of a much more robust response to the prior coronaviruses, which we know frequently are common cold viruses.
So that’s one interesting phenomenon they’ve noticed. They’ve also noticed that the antibodies were [different] in the CSF, which is a very interesting and important observation because we’ve had a lot of debate about whether SARS-CoV-2 as a virus attacks the central nervous system directly. But the indication now is that it may be more of a secondary phenomenon from the inflammation that happens in the body and then is ultimately transferred into the central nervous system. So a very interesting observation, number 2.
And number 3, one of the implications is that there could be some strategies based on these observations that may help us prevent neuro PASC complications. Fascinating neuroscience. Stay tuned.
So the future of neuroscience is bright and the future of neurology practice is bright.
McKaylee M Robertson et al.
The Epidemiology of Long Coronavirus Disease in US Adults
CID, December 2022; doi.org/10.1093/cid/ciac961
Abstract
We estimated the prevalence of long COVID and impact on daily living among a representative sample of adults in the United States.
Methods
We conducted a population-representative survey, 30 June–2 July 2022, of a random sample of 3042 US adults aged 18 years or older and weighted to the 2020 US population. Using questions developed by the UK's Office of National Statistics, we estimated the prevalence of long COVID, by sociodemographics, adjusting for gender and age.
Results
An estimated 7.3% (95% confidence interval: 6.1–8.5%) of all respondents reported long COVID, corresponding to approximately 18 828 696 adults. One-quarter (25.3% [18.2–32.4%]) of respondents with long COVID reported their day-to-day activities were impacted “a lot” and 28.9% had severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection more than 12 months ago. The prevalence of long COVID was higher among respondents who were female (adjusted prevalence ratio [aPR]: 1.84 [1.40–2.42]), had comorbidities (aPR: 1.55 [1.19–2.00]), or were not (vs were) boosted (aPR: 1.67 [1.19–2.34]) or not vaccinated (vs boosted) (aPR: 1.41 [1.05–1.91]).
Conclusions
We observed a high burden of long COVID, substantial variability in prevalence of SARS-CoV-2, and risk factors unique from SARS-CoV-2 risk, suggesting areas for future research. Population-based surveys are an important surveillance tool and supplement to ongoing efforts to monitor long COVID.
MayssamNehme et al.
Prevalence of Post-Coronavirus Disease Condition 12 Weeks After Omicron Infection Compared With Negative Controls and Association With Vaccination Status
CID, December 2022; doi.org/10.1093/cid/ciac947
Abstract
Background
Post-coronovirus disease (COVID) symptoms can persist several months after severe acute respiratory syndrome coronavirus 2 infection. Little is known, however, about the prevalence of post-COVID condition following infections from Omicron variants and how this varies according to vaccination status. This study evaluates the prevalence of symptoms and functional impairment 12 weeks after an infection by Omicron variants (BA.1 and BA.2) compared with negative controls tested during the same period.
Methods
Outpatient individuals who tested positive or negative for COVID-19 infection between December 2021 and February 2022 at the Geneva University Hospitals were followed 12 weeks after their test date.
Results
Overall, 11.7% of Omicron cases had symptoms 12 weeks after the infection compared with 10.4% of individuals who tested negative during the same period (P < .001), and symptoms were much less common in vaccinated versus nonvaccinated individuals with Omicron infection (9.7% vs 18.1%; P < .001). There were no significant differences in functional impairment at 12 weeks between Omicron cases and negative controls, even after adjusting for multiple potential confounders.
Conclusions
The differential prevalence of post-COVID symptoms and functional impairment attributed to Omicron BA.1 and BA.2 infection is low when compared with negative controls. Vaccination is associated with lower prevalence of post-COVID symptoms.
Janko Ž. Nikolich, and Clifford J. Rosen
Toward Comprehensive Care for Long Covid
NEJM, May 2023; DOI:10.1056/NEJMp2304550
Abstract
Three years into the Covid pandemic, SARS-CoV-2 is still with us. As the virus evolves, it continues to pose a health threat in terms of both acute infections (or reinfections) and postacute sequelae. In regard to the former, there is evidence that several pharmacologic interventions reduce the severity of infections, lessen morbidity, and lower mortality. Prevention programs have also been successful in reducing overall infection rates. These efforts can be traced in part to colossal federal support for work ranging from vaccine development to clinical trials to nationwide educational endeavors. Such impressive support is all the more striking in contrast to the void in patient care for a SARS-CoV-2 postviral syndrome that may affect 10% or more of infected people.1,2
The sequelae of SARS-CoV-2 infection can involve multiple organ systems and are often grouped together as “long Covid” or PASC (postacute sequelae of SARS-CoV-2).3 But the terms themselves are nebulous, the clinical presentations extremely variable, and the prognosis uncertain.4,5 The absence of evidence-based treatments further fuels the frustration of affected patients and their clinicians. Add to these problems our shaky and fragmented health care system, additionally wobbled by the pandemic, and the result is disarray in our approach to this complex and multifaceted disorder.
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The extent of the symptom complex of long Covid is unknown, in part because there is no well-accepted definition of the syndrome and because of the relatively poor penetration of care to marginalized populations that have been disproportionately affected by the pandemic. The Centers for Disease Control and Prevention (CDC) defines long Covid as a wide range of new, returning, or ongoing health problems occurring more than 4 weeks after someone becomes infected with SARS-CoV-2. The World Health Organization (WHO) does not fully define long Covid but classifies it by continuation or onset of new symptoms 3 months after the original bout of illness or positive test.
In October 2021, the world adopted International Classification of Diseases code U09.9 to help clinicians document visits of patients with long Covid. Basically, one or multiple symptoms persisting or occurring more than 4 weeks after the onset of acute SARS-CoV-2 infection are coded as U09.9. Signs and symptoms include shortness of breath, fatigue with or without exertion, myalgia, glucose intolerance, multisystem inflammatory syndrome, postural orthostatic tachycardia, peripheral neuropathy, and others reflective of multi–organ-system involvement.4,5 Although this categorization is helpful for research and tracking of electronic health records, it does little to help clinicians or affected people make their way through a maze of difficulties from diagnosis to treatment.
The pathophysiology of long Covid remains elusive, in part because of the multiple possible signs, symptoms, and organ systems involved.3 A lack of understanding of long Covid inevitably also complicates care. Long Covid clinics have been established to provide multidisciplinary care, although most affected patients are also followed by primary care providers or seen by various specialists, depending on the duration and severity of their dominant symptoms. Educational programs for patients and clinicians are lacking. Referrals to subspecialists such as cardiologists, pulmonologists, and neurologists are common but often lead to more delays, fragmentation of care, and frustration at all levels. Primary care providers feel the brunt of that frustration, both their patients’ and their own at their inability to help beyond deploying simple strategies, such as exercise or nutritional supplementation, that are used as preventive measures for healthy people.
Patients with long Covid are still subject to stigmatization because of perceived simulation or psychosomatization of symptoms. And most people with long Covid do not feel empowered to take control of their care. At the state and local levels, referral centers that focus on long Covid management are not only sparse and unevenly distributed, but also generally overbooked, difficult to access, and frequently far from patients’ homes. Moreover, there are few or no available treatment options that have been rigorously tested in clinical trials.
On the national level, as part of the initial federal response to long Covid, the National Institutes of Health launched the Researching COVID to Enhance Recovery (RECOVER) initiative (in which we are investigators), which selected a network of enrollment sites (hubs) that cover adults, pregnant people, and children in 33 states, the District of Columbia, and Puerto Rico. In the initial phase of RECOVER, each adult hub worked with community partners to enroll more than 12,000 participants whose clinical tests and data on characteristics are collected in associated biobanks and databases. The goal of adult RECOVER is threefold: to define the clinical spectrum and pathophysiology of long Covid, to determine its natural history and prevalence, and to characterize the way in which SARS-CoV-2 causes postacute sequelae.
In the adult RECOVER longitudinal study, the vast majority of participants were infected with SARS-CoV-2, although a small percentage were recruited as uninfected controls. Some but not all continue to have chronic sequelae from that infection. The second phase of adult RECOVER will involve a limited number of clinical trials for patients with long Covid. Similar trials are planned for RECOVER’s child cohort. In our view, this research initiative is comprehensive and scientifically sound. But many participants have conveyed to investigators their frustration with the fact that delivery of both their primary and specialty health care is, at best, dissociated from RECOVER and in many cases is fragmented, poorly coordinated, or even nonexistent.
RECOVER is a building block for ultimately establishing the clinical definition of long Covid. We believe that over and above this research effort, the country needs additional structures that can provide the capacity for clinicians, patients, caregivers, advocacy groups, employers, and government officials to learn about, adapt, and implement interventions, therapeutics, and other best practices to combat long Covid.
We suggest that this effort include several key features. First, it should support people with long Covid by coordinating clinical care and rehabilitation, reducing health care disparities, and addressing ongoing and complex medical and psychosocial needs, with a particular focus on patients who currently receive fragmented care or no care at all. Such support could be provided by means of national long Covidcenters of excellence. This program could begin by building out some centers involved in RECOVER so that they not only collect data and follow participants, but also provide comprehensive care for those patients and others with long Covid. RECOVER serves a cross section of underserved communities through research centers in both urban and rural areas and can act as a bridge to care provision for these patients.
Second, we need to define, continuously improve, and implement standards of care and best practices, built on evidence obtained through a coordinated exchange of information. Third, we can leverage innovative methods for disseminating information and providing support in order to educate clinicians, patients, and communities; broaden access to high-quality care; and further reduce disparities. And fourth, we will need to develop and implement workforce training programs for clinicians caring for patients with long Covid.
To implement such an ambitious program, we strongly urge Congress to consider appropriating funding in fiscal year 2024 for the Health Resources and Services Administration to competitively select centers of excellence in long Covid care by leveraging and expanding the initial investment in RECOVER hubs and other federally supported long Covid activities.
In addition, such centers could support and leverage, both nationally and throughout their states, greater educational initiatives from the CDC and the WHO for both clinicians and patients. Some examples include continuing education programs, grand rounds, and the Project ECHO (Extension for Community Healthcare Outcomes) model, a scalable and effective way of using electronic media to inform and facilitate changes in health and education for clinicians. These efforts should focus on symptom complexes, potential complications, and management strategies. We need to demystify the disease and empower affected people, involving them actively in their own care and in education and training. We also recommend that insurance providers reexamine criteria for disability claims and urge employers to gain a better understanding of this disorder and its wide-ranging implications. Most important, we need to put people and communities, not diseases, at the center of our health systems and empower them to take charge of their own health rather than be passive recipients of services.
If the prevalence of long Covid is indeed between 5 and 15%, we will continue to face an enormous challenge to our national health and our health care system moving forward. Innovative approaches will be needed to care for patients with long Covid, and these need to be backed by education, research, and support at all levels. It’sabout time.
Teresa C. Liu et al.
Perceived Cognitive Deficits in Patients With Symptomatic SARS-CoV-2 and Their Association With Post–COVID-19 Condition
JAMA, May 2023; doi:10.1001/jamanetworkopen.2023.11974
Abstract
Importance Neuropsychiatric symptoms are common in acute SARS-CoV-2 infection and in post–COVID-19 condition (PCC; colloquially known as long COVID), but the association between early presenting neuropsychiatric symptoms and PCC is unknown.
Objective To describe the characteristics of patients with perceived cognitive deficits within the first 4 weeks of SARS-CoV-2 infection and the association of those deficits with PCC symptoms.
Design, Setting, and Participants This prospective cohort study was conducted from April 2020 to February 2021, with follow-up of 60 to 90 days. The cohort consisted of adults enrolled in the University of California, Los Angeles, SARS-CoV-2 Ambulatory Program who had a laboratory-confirmed symptomatic SARS-CoV-2 infection and were either hospitalized in a University of California, Los Angeles, hospital or one of 20 local health care facilities, or were outpatients referred by a primary care clinician. Data analysis was performed from March 2022 to February 2023.
Exposure Laboratory-confirmed SARS-CoV-2 infection.
Main Outcomes and Measures Patients responded to surveys that included questions about perceived cognitive deficits modified from the Perceived Deficits Questionnaire, Fifth Edition, (ie, trouble being organized, trouble concentrating, and forgetfulness) and symptoms of PCC at 30, 60, and 90 days after hospital discharge or initial laboratory-confirmed infection of SARS-CoV-2. Perceived cognitive deficits were scored on a scale from 0 to 4. Development of PCC was determined by patient self-report of persistent symptoms 60 or 90 days after initial SARS-CoV-2 infection or hospital discharge.
Results Of 1296 patients enrolled in the program, 766 (59.1%) (mean [SD] age, 60.0 [16.7] years; 399 men [52.1%]; 317 Hispanic/Latinx patients [41.4%]) completed the perceived cognitive deficit items at 30 days after hospital discharge or outpatient diagnosis. Of the 766 patients, 276 (36.1%) perceived a cognitive deficit, with 164 (21.4%) having a mean score of greater than 0 to 1.5 and 112 patients (14.6 %) having a mean score greater than 1.5. Prior cognitive difficulties (odds ratio [OR], 1.46; 95% CI, 1.16-1.83) and diagnosis of depressive disorder (OR, 1.51; 95% CI, 1.23-1.86) were associated with report of a perceived cognitive deficit. Patients reporting perceived cognitive deficits in the first 4 weeks of SARS-CoV-2 infection were more likely to report symptoms of PCC than those without perceived cognitive deficits (118 of 276 patients [42.8%] vs 105 of 490 patients [21.4%]; χ21, 38.9; P < .001). Adjusting for demographic and clinical factors, perceived cognitive deficits in the first 4 weeks of SARS-CoV-2 were associated with PCC symptoms (patients with a cognitive deficit score of >0 to 1.5: OR, 2.42; 95% CI, 1.62-3.60; patients with cognitive deficit score >1.5: OR, 2.97; 95% CI, 1.86-4.75) compared to patients who reported no perceived cognitive deficits.
Conclusions and Relevance These findings suggest that patient-reported perceived cognitive deficits in the first 4 weeks of SARS-CoV-2 infection are associated with PCC symptoms and that there may be an affective component to PCC in some patients. The underlying reasons for PCC merit additional exploration.
Simone Turner et al.
Long COVID: pathophysiological factors and abnormalities of coagulation
Cell, April 2023; doi.org/10.1016/j.tem.2023.03.002
Abstract
Acute COVID-19 infection is followed by prolonged symptoms in approximately one in ten cases: known as Long COVID. The disease affects ~65 million individuals worldwide. Many pathophysiological processes appear to underlie Long COVID, including viral factors (persistence, reactivation, and bacteriophagic action of SARS CoV-2); host factors (chronic inflammation, metabolic and endocrine dysregulation, immune dysregulation, and autoimmunity); and downstream impacts (tissue damage from the initial infection, tissue hypoxia, host dysbiosis, and autonomic nervous system dysfunction). These mechanisms culminate in the long-term persistence of the disorder characterized by a thrombotic endothelialitis, endothelial inflammation, hyperactivated platelets, and fibrinaloidmicroclots. These abnormalities of blood vessels and coagulation affect every organ system and represent a unifying pathway for the various symptoms of Long COVID.
Joel Selvakumar et al.
Prevalence and Characteristics Associated With Post–COVID-19 Condition Among Nonhospitalized Adolescents and Young Adults
JAMA, March 2023; doi:10.1001/jamanetworkopen.2023.5763
Abstract
Importance The prevalence and baseline risk factors of post–COVID-19 condition (PCC) remain unresolved among the large number of young people who experienced mild COVID-19.
Objectives To determine the point prevalence of PCC 6 months after the acute infection, to determine the risk of development of PCC adjusted for possible confounders, and to explore a broad range of potential risk factors.
Design, Setting, and Participants This cohort study included nonhospitalized individuals from 2 counties in Norway between ages 12 and 25 years who underwent reverse transcription–polymerase chain reaction (RT-PCR) testing. At the early convalescent stage and at 6-month follow-up, participants underwent a clinical examination; pulmonary, cardiac, and cognitive functional testing; immunological and organ injury biomarker analyses; and completion of a questionnaire. Participants were classified according to the World Health Organization case definition of PCC at follow-up. Association analyses of 78 potential risk factors were performed.
Exposures SARS-CoV-2 infection.
Main Outcomes and Measures The point prevalence of PCC 6 months after RT-PCR testing in the SARS-CoV-2–positive and SARS-CoV-2–negative groups, and the risk difference with corresponding 95% CIs.
Results A total of 404 individuals testing positive for SARS-CoV-2 and 105 individuals testing negative were enrolled (194 male [38.1%]; 102 non-European [20.0%] ethnicity). A total of 22 of the SARS-CoV-2–positive and 4 of the SARS-CoV-2–negative individuals were lost to follow-up, and 16 SARS-CoV-2–negative individuals were excluded due to SARS-CoV-2 infection in the observational period. Hence, 382 SARS-CoV-2–positive participants (mean [SD] age, 18.0 [3.7] years; 152 male [39.8%]) and 85 SARS-CoV-2–negative participants (mean [SD] age, 17.7 [3.2] years; 31 male [36.5%]) could be evaluated. The point prevalence of PCC at 6 months was 48.5% in the SARS-CoV-2–positive group and 47.1% in the control group (risk difference, 1.5%; 95% CI, −10.2% to 13.1%). SARS-CoV-2 positivity was not associated with the development of PCC (relative risk [RR], 1.06; 95% CI, 0.83 to 1.37; final multivariable model utilizing modified Poisson regression). The main risk factor for PCC was symptom severity at baseline (RR, 1.41; 95% CI, 1.27-1.56). Low physical activity (RR, 0.96; 95% CI, 0.92-1.00) and loneliness (RR, 1.01; 95% CI, 1.00-1.02) were also associated, while biological markers were not. Symptom severity correlated with personality traits.
Conclusions and Relevance The persistent symptoms and disability that characterize PCC are associated with factors other than SARS-CoV-2 infection, including psychosocial factors. This finding raises questions about the utility of the World Health Organization case definition and has implications for the planning of health care services as well as for further research on PCC.
André Santa Cruz et al.
Post-acute sequelae of COVID-19 is characterized by diminished peripheral CD8+β7 integrin+ T cells and anti-SARS-CoV-2 IgA response
Nature, March 2023; doi.org/10.1038/s41467-023-37368-1
Abstract
Several millions of individuals are estimated to develop post-acute sequelae SARS-CoV-2 condition (PASC) that persists for months after infection. Here we evaluate the immune response in convalescent individuals with PASC compared to convalescent asymptomatic and uninfected participants, six months following their COVID-19 diagnosis. Both convalescent asymptomatic and PASC cases are characterised by higher CD8+ T cell percentages, however, the proportion of blood CD8+ T cells expressing the mucosal homing receptor β7 is low in PASC patients. CD8 T cells show increased expression of PD-1, perforin and granzyme B in PASC, and the plasma levels of type I and type III (mucosal) interferons are elevated. The humoral response is characterized by higher levels of IgA against the N and S viral proteins, particularly in those individuals who had severe acute disease. Our results also show that consistently elevated levels of IL-6, IL-8/CXCL8 and IP-10/CXCL10 during acute disease increase the risk to develop PASC. In summary, our study indicates that PASC is defined by persisting immunological dysfunction as late as six months following SARS-CoV-2 infection, including alterations in mucosal immune parameters, redistribution of mucosal CD8+β7Integrin+ T cells and IgA, indicative of potential viral persistence and mucosal involvement in the etiopathology of PASC.
YanXie et al.
Association of Treatment With Nirmatrelvir and the Risk of Post–COVID-19 Condition
JAMA, March 2023; doi:10.1001/jamainternmed.2023.0743
Abstract
Importance Post–COVID-19 condition (PCC), also known as long COVID, affects many individuals. Prevention of PCC is an urgent public health priority.
Objective To examine whether treatment with nirmatrelvir in the acute phase of COVID-19 is associated with reduced risk of PCC.
Design, Setting, and Participants This cohort study used the health care databases of the US Department of Veterans Affairs (VA) to identify patients who had a SARS-CoV-2 positive test result between January 3, 2022, and December 31, 2022, who were not hospitalized on the day of the positive test result, who had at least 1 risk factor for progression to severe COVID-19 illness, and who had survived the first 30 days after SARS-CoV-2 diagnosis. Those who were treated with oral nirmatrelvir within 5 days after the positive test (n = 35 717) and those who received no COVID-19 antiviral or antibody treatment during the acute phase of SARS-CoV-2 infection (control group, n = 246 076) were identified.
Exposures Treatment with nirmatrelvir or receipt of no COVID-19 antiviral or antibody treatment based on prescription records.
Main Outcomes and Measures Inverse probability weighted survival models were used to estimate the association of nirmatrelvir (vs control) with post–acute death, post–acute hospitalization, and a prespecified panel of 13 post–acute COVID-19 sequelae (components of PCC) and reported in relative scale as relative risk (RR) or hazard ratio (HR) and in absolute scale as absolute risk reduction in percentage at 180 days (ARR).
Conclusions and Relevance This cohort study found that in people with SARS-CoV-2 infection who had at least 1 risk factor for progression to severe disease, treatment with nirmatrelvir within 5 days of a positive SARS-CoV-2 test result was associated with reduced risk of PCC across the risk spectrum in this cohort and regardless of vaccination status and history of prior infection; the totality of findings suggests that treatment with nirmatrelvir during the acute phase of COVID-19 may reduce the risk of post–acute adverse health outcomes.
VasilikiTsampasian et al.
Risk Factors Associated With Post−COVID-19 Condition - A Systematic Review and Meta-analysis
JAMA, March 2023; doi:10.1001/jamainternmed.2023.0750
Abstract
Importance Post−COVID-19 condition (PCC) is a complex heterogeneous disorder that has affected the lives of millions of people globally. Identification of potential risk factors to better understand who is at risk of developing PCC is important because it would allow for early and appropriate clinical support.
Objective To evaluate the demographic characteristics and comorbidities that have been found to be associated with an increased risk of developing PCC.
Data sources Medline and Embase databases were systematically searched from inception to December 5, 2022.
Study Selection The meta-analysis included all published studies that investigated the risk factors and/or predictors of PCC in adult (≥18 years) patients.
Data Extraction and Synthesis Odds ratios (ORs) for each risk factor were pooled from the selected studies. For each potential risk factor, the random-effects model was used to compare the risk of developing PCC between individuals with and without the risk factor. Data analyses were performed from December 5, 2022, to February 10, 2023.
Main Outcomes and Measures The risk factors for PCC included patient age; sex; body mass index, calculated as weight in kilograms divided by height in meters squared; smoking status; comorbidities, including anxiety and/or depression, asthma, chronic kidney disease, chronic obstructive pulmonary disease, diabetes, immunosuppression, and ischemic heart disease; previous hospitalization or ICU (intensive care unit) admission with COVID-19; and previous vaccination against COVID-19.
Conclusions and Relevance This systematic review and meta-analysis demonstrated that certain demographic characteristics (eg, age and sex), comorbidities, and severe COVID-19 were associated with an increased risk of PCC, whereas vaccination had a protective role against developing PCC sequelae. These findings may enable a better understanding of who may develop PCC and provide additional evidence for the benefits of vaccination.
Christian R Kahlert et al.
Post-acute sequelae after SARS-CoV-2 infection by viral variant and vaccination status: a multicenter cross-sectional study
CID, March 2023; doi.org/10.1093/cid/ciad143
Abstract
Background
Disentangling the effects of SARS-CoV-2 variants and vaccination on the occurrence of post-acute sequelae of SARS-CoV-2 (PASC) is crucial to estimate and reduce the burden of PASC.
Conclusions
Previous infection with pre-Omicron variants was the strongest risk factor for PASC symptoms among our HCW. Vaccination prior to Omicron BA.1 infection was not associated with a clear protective effect against PASC symptoms in this population.
Evan Xu et al.
Long-term gastrointestinal outcomes of COVID-19
Nature, March 2023; doi.org/10.1038/s41467-023-36223-7
Abstract
A comprehensive evaluation of the risks and 1-year burdens of gastrointestinal disorders in the post-acute phase of COVID-19 is needed but is not yet available. Here we use the US Department of Veterans Affairs national health care databases to build a cohort of 154,068 people with COVID-19, 5,638,795 contemporary controls, and 5,859,621 historical controls to estimate the risks and 1-year burdens of a set of pre-specified incident gastrointestinal outcomes. We show that beyond the first 30 days of infection, people with COVID-19 exhibited increased risks and 1-year burdens of incident gastrointestinal disorders spanning several disease categories including motility disorders, acid related disorders (dyspepsia, gastroesophageal reflux disease, peptic ulcer disease), functional intestinal disorders, acute pancreatitis, hepatic and biliary disease. The risks were evident in people who were not hospitalized during the acute phase of COVID-19 and increased in a graded fashion across the severity spectrum of the acute phase of COVID-19 (non-hospitalized, hospitalized, and admitted to intensive care). The risks were consistent in comparisons including the COVID-19 vs the contemporary control group and COVID-19 vs the historical control group as the referent category. Altogether, our results show that people with SARS-CoV-2 infection are at increased risk of gastrointestinal disorders in the post-acute phase of COVID-19. Post-covid care should involve attention to gastrointestinal health and disease.
Ian C. Fischer et al.
Characterization of Mental Health in US Veterans Before, During, and 2 Years After the Onset of the COVID-19 Pandemic
JAMA, February 2023; doi:10.1001/jamanetworkopen.2023.0463
https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2801746
Abstract
Introduction
A considerable minority of US adults (approximately 13%)1,2 experienced significant increases in distress2 during the height of the COVID-19 pandemic. It is not clear whether these increases portend exacerbated or persistent courses of distress, and what risk or protective factors are associated with these courses.
In this study, we build upon our previous study of US military veterans,2 which characterized the prevalence of distress (ie, positive screens for major depressive disorder [MDD], generalized anxiety disorder [GAD], or posttraumatic stress disorder [PTSD]) before and 1 year into the COVID-19 pandemic by analyzing 2 additional years of longitudinal data, and identifying factors associated with exacerbated and persistent courses of distress.
Discussion
This nationally representative longitudinal study of US veterans revealed that, 1 year into the COVID-19 pandemic, the prevalence of positive screens for distress increased by 51%, with younger and female veterans demonstrating the highest increases, possibly due to unique pandemic-related stressors (eg, school closures; work and relationship disruptions).3 Nevertheless, 2 years later, distress prevalence returned to prepandemic levels, which aligns with prior work suggesting resilience is the modal response to stressful events.4
Despite this overall pattern of resilience, a significant minority of veterans had exacerbated (2.5%; approximately 450 000 based on US veteran population benchmarks) or persistent (5.0%; approximately 900 000) courses of distress. Veterans with exacerbated distress 2 years into the pandemic reported greater prepandemic alcohol use problems, greater likelihood of lifetime MDD or PTSD, and lower emotional stability. Possible mechanisms underlying these findings include alcohol-related neuroinflammatory or metabolic changes5 and higher levels of stress sensitization.6
Pandemic-related socioeconomic concerns were significantly associated with persistent distress. Younger age, lower community integration, and higher pandemic-related social restriction stress were also associated with this outcome. These findings underscore the importance of assessment, treatment, and policy strategies that target the economic and social needs of veterans with these risk factors.
Limitations of the current study included reliance on self-report and screening measures. Further research is needed to replicate these findings in other samples, identify factors associated with continued distress over time, and evaluate interventions and policies to mitigate distress in veterans at risk for persistent pandemic-related distress.
Carl Wahlgren et al.
Two-year follow-up of patients with post-COVID-19 condition in Sweden: a prospective cohort study
The Lancet, February 2023; doi.org/10.1016/j.lanepe.2023.100595
Abstract
Background
Few studies have reported the long-term health effects of COVID-19. The regional population-based Linköping COVID-19 study (LinCoS) included all patients hospitalised due to COVID-19 during the first pandemic wave. Four months post-discharge, over 40% (185/433) experienced persisting symptoms and activity/participation limitations, indicating post-COVID-19 condition (PCC). The present follow-up study aimed to determine the long-term recovery among these patients 24 months post-admission.
Methods
This prospective cohort study included all patients from LinCoS with PCC at four months post-discharge. We repeated the same structured interview at a 24-month follow-up to identify persisting symptoms and their impact on daily life. Intercurrent health issues were identified by reviewing medical records.
Findings
Of 185 patients with PCC at 4 months post-discharge, 181 were alive at the 24-month assessment and 165 agreed to participate. Of those, 21% (35/165) had been readmitted to hospital for various causes in the interim period. The majority of patients (139/165, 84%) reported persisting problems affecting everyday life at 24 months. Significant improvements were seen in the prevalence and magnitude of some symptoms/limitations compared with four months post-discharge. Cognitive, sensorimotor, and fatigue symptoms were the most common persisting symptoms at 24 months. No clear difference was evident between individuals treated in the intensive care unit (ICU) and non-ICU-treated individuals. Approximately half of those who were on sick leave related to PCC at four months after infection were on sick leave at 24 months.
Interpretation
This is one of the first studies to report 2-year outcomes in patients with PCC following COVID-19 hospitalisation. Despite some improvements over time, we found a high prevalence of persisting symptoms and a need for long-term follow-up and rehabilitation post COVID-19 infection.
Iwasaki A., Putrino D.
Why we need a deeper understanding of the pathophysiology of long COVID
The Lancet, February 2023; doi.org/10.1016/S1473-3099(23)00053-1
Abstract
The most recent estimate of people living with post-COVID-19 condition (also known as long COVID) globally has surpassed 65 million1 and, without clear diagnostic or treatment options available, this number is steadily increasing. There are more than 200 reported symptoms associated with long COVID,1 affecting virtually every organ system.
Although some long haulers recover, many people have had symptoms since early 2020. The condition is a blanket diagnosis that represents a heterogeneous set of pathophysiological processes. As such, several factors can affect the presentation of long COVID, such as the severity of acute infection, age, sex, pre-existing comorbidities, genetics, socioeconomic factors, and other environmental factors. Long haulers who survived severe acute SARS-CoV-2 infection are most likely to be men older than 50 years with lingering tissue damage and scarring. People with long COVID after a less-severe infection are most likely to be younger women (aged 36–50 years) whose acute infection has triggered adverse physiological responses.
The main disease hypotheses for the root causes of long COVID include viral persistence (infectious virus, viral RNA, or viral proteins), autoimmunity triggered by the infection, reactivation of latent viruses, and inflammation-triggered chronic changes leading to tissue dysfunction and damage
There is growing and compelling evidence that SARS-CoV-2 infects and produces its RNA and proteins in a wide range of cell types in tissues, including the gastrointestinal, respiratory, cardiovascular, lymphoid, endocrine, urogenital, ocular, skin, muscular, and peripheral nervous system and CNS tissues.2 Circulating spike proteins are observed in 60% of patients with long COVID between 2 and 12 months after infection.3 Although the presence of viral RNA and proteins do not necessarily indicate persistent infection, viral RNA can trigger innate immune responses and viral proteins might cause tissue damage and stimulate persistent activation of lymphocytes, which lead to chronic inflammation.
In people with long COVID, assessment of autoantibodies to human exoproteome using rapid extracellular antigen profiling revealed no significant differences from people without long COVID.4 However, autoantibodies to intracellular antigens5 or autoreactive T cells might have a role in long COVID.
There is also emerging evidence for latent herpesviruses reactivation in people with long COVID. Reactivation of latent Epstein-Barr virus, but not the acute mononucleosis infection, is found in people with long COVID,4, 6 and Epstein-Barr virus viraemia at the time of acute COVID is predictive for long COVID.5
Local inflammatory response to SARS-CoV-2 in one organ can cause lasting alterations in distant tissues and organs. In a mouse model, even mild lung-restricted COVID-19 (in which the infectious virus became undetectable within a week) was found to induce prolonged changes in the CNS, including microglial activation, oligodendrocyte loss, and reduced myelination, for up to 7 weeks after infection.7
Beyond these potential root causes, many secondary pathological changes have been observed in people with long COVID, including the formation of micro-clots and platelet activation,8 reduced cortisol,4, 5 and mitochondrial dysfunction.9
Despite the multifactorial pathogenesis, available data show that long COVID is an organic post-acute infection syndrome (PAIS) with clear physiological dysfunction that is often not consistently apparent using standard medical diagnostic tests. This discrepancy highlights the need for a new generation of more sensitive testing procedures for people with PAIS. Although it is not known whether pre-existing psychological diagnoses might influence the risk of long COVID (eg, by affecting the host endocrine and immune systems), it is neither productive nor clinically or scientifically valid to classify long COVID as a psychosomatic condition.
As avoiding COVID-19 becomes increasingly difficult, we argue that deep biological analyses will identify biomarkers for long COVID and possibly identify distinct endotypes driven by different root causes so that the risk of contracting long COVID is better defined. Biomarker identification will not only be crucial for identifying predisposing factors but also allow us to implement safer, evidence-based policies. Similarly, molecular, cellular, and physiological analyses will inform precision interventions that target the root causes of each long COVID endotype. For example, persistent viral infection could be targeted by antivirals; long COVID driven by autoimmune disease could be treated using monoclonal antibodies that target lymphocytes or drugs that block cytokines and cytokine signalling; and, if the reactivation of herpesviruses contributes to disease, targeting such viruses using antivirals or vaccines could be considered. Diagnostic criteria considering the root causes to prevent and treat long COVID will require large longitudinal studies. If therapeutic targeting of root causes is not feasible, the downstream pathological changes of long COVID could still be treated.
Ideally, potential therapies should be assessed in double-blinded, placebo-controlled, randomised clinical trials. However, such studies are quite costly, are labour intensive, and require substantial government, regulatory, and industry support.
Syndromes like Long COVID are not new. Other PAISs, such as myalgic encephalomyelitis and chronic fatigue syndrome and post-treatment Lyme disease syndrome, have overlapping symptoms with long COVID.10 Thus, the inclusion of individuals with other forms of PAIS as comparison groups in long COVID research is important for broadening overall understanding and widening the impact of this research. Finally, the current knowledge surrounding long COVID would not be possible without the hard work and dedication of patient-led communities striving for answers.
Wang S. et al.
Adherence to Healthy Lifestyle Prior to Infection and Risk of Post–COVID-19 Condition
JAMA, February 2023, doi:10.1001/jamainternmed.2022.6555
Abstract
Importance Few modifiable risk factors for post–COVID-19 condition (PCC) have been identified.
Objective To investigate the association between healthy lifestyle factors prior to SARS-CoV-2 infection and risk of PCC.
Design, Setting, and Participants In this prospective cohort study, 32 249 women in the Nurses’ Health Study II cohort reported preinfection lifestyle habits in 2015 and 2017. Healthy lifestyle factors included healthy body mass index (BMI, 18.5-24.9; calculated as weight in kilograms divided by height in meters squared), never smoking, at least 150 minutes per week of moderate to vigorous physical activity, moderate alcohol intake (5 to 15 g/d), high diet quality (upper 40% of Alternate Healthy Eating Index–2010 score), and adequate sleep (7 to 9 h/d).
Main Outcomes and Measures SARS-CoV-2 infection (confirmed by test) and PCC (at least 4 weeks of symptoms) were self-reported on 7 periodic surveys administered from April 2020 to November 2021. Among participants with SARS-CoV-2 infection, the relative risk (RR) of PCC in association with the number of healthy lifestyle factors (0 to 6) was estimated using Poisson regression and adjusting for demographic factors and comorbidities.
Results A total of 1981 women with a positive SARS-CoV-2 test over 19 months of follow-up were documented. Among those participants, mean age was 64.7 years (SD, 4.6; range, 55-75); 97.4% (n = 1929) were White; and 42.8% (n = 848) were active health care workers. Among these, 871 (44.0%) developed PCC. Healthy lifestyle was associated with lower risk of PCC in a dose-dependent manner. Compared with women without any healthy lifestyle factors, those with 5 to 6 had 49% lower risk (RR, 0.51; 95% CI, 0.33-0.78) of PCC. In a model mutually adjusted for all lifestyle factors, BMI and sleep were independently associated with risk of PCC (BMI, 18.5-24.9 vs others, RR, 0.85; 95% CI, 0.73-1.00, P = .046; sleep, 7-9 h/d vs others, RR, 0.83; 95% CI, 0.72-0.95, P = .008). If these associations were causal, 36.0% of PCC cases would have been prevented if all participants had 5 to 6 healthy lifestyle factors (population attributable risk percentage, 36.0%; 95% CI, 14.1%-52.7%). Results were comparable when PCC was defined as symptoms of at least 2-month duration or having ongoing symptoms at the time of PCC assessment.
Conclusions and Relevance In this prospective cohort study, pre-infection healthy lifestyle was associated with a substantially lower risk of PCC. Future research should investigate whether lifestyle interventions may reduce risk of developing PCC or mitigate symptoms among individuals with PCC or possibly other postinfection syndromes.
Ferrucci R. et al.
Brain positron emission tomography (PET) and cognitive abnormalities one year after COVID-19
Springerlink, January 2023; doi.org/10.1007/s00415-022-11543-8
Abstract
Emerging evidence indicates that the etiologic agent responsible for coronavirus disease 2019 (COVID-19), can cause neurological complications. COVID-19 may induce cognitive impairment through multiple mechanisms. The aim of the present study was to describe the possible neuropsychological and metabolic neuroimaging consequences of COVID-19 12 months after patients’ hospital discharge. We retrospectively recruited 7 patients (age [mean ± SD] = 56 years ± 12.39, 4 men) who had been hospitalized for COVID-19 with persistent neuropsychological deficits 12 months after hospital discharge. All patients underwent cognitive assessment and brain (18F-FDG) PET/CT, and one also underwent 18F-amyloid PET/CT. Of the seven patients studied, four had normal glucose metabolism in the brain. Three patients showed various brain hypometabolism patterns: (1) unilateral left temporal mesial area hypometabolism; (2) pontine involvement; and (3) bilateral prefrontal area abnormalities with asymmetric parietal impairment. The patient who showed the most widespread glucose hypometabolism in the brain underwent an 18F-amyloid PET/CT to assess the presence of Aβ plaques. This examination showed significant Aβ deposition in the superior and middle frontal cortex, and in the posterior cingulate cortex extending mildly in the rostral and caudal anterior cingulate areas. Although some other reports have already suggested that brain hypometabolism may be associated with cognitive impairment at shorter intervals from SarsCov-2 infection, our study is the first to assess cognitive functions, brain metabolic activity and in a patient also amyloid PET one year after COVID-19, demonstrating that cerebral effects of COVID-19 can largely outlast the acute phase of the disease and even be followed by amyloid deposition.
Richard S.A. et al.
Persistent COVID-19 Symptoms at 6 Months After Onset and the Role of Vaccination Before or After SARS-CoV-2 Infection
JAMA, doi:10.1001/jamanetworkopen.2022.51360
https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2800554
Abstract
Importance Understanding the factors associated with post-COVID conditions is important for prevention.
Objective To identify characteristics associated with persistent post–COVID-19 symptoms and to describe post–COVID-19 medical encounters.
Design, Setting, and Participants This cohort study used data from the Epidemiology, Immunology, and Clinical Characteristics of Emerging Infectious Diseases With Pandemic Potential (EPICC) study implemented in the US military health system (MHS); MHS beneficiaries aged 18 years or older who tested positive for SARS-CoV-2 from February 28, 2020, through December 31, 2021, were analyzed, with 1-year follow-up.
Exposures SARS-CoV-2 infection.
Main Outcomes and Measures The outcomes analyzed included survey-reported symptoms through 6 months after SARS-CoV-2 infection and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision diagnosis categories reported in medical records 6 months following SARS-CoV-2 infection vs 3 months before infection.
1.40-2.84), diabetes (RR, 1.46; 95% CI, 1.00-2.13), neurological (RR, 1.29; 95% CI, 1.02-1.64), and mental health–related medical encounters (RR, 1.28; 95% CI, 1.01-1.62) at 6 months after symptom onset than at baseline (before SARS-CoV-2 infection).
Conclusions and Relevance In this cohort study, more severe acute illness, a higher Charlson Comorbidity Index score, and being unvaccinated were associated with a higher risk of reporting COVID-19 symptoms lasting 28 days or more. Participants with COVID-19 were more likely to seek medical care for diabetes, pulmonary, neurological, and mental health–related illness for at least 6 months after onset compared with their pre-COVID baseline health care use patterns. These findings may inform the risk-benefit ratio of COVID-19 vaccination policy.
Evan Xu et al.
Risks and burdens of incident dyslipidaemia in long COVID: a cohort study
The Lancet, January 2023; doi.org/10.1016/S2213-8587(22)00355-2
Abstract
Background
Non-clinical evidence and a few human studies with short follow-ups suggest increased risk of dyslipidaemia in the post-acute phase of COVID-19 (ie, >30 days after SARS-CoV-2 infection). However, detailed large-scale controlled studies with longer follow-ups and in-depth assessment of the risks and burdens of incident dyslipidaemia in the post-acute phase of COVID-19 are not yet available. We, therefore, aimed to examine the risks and 1-year burdens of incident dyslipidaemia in the post-acute phase of COVID-19 among people who survive the first 30 days of SARS-CoV-2 infection.
Methods
In this cohort study, we used the national health-care databases of the US Department of Veterans Affairs to build a cohort of 51 919 participants who had a positive COVID-19 test and survived the first 30 days of infection between March 1, 2020, and Jan 15, 2021; a non-infected contemporary control group (n=2 647 654) that enrolled patients between March 1, 2020, and Jan 15, 2021; and a historical control group (n=2 539 941) that enrolled patients between March 1, 2018, and Jan 15, 2019. Control groups had no evidence of SARS-CoV-2 infection, and participants in all three cohorts were free of dyslipidaemia before cohort enrolment.
Our findings suggest increased risks and 1-year burdens of incident dyslipidaemia and incident lipid-lowering medications use in the post-acute phase of COVID-19 infection. Post-acute care for those with COVID-19 should involve attention to dyslipidaemia as a potential post-acute sequela of SARS-CoV-2 infection.
Yonker L.M. et al.
Circulating Spike Protein Detected in Post–COVID-19 mRNA Vaccine Myocarditis
AHA Journals, January 2023; doi/10.1161/CIRCULATIONAHA.122.061025
Abstract
BACKGROUND:
Cases of adolescents and young adults developing myocarditis after vaccination with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–targeted mRNA vaccines have been reported globally, but the underlying immunoprofiles of these individuals have not been described in detail.
CONCLUSIONS:
Immunoprofiling of vaccinated adolescents and young adults revealed that the mRNA vaccine–induced immune responses did not differ between individuals who developed myocarditis and individuals who did not. However, free spike antigen was detected in the blood of adolescents and young adults who developed post-mRNA vaccine myocarditis, advancing insight into its potential underlying cause.
Dumont R. et al.
A population-based serological study of post-COVID syndrome prevalence and risk factors in children and adolescents
Nature, November 2022; doi.org/10.1038/s41467-022-34616-8
Abstract
Post-COVID syndrome remains poorly studied in children and adolescents. Here, we aimed to investigate the prevalence and risk factors of pediatric post-COVID in a population-based sample, stratifying by serological status. Children from the SEROCoV-KIDS cohort study (State of Geneva, Switzerland), aged 6 months to 17 years, were tested for anti-SARS-CoV-2 N antibodies (December 2021-February 2022) and parents filled in a questionnaire on persistent symptoms in their children
(lasting over 12 weeks) compatible with post-COVID. Of 1034 children tested, 570 (55.1%) were seropositive. The sex- and age-adjusted prevalence of persistent symptoms among seropositive children was 9.1% (95%CI: 6.7;11.8) and 5.0% (95%CI: 3.0;7.1) among seronegatives, with an adjusted prevalence difference (ΔaPrev) of 4.1% (95%CI: 1.1;7.3). Stratifying per age group, only adolescents displayed a substantial risk of having post-COVID symptoms (ΔaPrev = 8.3%, 95%CI: 3.5;13.5). Identified risk factors for post-COVID syndrome were older age, having a lower socioeconomic status and suffering from chronic health conditions, especially asthma. Our findings show that a significant proportion of seropositive children, particularly adolescents, experienced persistent COVID symptoms. While there is a need for further investigations, growing evidence of pediatric post-COVID urges early screening and primary care management.
Buone pratiche cliniche per la gestione e presa in carico delle persone con long-COVID
https://snlg.iss.it/wp-content/uploads/2022/11/BuonePraticheLongCovid.pdf
Ahmad F.B et al.
Identification of Deaths With Post-acute Sequelae of COVID-19 From Death Certificate Literal Text: United States, January 1, 2020–June 30, 2022
CDC, December 2022; doi.org/10.15620/cdc:121968
Abstract
Objectives—This study describes the use of death certificate literal text to identify and quantify COVID-19 deaths with post-acute sequelae of COVID-19 (PASC), or long COVID, in the National Vital Statistics System (NVSS). Methods—Data are based on final and provisional NVSS death certificate data for deaths occurring in the United States during January 1, 2020– June 30, 2022. Deaths were limited to those with the International Classification of Diseases, 10th Revision (ICD–10) cause-of-death code U07.1 and literal text with keywords referring to PASC or long COVID. Data are based on death records received and processed by the National Center for Health Statistics as of October 7, 2022. The long COVID death rate from July 1, 2021, through June 30, 2022, was highest among adults aged 85 and over, non-Hispanic American Indian or Alaska Native people, and males. Non-Hispanic Asian people had the lowest death rate.
Magnusson K et al.
Post-covid medical complaints following infection with SARS-CoV-2 Omicron vs Delta variants
Nature, November 2022; doi.org/10.1038/s41467-022-35240-2
Abstract
The SARS-CoV-2 Omicron (B.1.1.529) variant has been associated with less severe acute disease, however, concerns remain as to whether long-term complaints persist to a similar extent as for earlier variants
Our findings suggest that the acute and sub-acute burden of post-covid complaints on health services is similar for Omicron and Delta. The chronic burden may be lower for Omicron vs Delta when considering musculoskeletal pain, but not when considering other typical post-covid complaints.
Padovani A., Pilotto A.
Looking for lights in the fog of long-term neurological COVID
Nature, November 2022; doi.org/10.1038/s41582-022-00750-6
Abstract
A new study provides evidence for an association between COVID-19 and long-term neurological syndromes. The findings highlight the need for further research into the long-term neurological consequences of SARS-CoV-2 infection and the development of strategies that lessen the effects of these consequences on patient quality of life and on healthcare systems.
A large body of literature has reported a higher rate of neurological syndromes during acute COVID-19 than in healthy individuals. However, whether SARS-CoV-2 infection leads to a higher risk of long-term neurological consequences is still unclear. A wide spectrum of symptoms, including impaired concentration, headache, hyposmia, fatigue and myalgias, can persist for months after infection as part of a constellation now referred to as long COVID. The neurological syndromes that make up long COVID vary widely among individuals, and the relationship between these symptoms and SARS-CoV-2 infection is a matter of debate — it can be coincidental, consequential or interacting1. The existing data on long COVID are rather heterogeneous, probably as a result of differences among the study populations and diagnostic criteria used, a lack of standardized assessment and the high risk of recall bias, which applies to all studies of SARS-CoV-2. Furthermore, one study reported that long-term neurological symptoms might be more associated with the belief of having been infected with SARS-CoV-2 than with having laboratory-confirmed SARS-CoV-2 infection, thus limiting the interpretation of available data2. Nevertheless, neurological long COVID represents a substantial health and economic burden, which demonstrates an urgent need to disentangle the involvement of different neurological disorders by various mechanisms and to develop effective strategies for prevention and care.
Importantly, previous findings have reported that only 5–20% of individuals infected with SARS-CoV-2 have symptoms and only 5–20% of individuals with symptoms will require hospitalization. Age, premorbid health status and frailty have an important role in modulating the short and long-term outcomes of COVID-19. Several studies have shown that COVID-19-related symptoms and clinical course are more severe in individuals who are older and have multimorbidities than in younger, healthy adults4. This issue is crucial, as most data on long COVID are derived from hospitalized or symptomatic individuals, who are at higher risk of deterioration and long-term disease burden, but also present with worse premorbid health conditions than individuals with asymptomatic infection5. A large body of literature has shown that up to a third of individuals hospitalized with acute COVID-19 either experience worsening of premorbid neurological disturbances or present with new neurological complications during hospitalization. Furthermore, there is evidence that most individuals with long COVID either already had a premorbid neurological disease or are affected by the consequences of a COVID-19-related neurological disorder, such as stroke or encephalitis.
Interestingly, younger adults exhibited a higher COVID-19-related risk of memory and cognitive disorders, sensory disorders and other neurological disorders (including Guillain–Barré syndrome and encephalitis or encephalopathy), probably owing to a combination of immunological and psychological factors. Indeed, neuroimaging studies have reported that COVID-19 can affect brain health by triggering an abnormal inflammatory response, which has been claimed to be the main pathogenetic mechanism of both short-term and long-term symptoms of COVID-191,8,9. Several biological, psychological and social factors might also
weaken resilience to COVID-19 and contribute to the long-term burden of the disease (Fig. 1). Overcoming the challenge of the long-term consequences of COVID-19 therefore requires us to take into account the complexity of premorbid health status and severity of disease, to unravel the contributions of different conditions in order to identify possible avenues for the most appropriate care.
Kovarik J.J. et al.
A multi-omics based anti-inflammatory immune signature characterizes Long COVID Syndrome
CELL, December 2022; doi.org/10.1016/j.isci.2022.105717
Abstract
To investigate Long COVID Syndrome (LCS) pathophysiology, we performed an exploratory study with blood plasma derived from three groups: 1) healthy vaccinated individuals without SARS-CoV-2 exposure; 2) asymptomatic recovered patients at least three months after SARS-CoV-2 infection and; 3) symptomatic patients at least 3 months after SARS-CoV-2 infection with chronic fatigue syndrome or similar symptoms, here designated as Long COVID Syndrome (LCS) patients. Multiplex cytokine profiling indicated slightly elevated pro-inflammatory cytokine levels in recovered individuals in contrast to LCS patients.
Jeremy Werner Deuel et al.
Persistence, prevalence, and polymorphism of sequelae after COVID-19 in unvaccinated, young
adults of the Swiss Armed Forces: a longitudinal, cohort study (LoCoMo)
The Lancet, August 2022; doi.org/10.1016/S1473-3099(22)00449-2
Abstract
Persistent COVID-19 sequelae could have global, public health ramifications. We therefore aimed to describe sequelae presenting more than 180 days after COVID-19—focussing on several organ systems, general health, and laboratory parameters—in non-hospitalised, unvaccinated, young adults. Young, previously healthy, individuals largely recover from SARS-CoV-2 infection. However, the constellation of higher BMI, dyslipidaemia, and lower physical endurance 180 days after COVID-19 is suggestive of a higher risk of developing metabolic disorders and possible cardiovascular complications. These findings will guide future investigations and follow-up management.
Margalit I. et al.
Risk Factors and Multidimensional Assessment of Long Coronavirus Disease Fatigue: A Nested CaseControl Study
CID, November 2022; doi.org/10.1093/cid/ciac283
Abstract
Background: Fatigue is the most prevalent and debilitating long-COVID (coronavirus disease) symptom; however, risk factors and pathophysiology of this condition remain unknown. We assessed risk factors for long-COVID fatigue and explored its possible pathophysiology. Methods: This was a nested case-control study in a COVID recovery clinic. Individuals with (cases) and without (controls) significant fatigue were included. We performed a multidimensional assessment evaluating various parameters, including pulmonary function tests and cardiopulmonary exercise testing, and implemented multivariable logistic regression to assess risk factors for significant long-COVID fatigue. Results: A total of 141 individuals were included. The mean age was 47 (SD: 13) years; 115 (82%) were recovering from mild coronavirus disease 2019 (COVID-19). Mean time for evaluation was 8 months following COVID-19. Sixty-six (47%) individuals were classified with significant long-COVID fatigue. They had a significantly higher number of children, lower proportion of hypothyroidism, higher proportion of sore throat during acute illness, higher proportions of long-COVID symptoms, and of physical limitation in daily activities. Individuals with long-COVID fatigue also had poorer sleep quality and higher degree of depression. They had significantly lower heart rate [153.52 (22.64) vs 163.52 (18.53); P = .038] and oxygen consumption per kilogram [27.69 (7.52) vs 30.71 (7.52); P = .036] at peak exercise. The 2 independent risk factors for fatigue identified in multivariable analysis were peak exercise heart rate (OR: .79 per 10 beats/minute; 95% CI: .65-.96; P = .019) and longCOVID memory impairment (OR: 3.76; 95% CI: 1.57-9.01; P = .003). Conclusions: Long-COVID fatigue may be related to autonomic dysfunction, impaired cognition, and decreased mood. This may suggest a limbic-vagal pathophysiology.
Venkataramani V., Winkler F.
Cognitive Deficits in Long Covid-19
NEJM, November 2022; DOI:10.1056/NEJMcibr2210069
Abstract
Some patients who have recovered from an infection have reported transient or even lasting cognitive dysfunction. This includes patients who have been infected with SARS-CoV-2, many of whom, including those with mild disease, have reported deficits in attention, executive functioning, language, processing speed, and memory — symptoms collectively referred to as “brain fog.” Together with increased incidence of anxiety, depression, sleep disorder, and fatigue, this syndrome of cognitive impairment contributes substantially to the morbidity of post–Covid-19 conditions (also called “long Covid”). Nevertheless, Covid-related brain fog is difficult to diagnose and to separate from other reasons for the symptoms in an individual patient, because neurocognitive longitudinal data for patients are rarely available. (On a population level, however, cognitive decline after Covid has been documented.1) Physicians are generally reluctant to accept a condition as an organic disease without a pathobiologic concept or the ability to measure the disease in a given patient, as is the case with post-Covid brain fog. Results of a study recently reported by Fernández-Castañeda and colleagues may represent a pivot in our understanding of this sequela.2 Using a mouse model, the investigators explored how mild respiratory infections of SARS-CoV-2 could lead to neuroinflammation and subsequent brain damage through multilineage neural cell dysregulation (Figure 1). The investigators modeled mild respiratory Covid in a mouse expressing the viral-entry receptor for SARS-CoV-2 (angiotensin-converting enzyme 2 in humans) in the trachea and lung by delivering SARS-CoV-2 intranasally. They detected no SARS-CoV-2 in the brain but found signs of neuroinflammation in elevated levels of chemokines in cerebrospinal fluid and serum, each with a distinct time course. These changes led to activation of microglia in subcortical and hippocampal white-matter regions (but not in gray matter), with distinct effects on specific neural cell populations. Of note, these findings were supported by similar results in a small group of patients who were found to have SARS-CoV-2 infection and no severe lung damage at the time of death. Microglia are resident macrophage cells in the central nervous system. Although they contribute to the homeostasis of the central nervous system and refinement of neuronal networks by removing dendritic spines and synapses during the development of neurons, microglia can transition to an activated, neurotoxic state, as seen in this mouse model. In the subcortical white matter, microglial activation was associated with loss of both oligodendrocyte precursors and mature oligodendrocytes; consistent with this loss, there was also loss of myelin and myelinated axons for at least 7 weeks after the infection began. Myelin insulates axons and is critical to the speed of electrical conduction along neurons and to axonal metabolism. The loss of myelinated axons impairs the structure and function of neuronal networks. In the hippocampus, the activation of microglia was associated with inhibited neurogenesis, which could explain impaired memory formation in patients. The activation of microglia appeared to be mediated by persistently elevated levels of a molecule called C-C motif chemokine 11 (CCL11). CCL11 has been associated with aging and with inhibition of neurogenesis.3 Systemic intraperitoneal injection of CCL11 into mice resulted in the activation of hippocampal microglia but not microglia in the subcortical white matter. Consistent with these findings, persons with long Covid and cognitive deficits had higher levels of serum CCL11 than those with long Covid who lacked cognitive symptoms. The patients, like the mice, had mild disease, and they were infected before the availability of vaccines, but their numbers were small (48 with cognitive deficits and 15 without them). The effect of CCL11 on microglial activation in the hippocampus and inhibition of neurogenesis warrants further exploration of the effects of chemokines and cytokines specific to brain circuits and potentially offers a framework to study, prevent, and treat the neurologic and psychiatric symptoms of long Covid. The findings of Fernández-Castañeda et al. also have pathobiologic parallels to the cognitive impairment syndromes that have occurred after cancer therapy4 and after H1N1 influenza infection. (The investigators also found a temporal correlation between elevated levels of chemokines and cytokines and impaired hippocampal neurogenesis after H1N1 infection in a mouse model.) Could these findings lead to a cure for Covid-related brain fog? Several drugs that target activated microglia have been tested in preclinical models of mechanistically similar syndromes of cognitive impairment. Pexidartinib, an inhibitor of the CSF1 receptor, has been approved by the Food and Drug Administration for the treatment of symptomatic tenosynovial giant-cell tumors and can deplete microglia. Certain nonsteroidal antiinflammatory agents and tetracyclines can inhibit microglia. Findings from the study by Fernández-Castañeda and colleagues support the testing of microglial modulators to treat Covid-related brain fog. Study of the targeting of upstream regulators of microglial activation like CCL11 could also be beneficial. The study also implicates CCL11 as a candidate biomarker. If this finding is validated through future study, levels of CCL11 in the plasma or cerebrospinal fluid could potentially identify patients with Covid-related cognitive impairment. Assays of CCL11 could also be used to study the effect of vaccinations against Covid on brain fog–related changes. However, because only small patient cohorts were studied and factors such as a patient’s sex and history of autoimmune disease may influence serum levels of CCL11, large cohort clinical studies are needed to exclude confounder variables and further substantiate CCL11 as a biomarker. Specificity may increase when other cytokine or chemokine profiles are included or with a narrower focus on CCL11 levels in the cerebrospinal fluid, since there is a substantial overlap of CCL11 serum levels in persons with brain fog and those without. The finding of axonal demyelination (or impaired myelination) in sections of mouse brain could inspire the development of new magnetic resonance imaging biomarkers for humans.1 It should be noted, however, that Fernández-Castañeda et al. used the earliest strain of SARS-CoV-2 (known as the original Wuhan-Hu-1 isolate or USA-WA1/2020); the relevance of their findings to brain fog associated with infection by other SARS-CoV-2 variants seems likely but uncertain. Moreover, as the authors themselves noted, the contribution of other cell types, such as astrocytes, to Covid-related brain fog may be substantive. Finally, there is the usual caveat that mice are not humans, so these findings warrant robust tests of replication in studies involving a larger number of patients. Although the findings of brain dysfunction and patterns of damage during and after Covid are worrisome, especially given the similarities with changes in human neurodegenerative diseases,5 translational studies such as the one reported by Fernández-Castañeda may point to paths toward accurate diagnoses and treatments.
O'Hare A.M. et al.
Complexity and Challenges of the Clinical Diagnosis and Management of Long COVID
JAMA, November 2022, doi:10.1001/jamanetworkopen.2022.40332
Abstract
Importance There is increasing recognition of the long-term health effects of SARS-CoV-2 infection (sometimes called long COVID). However, little is yet known about the clinical diagnosis and management of long COVID within health systems.
Objective To describe dominant themes pertaining to the clinical diagnosis and management of long COVID in the electronic health records (EHRs) of patients with a diagnostic code for this condition (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision [ICD-10] code U09.9).
In qualitative analysis of documentation pertaining to long COVID in patients’ EHRs 2 dominant themes were identified: (1) clinical uncertainty, in that it was often unclear whether particular symptoms could be attributed to long COVID, given the medical complexity and functional limitations of many patients and absence of specific markers for this condition, which could lead to ongoing monitoring, diagnostic testing, and specialist referral; and (2) care fragmentation, describing how post–COVID-19 care processes were often siloed from and poorly coordinated with other aspects of care and could be burdensome to patients.
Conclusions and Relevance This qualitative study of documentation in the VA EHR highlights the complexity of diagnosing long COVID in clinical settings and the challenges of caring for patients who have or are suspected of having this condition.
The Lancet Regional Health – Europa
Long COVID: An opportunity to focus on post-acute infection syndromes
Lancet, November 2022; doi.org/10.1016/j.lanepe.2022.100540
Abstract
Long COVID is known by different names, such as post-COVID-19 condition, post-COVID-19 syndrome, or post-COVID conditions, all of which include a wide range of persistent or new symptoms that develop after SARS-CoV-2 infection and last for typically more than 12 weeks to months and up to 2 years, so far. The most common symptoms can be broadly categorised into neurological symptoms (fatigue, brain fog, and headache), respiratory symptoms (chest pain and shortness of breath), and diverse symptoms (heart palpitations and muscle pain). These symptoms are often debilitating enough to leave patients unable to work and are similar to those of Myalgic encephalomyelitis/chronic fatigue syndrome, and those triggered after infections with Ebola virus, poliovirus, borrelia (Lyme Disease), and even SARS-CoV, which fall under the well-known concept of post-acute infection syndrome.
Post-acute infection syndromes have always been neglected, hindering the development of diagnostic or treatment tools. However, the recent amount of attention and resources allocated to long COVID could present the perfect opportunity for breakthroughs in the treatment of post-acute infection syndromes. At present, at least 17 million people have long COVID in the WHO European region, in addition to the unknown number of people with other post-acute infection syndromes. Thus, post-acute infection syndromes could pose a substantial public health burden in the near future if appropriate measures are not immediately taken to provide better diagnostic care, treatment, and clinical infrastructure. Therefore, governments and the medical and
scientific community must commit to funding and accelerating research to develop targeted and effective treatments for post-acute infection syndromes.
Considering that COVID-19 cases are predicted to increase in the coming winter months and vaccination against SARS-CoV-2 lowers the risk of long COVID after infection by only 15%, it is absolutely crucial that governments implement a public health strategy to provide care and support for people with long COVID. The WHO Regional Office for Europe has launched a COVID-19 containment strategy, which focuses on community surveillance, case detection, access to oral antivirals, vaccination roll-out, and mental health promotion. However, these efforts might not be sufficient to prevent new infections and hence new cases of long COVID. At present, the most effective way to prevent long COVID is to prevent SARS-CoV-2 infections by vaccination and non-pharmaceutical interventions.Çöie, wearing masks, avoiding crowded or closed places, and self-isolating at the first sign of infection.
The emergence of long COVID has reiterated the low importance attributed to post-acute infection syndromes by doctors and the scientific community and has also highlighted a considerable gap in scientific knowledge. Fortunately, the initial apathetic response to long COVID evolved remarkably quickly, with the allocation of large amounts of funding for research and the establishment of specialised long COVID clinics, which had not been seen before for other post-acute infection syndromes. This spotlight on long COVID stands as an opportunity to shed light on other known post-acute infection syndromes, but also to set an example for future infectious outbreaks.
Thompson E.J. et al.
Psychological distress, depression, anxiety, and life satisfaction following COVID-19 infection: evidence from 11 UK longitudinal population studies
Lancet, November 2022; doi.org/10.1016/S2215-0366(22)00307-8
Abstract
The authors aimed to examine whether COVID-19 is associated with deterioration in mental health while considering pre-pandemic mental health, time since infection, subgroup differences, and confirmation of infection via self-reported test and serology data.
WHO - World Health Organization
Post COVID-19 condition (Long Covid)
https://www.who.int/europe/news-room/fact-sheets/item/post-covid-19-condition
Abstract
Post COVID-19 condition, also known as long COVID, occurs in individuals with a history of probable or confirmed SARS-CoV-2 infection, usually 3 months from the onset of COVID-19. Symptoms last for at least 2 months and cannot be explained by an alternative diagnosis.
M. Monje& A. Iwasaki
The Neurobiology of Long COVID
Neuron, October 2022; doi.org/10.1016/j.neuron.2022.10.006
Abstract
A wide range of neurological and neuropsychiatricsymptoms are common features of acute COVID19 and post-acute COVID-19 syndrome (PACS) or long COVID. Understanding the mechanisticunderpinnings of long COVID may help to elucidate unifyingprinciples of nervous system pathobiologyshared with othersyndromes of neurological and neuropsychiatricdysfunctionthat can occur after infections and other immune challenges.
L. A. Malone et al.
Multi-disciplinary collaborative consensus guidancestatement on the assessment and treatment of postacutesequelae of SARS-CoV-2 infection (PASC) in children and adolescents
PM&R, September 2022; doi.org/10.1002/pmrj.12890
Abstract
Children infected with severe acute respiratorysyndrome coronavirus 2 (SARS-CoV-2) are generallyasymptomatic or have mild acute symptoms with low rates of hospitalization and death. Some childrendevelopotherpostacutemanifestations of COVID, includingmultisysteminflammatorysyndrome in children or postacutesequelae of SARS-CoV-2 infection. The latterpost-COVIDconditionmay be knownas long COVID, long-haul COVID, postacute COVID-19, long-termeffects of COVID, or chronic COVID. Some childrenmayhaveonly one or twosymptoms of PASC, whereasothersmayhavemultiple symptoms.Researchisongoing to betterunderstand the pathogenesisbehind PASC in bothchildren and adults and optimal treatment approaches.
J.J. Frere et al.
SARS-CoV-2 infection in hamsters and humans results in lasting and unique systemic perturbations after recovery.
Science Translational Medicine, September 2022; doi: 10.1126/scitranslmed.abq3059
Abstract
To better understand the mechanism underlying long COVID biology, the authors compared the short- and long-term systemic responses in the golden hamster after either SARS-CoV-2 or influenza A virus (IAV) infection.
C.J. Wild et al.
Disentangling the cognitive, physical, and mental health sequelae of COVID-19
Cell Reports Medicine, October 2022; doi.org/10.1016/j.xcrm.2022.100750
Abstract
As COVID-19 cases exceed hundreds of millions globally, many survivors face cognitive challenges and prolonged symptoms. In this cross-sectional online study, 478 adult volunteers who self-reported a positive test for COVID-19 (mean = 30 days since most recent test) perform significantly worse than pre-pandemic norms on cognitive measures of processing speed, reasoning, verbal, and overall performance, but not shortterm memory, suggesting domain-specific deficits. Cognitive differences are even observed in participants who did not require hospitalization. Factor analysis of health- and COVID-related questionnaires reveals two clusters of symptoms—one that varies mostly with physical symptoms and illness severity, and one with mental health. Cognitive performance is positively correlated with the global measure encompassing physical symptoms, but not the one that broadly describes mental health, suggesting that the subjective experience of ‘‘long COVID’’ relates to physical symptoms and cognitive deficits, especially executive dysfunction.
A.C. Mendes Paranhos et al.
Sociodemographic characteristics and comorbidities of patients with long covid and persistent olfactory dysfunction
JamaInfectiousDiseases, September2022;doi:10.1001/jamanetworkopen.2022.30637
Abstract
In this cross-sectional study of 219 patients with long COVID and neurologic symptoms, 64% had olfactory dysfunction, with the highest prevalence among women, adults, and outpatients. Patients with olfactory dysfunction may develop severe olfactory loss (hyposmia or anosmia) that may persist for more than 1 year after the onset of symptoms.This study suggests that olfactory dysfunction in patients with long COVID may become permanent.
H. Zhang et al.
Post-infection rehabilitation of COVID-19 patients: Findings and prospects
Lancet Regional Health - Europe, November 2022; doi: 10.1016/j.lanepe.2022.100496
Abstract
As the COVID-19 pandemic continues, approximately 2 million people in the UK and nearly 19% of adults with COVID-19 in the U.S have reported long COVID, or post COVID-19 condition after infection, which is defined as sequalae that persist for at least 4 weeks after acute infection or 3 months after infection for at least 2 months and cannot be explained by other known causes.The diverse clinical manifestations of long COVID, which reduce activity ability and health-related quality of life (HRQoL), and impose considerable socioeconomic and health burdens, have attracted attention. Severe patients or those received treatment in intensive care unit (ICU) are susceptible to long COVID with complaints of decreased activity ability, cognition, and psychological function, similar to postintensive care syndrome (PICS), requiring medical rehabilitation services to alleviate disability. Given the continuation of the coronavirus pandemic, the need for rehabilitation aiming to improve functional levels has increased.
C. Kedor et al.
A prospective observational study of post-COVID-19 chronic fatigue syndrome following the first pandemic wave in Germany and biomarkers associated with symptom severity
Nature Communications, August 2022; doi: 10.1038/s41467-022-32507-6
Abstract
A subset of patients has long-lasting symptoms after mild to moderate Coronavirus disease 2019 (COVID-19). In a prospective observational cohort study, the authors analyze clinical and laboratory parameters in 42 post-COVID-19 syndrome patients (29 female/13 male, median age 36.5 years) with persistent moderate to severe fatigue and exertion intolerance six months following COVID-19. Further they evaluate an age- and sex-matched postinfectious non-COVID-19 myalgic encephalomyelitis/chronic fatigue syndrome cohort comparatively. Most post-COVID-19 syndrome patients are moderately to severely impaired in daily live. Disease severity and symptom burden is similar in post-COVID-19 syndrome/myalgic encephalomyelitis/chronic fatigue syndrome and non-COVID-19/myalgic encephalomyelitis/chronic fatigue syndrome patients.
P.M. Mannucci et al.
Progressive decrease of the healthcare impact of the post-COVID condition after the first disease wave in Lombardy, Italy
J of Internal Medicine, August 2022; doi.org/10.1111/joim.13554
Abstract
The northern Italian region of Lombardy (population 10 million) was the first large European area to be heavily hit in the early months of 2020 by the first wave of the SARS-CoV-2 pandemic due to the original Wuhan coronavirus strain. During the period of March to May, the total number of deaths registered in Lombardy increased by 111% in comparison with the average number in the same months of 2015–2019. This gloomy scenario led the authors to consider the region as a model to evaluate the impact of the sequels of the pandemic (the so-called “post-COVID condition”) on the healthcare service of the region by using the administrative claims database made available to us for academic purposes. The authors have demonstrated as a comparison point that nonfatal events leading to the use of the regional health service—hospitalizations and emergency room and outpatient medical visits—were much more frequent than in the corresponding semester of 2019, when the region was not yet hit by the pandemic.
L. Huang et al.
Health outcomes in people 2 years after surviving hospitalisation with COVID-19: a longitudinal cohort study
Lancet Respiratory Med, September 2022; doi: 10.1016/S2213-2600(22)00126-6
Abstract
With the ongoing COVID-19 pandemic, growing evidence shows that a considerable proportion of people who have recovered from COVID-19 have long-term effects on multiple organs and systems. A few longitudinal studies have reported on the persistent health effects of COVID-19, but the follow-up was limited to 1 year after acute infection. The aim of this study was to characterise the longitudinal evolution of health outcomes in hospital survivors with different initial disease severity throughout 2 years after acute COVID-19 infection and to determine their recovery status.
The authors did an ambidirectional, longitudinal cohort study of individuals who had survived hospitalisation with COVID-19 and who had been discharged from Jin Yin-tan Hospital (Wuhan, China) between Jan 7 and May 29, 2020. They measured health outcomes 6 months (June 16-Sept 3, 2020), 12 months (Dec 16, 2020-Feb 7, 2021), and 2 years (Nov 16, 2021-Jan 10, 2022) after symptom onset with a 6-min walking distance (6MWD) test, laboratory tests, and a series of questionnaires on symptoms, mental health, health-related quality of life (HRQoL), return to work, and health-care use after discharge. Interpretation: Regardless of initial disease severity, COVID-19 survivors had longitudinal improvements in physical and mental health, with most returning to their original work within 2 years; however, the burden of symptomatic sequelae remained fairly high. COVID-19 survivors had a remarkably lower health status than the general population at 2 years. The study findings indicate that there is an urgent need to explore the pathogenesis of long COVID and develop effective interventions to reduce the risk of long COVID.
M. Zappa et al.
Knowing the new Omicron BA.2.75 variant ('Centaurus'): A simulation study
European J Internal Medicine, August 2022; doi: 10.1016/j.ejim.2022.08.009
Abstract
Omicron BA.5 is the most dominant strain of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), with an estimated 85% of cases in United States. A new subvariant known as BA.2.75 was detected in India in May 2022, and several cases have been recently reported. It is not clear how mutations of this subvariant in the gene encoding for receptor binding domain (RBD) of the spike (S) protein of the virus can affect rate of infectivity. The authors studied the effect of mutations of BA.2.75 subvariant on RBD, the conformational dynamics of the S protein and its adhesivity to ACE2 receptors.
E. Waltz
Could long COVID be linked to herpes viruses? Early data offer a hint
Nature News, August 2022; https://www.nature.com/articles/d41586-022-02296-5
Abstract
Low cortisol levels and herpes-virus reactivation are associated with prolonged COVID-19 symptoms, preliminary research suggests. Researchers looking for biological drivers and markers of long COVID have linked the syndrome to herpes viruses, as well as to reduced levels of a stress hormone.
Heidi Ledford/Nature
Il lungo percorso verso trattamenti per il long COVID
Le Scienze, August 2022;
https://www.lescienze.it/news/2022/08/30/news/sindrome_long_covid_sintomi_diversi_coaguli_affaticamento_ricerca_terapia_farmaci-10048186/
Abstract
Dopo un inizio lento, mentre medici e pazienti andavano a tentoni alla ricerca di trattamenti per alleviare i sintomi di questa sindrome, i ricercatori stanno cominciando a testare in modo più sistematico l'efficacia delle possibili terapie
J. Klein et al.
Distinguishing features of Long COVID identified through immune profiling
medRxiv, August 2022; doi.org/10.1101/2022.08.09.22278592
Abstract
SARS-CoV-2 infection can result in the development of a constellation of persistent sequelae following acute disease called post-acute sequelae of COVID-19 (PASC) or Long COVID1–3. Individuals diagnosed with Long COVID frequently report unremitting fatigue, post-exertional malaise, and a variety of cognitive and autonomic dysfunctions1–3; however, the basic biological mechanisms responsible for these debilitating symptoms are unclear. Here, 215 individuals were included in an exploratory, cross-sectional study to perform multi-dimensional immune phenotyping in conjunction with machine learning methods to identify key immunological features distinguishing Long COVID. Marked differences were noted in specific circulating myeloid and lymphocyte populations relative to matched control groups, as well as evidence of elevated humoral responses directed against SARS-CoV-2 among participants with Long COVID. Further, unexpected increases were observed in antibody responses directed against non-SARS-CoV-2 viral pathogens, particularly Epstein-Barr virus. Analysis of circulating immune mediators and various hormones also revealed pronounced differences, with levels of cortisol being uniformly lower among participants with Long COVID relative to matched control groups. Integration of immune phenotyping data into unbiased machine learning models identified significant distinguishing features critical in accurate classification of Long COVID, with decreased levels of cortisol being the most significant individual predictor. These findings will help guide additional studies into the pathobiology of Long COVID and may aid in the future development of objective biomarkers for Long COVID.
F. Halford et al.
Variation in reported SARS-CoV-2 cases after testing policy changes
Lancet Infect Dis, August 2022; doi: 10.1016/S1473-3099(22)00572-2
Abstract
SARS-CoV-2 testing policies in England continually varied up to April 1, 2022, when, as part of the UK Government's Living with COVID-19 strategy, access to free community testing ended for most of the population. These policy changes were reflected in the number of COVID-19 cases reported in England. It is discussed how surveillance systems for SARS-CoV-2 need to be representative to ensure the provision of high-quality information to understand the ongoing impact of COVID-19.
N. Perico et al.
Home as the new frontier for the treatment of COVID-19: the case for anti-inflammatory agents
Lancet Infect Dis, August 2022; doi.org/10.1016/ S1473-3099(22)00433-9
Abstract
COVID-19, caused by SARS-CoV-2, is characterised by a broad spectrum of symptom severity that requires varying amounts of care according to the different stages of the disease. Intervening at the onset of mild to moderate COVID-19 symptoms in the outpatient setting would provide the opportunity to prevent progression to a more severe illness and long-term complications. As early disease symptoms variably reflect an underlying excessive inflammatory response to the viral infection, the use of anti-inflammatory drugs, especially non-steroidal anti-inflammatory drugs (NSAIDs), in the initial outpatient stage of COVID-19 seems to be a valuable therapeutic strategy. A few observational studies have tested NSAIDs (especially relatively selective COX-2 inhibitors), often as part of multipharmacological protocols, for early outpatient treatment of COVID-19. The findings from these studies are promising and point to a crucial role of NSAIDs for the at-home management of people with initial COVID-19 symptoms.
T. Moore et al.
SARS-CoV-2-Specific Memory B Cell Responses Are Maintained After Recovery from Natural Infection and Postvaccination
Viral Immunol., July 2022 ; doi: 10.1089/vim.2022.0013
Abstract
Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory coronavirus 2 (SARS-CoV-2), has resulted in major worldwide disruption and loss of life over the last 2 years. Many research studies have shown waning serological SARS-CoV-2-specific IgG antibody titers over time, yet, it is unclear whether these changes are reflected in the potential functional reactivation of SARS-CoV-2 antigen-specific memory B cells (MBC) populations. This is especially true in the contexts of differing COVID-19 disease severity and after vaccination regimens. This study aimed to investigate these by polyclonal in vitro reactivation of MBC populations followed by analysis using SAR-CoV-2 antigen-specific B cell ELISpots and IgG antibody ELISAs. Natural disease-associated differences were investigated in 52 donors who have recovered from COVID-19 with varying disease severity, from asymptomatic to severe COVID-19 disease, accompanied by a longitudinal evaluation in a subset of donors. Overall, these data showed limited disease severity-associated differences between donor groups but did show that COVID-19 serologically positive donors had strong antigen-specific MBC-associated responses. MBC responses were better maintained 6 months after recovery from infection when compared to serological antigen-specific IgG antibody titers. A similar investigation after vaccination using 14 donors showed robust serological antigen-specific antibody responses against spike protein that waned over time. MBC-associated responses against spike protein were also observed but showed less waning over time, indicating maintenance of a protective response 6 months after vaccination. Further research is required to evaluate these putatively functional SARS-CoV-2-specific responses in the context of long-term protection mediated by vaccination against this pathogen.
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.
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.
