H5N1

Multiomic characterisation of the long-term sequelae of SARS survivors: A clinical observational study

Thanks to @OmegaMom for providing the link to this February report in eClinicalMedicine: Multiomic characterisation of the long-term sequelae of SARS survivors: a clinical observational study. SARS affected far fewer people than COVID-19, but survivors were very much at risk of long SARS. The summary:

Background  

We aimed to characterise the long-term health outcomes of survivors of severe acute respiratory syndrome (SARS) and determine their recovery status and possible immunological basis.  

Methods  

We performed a clinical observational study on 14 health workers who survived SARS coronavirus infection between Apr 20, 2003 and Jun 6, 2003 in Haihe Hospital (Tianjin, China). Eighteen years after discharge, SARS survivors were interviewed using questionnaires on symptoms and quality of life, and received physical examination, laboratory tests, pulmonary function tests, arterial blood gas analysis, and chest imaging. Plasma samples were collected for metabolomic, proteomic, and single-cell transcriptomic analyses. The health outcomes were compared 18 and 12 years after discharge. Control individuals were also health workers from the same hospital but did not infect with SARS coronavirus.  

Findings  

Fatigue was the most common symptom in SARS survivors 18 years after discharge, with osteoporosis and necrosis of the femoral head being the main sequelae. The respiratory function and hip function scores of the SARS survivors were significantly lower than those of the controls. Physical and social functioning at 18 years was improved compared to that after 12 years but still worse than the controls. Emotional and mental health were fully recovered.  

Lung lesions on CT scans remained consistent at 18 years, especially in the right upper lobe and left lower lobe lesions. Plasma multiomics analysis indicated an abnormal metabolism of amino acids and lipids, promoted host defense immune responses to bacteria and external stimuli, B-cell activation, and enhanced cytotoxicity of CD8+ T cells but impaired antigen presentation capacity of CD4+ T cells.  

Interpretation  

Although health outcomes continued to improve, our study suggested that SARS survivors still suffered from physical fatigue, osteoporosis, and necrosis of the femoral head 18 years after discharge, possibly related to plasma metabolic disorders and immunological alterations.

Outcomes of SARS-CoV-2 reinfection

Via Research Square, a preprint: Outcomes of SARS-CoV-2 Reinfection. This is a disturbing finding. The abstract, re-formatted and with my bolding:

First infection with SARS-CoV-2 is associated with increased risk of acute and post-acute death and sequelae in the pulmonary and extrapulmonary organ systems. However, whether reinfection adds to the risk incurred after the first infection is not clear. 

Here we use the national health care databases of the US Department of Veterans Affairs to build a cohort of people with first infection (n = 257,427), reinfection (2 or more infections, n = 38,926), and a non-infected control group (n = 5,396,855) to estimate risks and 6-month burdens of all-cause mortality, hospitalization, and a set of pre-specified incident outcomes. 

We show that compared to people with first infection, reinfection contributes additional risks of all-cause mortality, hospitalization, and adverse health outcomes in the pulmonary and several extrapulmonary organ systems (cardiovascular disorders, coagulation and hematologic disorders, diabetes, fatigue, gastrointestinal disorders, kidney disorders, mental health disorders, musculoskeletal disorders, and neurologic disorders); 

the risks were evident in those who were unvaccinated, had 1 shot, or 2 or more shots prior to the second infection; 

the risks were most pronounced in the acute phase, but persisted in the post-acute phase of reinfection, and most were still evident at 6 months after reinfection. 

Compared to non-infected controls, assessment of the cumulative risks of repeated infection showed that the risk and burden increased in a graded fashion according to the number of infections. 

The constellation of findings shows that reinfection adds non-trivial risks of all-cause mortality, hospitalization, and adverse health outcomes in the acute and post-acute phase of the reinfection. Reducing overall burden of death and disease due to SARS-CoV-2 will require strategies for reinfection prevention.

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

Via The Lancet Respiratory Medicine: Clinical characteristics with inflammation profiling of long COVID and association with 1-year recovery following hospitalisation in the UK: a prospective observational study. The implications of this study are very worrying: a majority of hospitalized COVID survivors experience serious sequelae for up to a year after recovery (and some likely much longer). The summary:

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 patient-perceived 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.

Science & Tech Spotlight: Long COVID

Via the US Government Accountability Office: Science & Tech Spotlight: Long COVID. Excerpt:

Fast Facts 

How many people in the U.S. have developed "long COVID"?  

It could be in the range of 7.7–23 million, some estimates say.  

We discuss what is and isn't known about long COVID—new, returning, or ongoing health problems 4 or more weeks after an initial case of COVID-19. For example, some people with the condition experience chronic fatigue and have to stop working, which can affect their income and health insurance. But other economic effects are still unclear.  

The federal government is taking steps to fund more research and help affected people. We describe challenges it could encounter and provide questions for policymakers to consider.

See also this report in The Washington Post.

COVID-19 is in for the long haul

Here's a screenshot of this evening's Johns Hopkins Coronavirus COVID-19 (2019-nCoV) dashboard:

It's notable for several reasons. First, the US is now far back in the 28-day case count—seventh, behind Germany, South Korea, Russia, Vietnam, France, and Brazil.

 

Second, almost all the case and mortality numbers are likely severe undercounts, since so many countries have simply abandoned any pretence of testing and contact tracing. I would not be shocked if the true number of cases were around 1.5 billion, and deaths close to 20 million.

 

The numbers for Russia (3.7 million cases in the last 28 days, 20,000 deaths) and Ukraine (458,000 cases, 3,800 deaths) are especially implausible, given the events of the past 15 days. But we'll surely see an explosive growth in cases as over 2 million Ukrainians move through Europe in search of refuge.

 

The early-success countries have largely succumbed to Omicron. While China pursues its zero-COVID policy, it's still recorded 539,000 cases and 2,600 deaths. Hong Kong has seen 533,000 cases in 28 days, and 2,600 deaths. Vietnam racked up 26 million cases in the last 28 days, and 2,400 deaths. New Zealand had 267,000 cases and 12 deaths; it had only 38,900 cases in the previous 23 months of the official pandemic.

 

The graphs on the right tell us that the Omicron spike has fallen sharply from its peak of 23,333,000 in the week ending January 23; we're now at 10,706,000 as of the week ending March 6. That looks impressive, but it's still about 5 million more than the three previous waves.

 

Omicron also drove a spike in deaths, peaking at 75,000 in the week of February 13 and now fallen to 50,400. Meanwhile, vaccinations have fallen from a recent high of 257,000 in the week of February 6 to 105,600 in the week ending March 6.

 

Yet many countries are effectively declaring the pandemic over, making masks and distancing optional, junking vaccine passports, and dropping regular reports by public health officials. Governments seem to think COVID-19 can now sink back into the background noise with other diseases, while we turn our attention to war and inflation and the next election.

 

On February 1, Johns Hopkins reported 381,232,070 cases, so we have seen almost 72 million cases of COVID-19 in the past six weeks alone. Even if the Omicron spike continue to drop, the next six weeks will see tens of millions more cases, and likely another 40 or 50 thousand people now alive will be dead before May 1. 

 

We are nowhere near the end of the pandemic. In fact, I expect it will in many ways get worse as healthcare systems really do collapse, and as sequelae like Long COVID affect more and more cases. The pandemic that began two years ago really is in the for long haul.

SARS-CoV-2 is associated with changes in brain structure in UK Biobank

Via Nature: SARS-CoV-2 is associated with changes in brain structure in UK Biobank. This seems likely to become a very important paper. The abstract:

There is strong evidence for brain-related abnormalities in COVID-19. It remains unknown however whether the impact of SARS-CoV-2 infection can be detected in milder cases, and whether this can reveal possible mechanisms contributing to brain pathology. 

Here, we investigated brain changes in 785 UK Biobank participants (aged 51–81) imaged twice, including 401 cases who tested positive for infection with SARS-CoV-2 between their two scans, with 141 days on average separating their diagnosis and second scan, and 384 controls. The availability of pre-infection imaging data reduces the likelihood of pre-existing risk factors being misinterpreted as disease effects. 

We identified significant longitudinal effects when comparing the two groups, including: (i) greater reduction in grey matter thickness and tissue-contrast in the orbitofrontal cortex and parahippocampal gyrus, (ii) greater changes in markers of tissue damage in regions functionally-connected to the primary olfactory cortex, and (iii) greater reduction in global brain size. The infected participants also showed on average larger cognitive decline between the two timepoints. Importantly, these imaging and cognitive longitudinal effects were still seen after excluding the 15 cases who had been hospitalised. 

These mainly limbic brain imaging results may be the in vivo hallmarks of a degenerative spread of the disease via olfactory pathways, of neuroinflammatory events, or of the loss of sensory input due to anosmia. Whether this deleterious impact can be partially reversed, or whether these effects will persist in the long term, remains to be investigated with additional follow up.

Pandemics disable people — the history lesson that policymakers ignore

Via Nature, an excellent article by Laura Spinney: Pandemics disable people — the history lesson that policymakers ignore. Excerpt:

When Ashley Shew turned up for an appointment at a medical centre in spring 2020, a member of staff told her she could remove her mask because only people with pre-existing conditions were vulnerable to COVID-19. Shew was surprised. “A hard-of-hearing amputee battered by chemotherapy and more”, as she describes herself, she is a regular at the centre — the appointment that day concerned her prosthetic leg. Who, she wondered, did the staff member think counted as a person with pre-existing conditions?  

The invisibility of disability is not new, says Shew, a 38-year-old philosopher who explores the intersection of technology and disability at Virginia Polytechnic Institute and State University in Blacksburg. “But it is particularly deadly that we don’t frame COVID-19 as a disability issue,” she says. “Even linguistically we’re pointed away from it. ‘Pre-existing conditions’ is a way of not saying ‘disability’.”  

From the beginning of this pandemic, people with disabilities understood that the disease would target them and would swell their ranks. Disability historians knew that there was a penumbra of ill health to previous mass-death events. Health economists warned that, as with tuberculosis, HIV and other diseases, morbidity would stalk mortality. Too many others have clung stubbornly to a belief that COVID-19 is something from which a minority of people die, and that most bounce back quickly and intact, with only their immune system updated. The longer the pandemic drags on, the harder it is to maintain that fiction.  

Two years in, the debilitating tail of the pandemic has revealed itself in the form of tens of millions of people living with long COVID1. It is high time to ask whether attitudes to disability will change as a result. Will society grasp that the body can be altered for a long period — even permanently — by infectious disease, just as it seems to have accepted that the body politic will never be the same again? And will it make the necessary accommodations?  

These questions have been asked before.  

Long influenza  

Consider the ‘mother of all pandemics’ — the 1918 Spanish influenza outbreak. Even in the 1920s, scientists understood that this flu had neurological and other effects. The most notorious and debated of those — still — is the overlapping pandemic of encephalitis lethargica (EL) or ‘sleepy sickness’. Eighty per cent of EL survivors went on to develop a Parkinson’s-like disease. According to cell biologist Richard Smeyne at the Jefferson Hospital for Neuroscience in Philadelphia, Pennsylvania, it has never been proved biologically that flu caused both EL and this post-encephalitic parkinsonism — at least not in the sense of catching the virus in flagrante in the brain tissue of people who had died. Yet the statistical case for it seems strong. 

The neurological tails of two subsequent flu pandemics, in 1957 and 1968, were less pronounced, but both were followed by rises in cases of encephalitis (brain inflammation), among other conditions. Once again, researchers failed to demonstrate a clear causal link with an earlier flu infection, but it has since been established that the flu virus can infect the brain and trigger inflammation there and elsewhere in the body. Clinicians see this after every flu season, in a wave of strokes and heart attacks predominantly among older people. And flu can cause encephalitis in children. It’s rare, but it can kill, and those who survive can be left with long-term brain damage.

Long-term cardiovascular outcomes of COVID-19

Via Nature Medicine: Long-term cardiovascular outcomes of COVID-19. The abstract:

The cardiovascular complications of acute coronavirus disease 2019 (COVID-19) are well described, but the post-acute cardiovascular manifestations of COVID-19 have not yet been comprehensively characterized. Here we used national healthcare databases from the US Department of Veterans Affairs to build a cohort of 153,760 individuals with COVID-19, as well as two sets of control cohorts with 5,637,647 (contemporary controls) and 5,859,411 (historical controls) individuals, to estimate risks and 1-year burdens of a set of pre-specified incident cardiovascular outcomes. 

We show that, beyond the first 30 d after infection, individuals with COVID-19 are at increased risk of incident cardiovascular disease spanning several categories, including cerebrovascular disorders, dysrhythmias, ischemic and non-ischemic heart disease, pericarditis, myocarditis, heart failure and thromboembolic disease. These risks and burdens were evident even among individuals who were not hospitalized during the acute phase of the infection and increased in a graded fashion according to the care setting during the acute phase (non-hospitalized, hospitalized and admitted to intensive care). 

Our results provide evidence that the risk and 1-year burden of cardiovascular disease in survivors of acute COVID-19 are substantial. Care pathways of those surviving the acute episode of COVID-19 should include attention to cardiovascular health and disease.

Do vaccines protect from long COVID?

Via The Lancet Respiratory Medicine: Do vaccines protect from long COVID?

On Jan 6, 2022, the UK Government's Office of National Statistics (ONS) published their latest report on the prevalence of long COVID in the UK from a representative survey. As of Dec 6, 2021, around 1·266 million people living in the UK had self-reported long COVID (95% CI 1·228–1·304; 2% of the total population), defined as symptoms persisting for more than 4 weeks after the first confirmed or suspected COVID-19 infection. Of these individuals, 892 000 (70%) had confirmed or suspected COVID-19 at least 12 weeks previously. Fatigue was the most common symptom reported, followed by loss of smell, shortness of breath, and difficulty concentrating.  

The numbers in the ONS report are high enough to give pause for concern, particularly as long COVID was reported in all sub-populations, including around 77 000 children aged 2–16 years and 134 000 people aged 17–25 years. Yet there is still uncertainty about the true prevalence of long COVID in adults and children following infection. A previous ONS article suggested that, of individuals who tested positive for COVID-19 infection in the UK between April, 2020, and August, 2021, between 3% and 12% had new or ongoing symptoms 12 weeks after the initial infection, including people who were not symptomatic during the acute phase.

Part of the problem with assessing the prevalence of long COVID is an absence of consistent information on terminology, definitions, and diagnosis of the condition. For example, a guideline from the UK National Institute for Clinical Excellence (NICE) defines long COVID as signs and symptoms that continue or develop after acute COVID‑19 from 4 weeks onwards, whereas WHO uses the term post COVID-19 condition, defined as occurring in individuals 3 months from the onset of SARS-CoV-2 infection.  

Additionally, a substantial proportion of patients might have persistent symptoms for a year or more after infection; more than half a million individuals (40%) from the January 2022 ONS report who described having long COVID had been infected at least 1 year ago. However, the general consensus is that long COVID is the failure to return to normal, pre-COVID levels of health, and is surprisingly common.  

More research is needed to gauge the full spectrum of symptoms of long COVID to facilitate diagnosis of the condition; as well as fatigue and shortness of breath, the NICE guideline lists many other commonly reported symptoms including palpitations, neurological symptoms such as dizziness, and gastrointestinal symptoms including nausea and weight loss.  

As Annelise Wilder-Smith (London School of Hygiene & Tropical Medicine, London, UK) commented “Long COVID is so much more than just chronic fatigue, and ranges from reduced stamina for athletes to erectile dysfunction in young men.”  

Research is also needed to understand why after acute COVID-19 infection, the impact of the disease varies from patient to patient, from full recovery to severe persistent symptoms affecting multiple organs and mental health. Anthony De Soyza (National Institute of Health Research Newcastle Biomedical Research Centre, Newcastle University, Newcastle, UK) commented “Long COVID can arise in people who had mild acute COVID [and] so can affect anyone. Long COVID affects people differently and might well be a number of distinct subtype[s], each requiring better understanding of what causes the particular symptoms and how best to treat—this requires ongoing research.”  

Wilder-Smith added “Long COVID may be due to persistence of the virus, an autoimmune response, or damage triggered by the acute illness, but we need more data to answer this question.”

The data on long COVID are worrying, particularly during the current increase in global cases of COVID-19 infection. There are, however, encouraging emerging data that individuals who are vaccinated against COVID-19 are less likely to report long COVID symptoms. For example, a case-control study of 1·2 million users of a COVID symptom tracker app in the UK showed that there were lower odds of symptoms lasting 28 days or more in individuals who had received two vaccine doses (odds ratio 0·51 [95% CI 0·32–0·82]; p=0·0060)—ie, the risk of developing long COVID was reduced by around 50% in those who were double vaccinated.

Wilder-Smith said “Even if COVID-19 did not cause deaths, the high morbidity as a result of this viral infection would justify vaccinating all. The reasons for vaccination beyond the most pressing need to avert severe disease and deaths are manifold, but foremost it is to prevent long COVID.” De Soyza added “Ideally preventing both acute severe COVID through vaccination and also reducing the chances of long COVID represents an additional driver to support people to get vaccinated.”

COVID-19 Longhauler Advocacy Project

From the project's website: COVID-19 Longhauler Advocacy Project.

The COVID-19 Longhauler Advocacy Project was founded in June 2020 with a focus on Long COVID advocacy, education, research and support. We have been instrumental in educating medical providers, researchers, and patients about Long COVID and its associated conditions, in addition to highlighting the community's trends, experiences and needs to assist in “filling the gaps” and expediting the work that will lead to solutions. 

We are constantly reassessing the community to continue to advocate and educate using the most accurate and up to date information and trends that arise out of the Long COVID community via social media, patient-led research and peer-reviewed research. We are currently in the process of becoming a 501(c)(3) non profit organization to expand the work we are able to do.

I'm adding the project to the COVID-19 Links list.