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An observational study of more than 70,000 people in 302 UK hospitals finds that one in two people hospitalised with COVID-19 developed at least one complication. The new study, published in The Lancet [1], is the first to systematically assess a range of in-hospital complications, and their associations with age, sex and ethnicity, and their outcomes for the patients.
The authors say these complications are likely to have important short- and long-term impacts for patients, healthcare utilisation, healthcare system preparedness, and society amidst the ongoing COVID-19 pandemic. They also note that these complications are different to long COVID symptoms in patients with COVID-19 who were not hospitalised.
The authors say that complications in patients admitted to hospital with COVID-19 are high, even in young, previously healthy individuals – with 27% of 19-29 year olds and 37% of 30-39 year olds experiencing a complication. They also note that acute complications are associated with reduced ability to self-care at discharge – with 13% of 19-29 year olds and 17% of 30-39 year olds unable to look after themselves once discharged from hospital.
The study looked at cases between 17 January and 4 August 2020 before vaccines were widely available, and new variants of the virus had not arisen. However, the authors note that their findings remain relevant in dispelling suggestions that COVID-19 presents no risk to younger healthy adults, many of whom remain unvaccinated.
The authors warn that policymakers must consider the risk of complications for those who survive COVID-19, not just mortality, when making decisions around easing restrictions. The authors predict that COVID-19 complications are likely to cause significant challenges for individuals and for the health and social care system in the coming years. Policy makers and health-care planners should anticipate that large amounts of health and social care resources will be required to support those who survive COVID-19.
Chief Investigator and joint senior author of the study, Professor Calum Semple, University of Liverpool, UK, said: “This work contradicts current narratives that COVID-19 is only dangerous in people with existing comorbidities and the elderly. Dispelling and contributing to the scientific debate around such narratives has become increasingly important. Disease severity at admission is a predictor of complications even in younger adults, so prevention of complications requires a primary prevention strategy, meaning vaccination.”
Kidney, heart and lungs
Commenting on the research, joint senior author Professor Ewen Harrison from the University of Edinburgh, UK, said: “Patients in hospital with COVID-19 frequently had complications of the disease, even those in younger age groups and without pre-existing health conditions. These complications could affect any organ, but particularly the kidney, heart and lungs. Those with complications had poorer health on discharge from hospital, and some will have long-term consequences. We now have a more detailed understanding of COVID-19 and the risks posed, even to younger otherwise healthy people.”
He added: “Our review highlights some insightful patterns and trends that can inform healthcare systems and policy maker responses to the impacts of COVID-19. Our results can also inform public health messaging on the risk COVID-19 poses to younger otherwise healthy people at a population level, particularly in terms of the importance of vaccination for this group.”
Previous research on the impact of COVID-19 on patients has focussed on the numbers of deaths or on outcomes related to one specific organ system or health condition.
The new study assessed in-hospital complications in adults aged 19 years or over with confirmed or highly suspected SARS-CoV-2 infection leading to COVID-19 disease. Data were collected by nurses and medical students, and included the participants’ age, sex at birth, health measures when hospitalised, and comorbidities (such as asthma, chronic cardiac disease, chronic haematological disease, chronic kidney disease, chronic neurological disease, chronic pulmonary disease, HIV/AIDS, cancer, liver disease, obesity, rheumatological disorders, and smoking).
In addition, they collected data on the respiratory, neurological, cardiovascular, renal, gastrointestinal and systemic complications participants experienced while in hospital [2]. Complications were assessed at multiple timepoints until discharge or, if the patient was not discharged, 28 days after hospitalisation. The study also investigated the ability of patients to look after themselves when discharged from hospital.
80,388 patients were included in the study, but 7,191 were excluded due to duplicated medical records, as they were not eligible for the study, or because no data was collected on the compilations they experienced while in hospital.
Of the remaining 73,197 patients, 56% were men, 81% had an underlying health condition, 74% were of white ethnicity, and the average age of the cohort was 71 years. Almost one in three participants (32%, 23,092 of 73,197) in the study died.
Most common complications
Overall, complications occurred in 50% of all participants, including in 44% (21,784 of 50,105) of participants who survived.
The most common complications were renal (affecting almost one in four people, 24%, 17,752), respiratory (affecting around one in five people, 18%, 13,486), and systemic (affecting one in six, 16%, 11,895). However, cardiovascular complications were reported in around one in eight participants (12%, 8,973), and neurological (less than one in 20, 4%, 3,115), and gastrointestinal or liver (less than 11%, 7,901) complications were also reported. Specifically, acute kidney injury, probable acute respiratory distress syndrome, liver injury, anaemia, and cardiac arrhythmia were the most common complications.
The incidence of complications rose with increasing age, occurring in 39% (3,596 of 9,249) of 19-49 year olds, compared to 51% (32,771 of 63,948) of people aged 50 and older. Going up the age ranges, 27% of 19-29 year olds hospitalised with COVID-19 developed a complication, 37% of 30-39 year olds, 43% of 40-49 year olds, 49% of 50-59 year olds, 54% of 60-69 year olds, 52% of 70-79 year olds, 51% of 80-89 year olds, and 50% of people aged 90 or over (see Table 1).
Complications were more common in men compared with females, with males aged older than 60 years the most likely group to have at least one complication (women aged under 60 years: 37% [2,814 of 7,689] and men 49% [5,179 of 10,609]; women aged 60 years and over: 48% [11,707 of 24,288] and men 55% [16,579 of 30,416]).
People of white, South Asian, and East Asian ethnicities had similar rates of complications, but rates were highest in Black people (58% [1,433 of 2,480] in Black patients vs 49% [26,431 of 53,780] in white patients).
Self-care compromised
Following hospitalisation, 27% (13,309 of 50,105) of patients were less able to look after themselves than before COVID-19, and this was more common with older age, being male, and in people who received critical care. The association between having a complication and worse ability for self-care remained irrespective of age, sex, socioeconomic status, and which hospital someone received treatment in. Neurological complications were associated with the biggest impact on ability for self-care.
Strain on health and social care resources
Based on these rates, the authors say that policymakers and healthcare planners should anticipate that large amounts of health and social care resources will be required to support those who survive COVID-19. This includes adequate provision of staffing and equipment – for example, provision of follow-up clinics for those who have sustained in-hospital complications such as acute kidney injury or respiratory tract infection.
Dr Thomas Drake, co-author from the University of Edinburgh, UK, said: “Our research looked at a wide range of complications, and found that short-term damage to several organs is extremely common in those treated in hospital for COVID-19. These complications were common in all age groups, not just in older people or those with pre-existing health conditions. People who have complications will often need expert care and extra help to recover from their initial hospital admission. Our study shows it is important to consider not just death from COVID-19, but other complications as well. This should provide policy makers with data to help them make decisions about tackling the pandemic and planning for the future. We are still studying the participants in our study to understand what the long-term effects of COVID-19 on their health. The results from these ongoing studies will be particularly useful, as we found many people who survive COVID-19 and develop complications are from economically active age groups.”
Aya Riad, joint co-author from the University of Edinburgh, UK, said: “It is important that with the high risk of complications and the impact these have on people, that complications of COVID-19, not just death, are considered when making decisions on how best to tackle the pandemic. Just focussing on death from COVID-19 is likely to underestimate the true impact, particularly in younger people who are more likely to survive severe COVID-19.”
The authors note that around 85% of participants had a positive SARS-CoV-2 RT-PCR test, and patients who did not have a positive test recorded similar or slightly lower rates of in-hospital complications.
Study limitations
They also note some limitations, including that the data does not provide a long-term picture, and that the timings of complications and patients quality of life were not studied. In addition, the complications in the study were predefined and not specific to COVID-19, so may underestimate some areas as these were added later. In addition, as it was inappropriate to subject patients to numerous tests, patients did not undergo additional tests for complications, and the authors say that the true burden of complications is likely to be higher.
[2] Data were collected on organ-specific complications including complex respiratory (bacterial pneumonia, acute respiratory distress syndrome [ARDS], empyema, pneumothorax, and pleural effusion), neurological (meningitis, encephalitis, seizure, and stroke), cardiovascular (thromboembolism, heart failure, myocarditis, endocarditis, arrhythmia, cardiomyopathy, myocardial ischaemia, and cardiac arrest), acute kidney injury, gastrointestinal (acute liver injury, pancreatitis, and gastrointestinal haemorrhage), and other systemic complications (coagulopathy, disseminated intravascular coagulation, anaemia, and bloodstream infection).
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Researchers at UC San Francisco have successfully developed a ‘speech neuroprosthesis’ that has enabled a man with severe paralysis to communicate in sentences, translating signals from his brain to the vocal tract directly into words that appear as text on a screen.
The achievement, which was developed in collaboration with the first participant of a clinical research trial, builds on more than a decade of effort by UCSF neurosurgeon Edward Chang, MD, to develop a technology that allows people with paralysis to communicate even if they are unable to speak on their own. The study appears July 15 in the New England Journal of Medicine.
“To our knowledge, this is the first successful demonstration of direct decoding of full words from the brain activity of someone who is paralyzed and cannot speak,” said Chang, the Joan and Sanford Weill Chair of Neurological Surgery at UCSF, Jeanne Robertson Distinguished Professor, and senior author on the study. “It shows strong promise to restore communication by tapping into the brain’s natural speech machinery.”
Each year, thousands of people lose the ability to speak due to stroke, accident, or disease. With further development, the approach described in this study could one day enable these people to fully communicate.
Previously, work in the field of communication neuroprosthetics has focused on restoring communication through spelling-based approaches to type out letters one-by-one in text. Chang’s study differs from these efforts in a critical way: his team is translating signals intended to control muscles of the vocal system for speaking words, rather than signals to move the arm or hand to enable typing. Chang said this approach taps into the natural and fluid aspects of speech and promises more rapid and organic communication.
“With speech, we normally communicate information at a very high rate, up to 150 or 200 words per minute,” he said, noting that spelling-based approaches using typing, writing, and controlling a cursor are considerably slower and more laborious. “Going straight to words, as we’re doing here, has great advantages because it’s closer to how we normally speak.”
Over the past decade, Chang’s progress toward this goal was facilitated by patients at the UCSF Epilepsy Center who were undergoing neurosurgery to pinpoint the origins of their seizures using electrode arrays placed on the surface of their brains. These patients, all of whom had normal speech, volunteered to have their brain recordings analyzed for speech-related activity. Early success with these patient volunteers paved the way for the current trial in people with paralysis.
Previously, Chang and colleagues in the UCSF Weill Institute for Neurosciences mapped the cortical activity patterns associated with vocal tract movements that produce each consonant and vowel. To translate those findings into speech recognition of full words, David Moses, PhD, a postdoctoral engineer in the Chang lab and one of the lead authors of the new study, developed new methods for real-time decoding of those patterns and statistical language models to improve accuracy.
But their success in decoding speech in participants who were able to speak didn’t guarantee that the technology would work in a person whose vocal tract is paralyzed. “Our models needed to learn the mapping between complex brain activity patterns and intended speech,” said Moses. “That poses a major challenge when the participant can’t speak.”
In addition, the team didn’t know whether brain signals controlling the vocal tract would still be intact for people who haven’t been able to move their vocal muscles for many years. “The best way to find out whether this could work was to try it,” said Moses.
To investigate the potential of this technology in patients with paralysis, Chang partnered with colleague Karunesh Ganguly, MD, PhD, an associate professor of neurology, to launch a study known as “BRAVO” (Brain-Computer Interface Restoration of Arm and Voice). The first participant in the trial is a man in his late 30s who suffered a devastating brainstem stroke more than 15 years ago that severely damaged the connection between his brain and his vocal tract and limbs. Since his injury, he has had extremely limited head, neck, and limb movements, and communicates by using a pointer attached to a baseball cap to poke letters on a screen.
The participant, who asked to be referred to as BRAVO1, worked with the researchers to create a 50-word vocabulary that Chang’s team could recognize from brain activity using advanced computer algorithms. The vocabulary – which includes words such as “water,” “family,” and “good” – was sufficient to create hundreds of sentences expressing concepts applicable to BRAVO1’s daily life.
For the study, Chang surgically implanted a high-density electrode array over BRAVO1’s speech motor cortex. After the participant’s full recovery, his team recorded 22 hours of neural activity in this brain region over 48 sessions and several months. In each session, BRAVO1 attempted to say each of the 50 vocabulary words many times while the electrodes recorded brain signals from his speech cortex.
To translate the patterns of recorded neural activity into specific intended words, the other two lead authors of the study, Sean Metzger, MS and Jessie Liu, BS, both bioengineering doctoral students in the Chang Lab used custom neural network models, which are forms of artificial intelligence. When the participant attempted to speak, these networks distinguished subtle patterns in brain activity to detect speech attempts and identify which words he was trying to say.
To test their approach, the team first presented BRAVO1 with short sentences constructed from the 50 vocabulary words and asked him to try saying them several times. As he made his attempts, the words were decoded from his brain activity, one by one, on a screen.
Then the team switched to prompting him with questions such as “How are you today?” and “Would you like some water?” As before, BRAVO1’s attempted speech appeared on the screen. “I am very good,” and “No, I am not thirsty.”
The team found that the system was able to decode words from brain activity at rate of up to 18 words per minute with up to 93 percent accuracy (75 percent median). Contributing to the success was a language model Moses applied that implemented an “auto-correct” function, similar to what is used by consumer texting and speech recognition software.
Moses characterized the early trial results as a proof of principle. “We were thrilled to see the accurate decoding of a variety of meaningful sentences,” he said. “We’ve shown that it is actually possible to facilitate communication in this way and that it has potential for use in conversational settings.”
Looking forward, Chang and Moses said they will expand the trial to include more participants affected by severe paralysis and communication deficits. The team is currently working to increase the number of words in the available vocabulary, as well as improve the rate of speech.
Both said that while the study focused on a single participant and a limited vocabulary, those limitations don’t diminish the accomplishment. “This is an important technological milestone for a person who cannot communicate naturally,” said Moses, “and it demonstrates the potential for this approach to give a voice to people with severe paralysis and speech loss.”
Co-authors on the paper include Sean L. Metzger, MS; Jessie R. Liu; Gopala K. Anumanchipalli, PhD; Joseph G. Makin, PhD; Pengfei F. Sun, PhD; Josh Chartier, PhD; Maximilian E. Dougherty; Patricia M. Liu, MA; Gary M. Abrams, MD; and Adelyn Tu-Chan, DO, all of UCSF. Funding sources included National Institutes of Health (U01 NS098971-01), philanthropy, and a sponsored research agreement with Facebook Reality Labs (FRL), which completed in early 2021.
Neuroprosthesis for Decoding Speech in a Paralyzed Person with Anarthria. New England Journal of Medicine, 2021; 385 (3): 217 DOI: 10.1056/NEJMoa2027540
By Tracy Hussell
Professor of Inflammatory Disease, University of Manchester
Late last year, I asked: is it safe to have more than one type of COVID-19 vaccine? A trial has now addressed that question, as well as what effect combining different vaccine types has on immunity.
Most COVID-19 vaccines require two doses, and the usual strategy is to give people the same vaccine type for both. But the Com-Cov study, led by the University of Oxford, recruited over 800 participants from across the UK to investigate the effects of giving people different vaccines for their first and second jabs. Two vaccines were studied: those made by Pfizer and AstraZeneca.
So, is mix and match an option? The trial’s results are preliminary, having yet to be reviewed by other scientists, but the answer appears to be yes. Giving people different types of COVID-19 vaccine appears not only to be safe, but also a potential way of boosting protection against the coronavirus.
However, the exact benefits depend on which vaccine goes first and which second. Taking the AstraZeneca vaccine followed by the Pfizer one resulted in a striking increase in antibodies against the coronavirus’s spike protein (a key part of its outer structure) compared to using the AstraZeneca vaccine for both doses or Pfizer followed by AstraZeneca.
Taking the AstraZeneca vaccine followed by Pfizer resulted in a better T cell response than all other combinations of doses. T cells – also known as T lymphocytes – are immune cells that help kill invading germs (such as the coronavirus) and support antibody production.
The Com-Cov study will next look at whether mixing and matching doses like this provides as good results when a larger gap is left between doses. The time between doses in this initial trial was 28 days, but a parallel study is stretching this to 84 days. The results are yet to be reported.
Other researchers have also been studying mixing vaccine types to fight COVID-19. A Spanish study recently reported that people who initially received the AstraZeneca vaccine experienced a massive increase to their antiviral immunity when given a second dose of the Pfizer vaccine – providing more evidence that Pfizer works well as a booster.
To understand why these beneficial effects might be happening, it’s important to understand how the AstraZeneca and Pfizer vaccines work. Both present a key element of the coronavirus – again, the spike protein – to the immune system, but do so using different methods.
The Pfizer approach packs the genetic code for the coronavirus’s spike protein into fatty nanoparticles. When these particles enter the body’s cells, the code is read and copies of the spike protein are produced, leading to an immune response. The AstraZeneca vaccine delivers the same genetic code but uses a weakened form of a common cold virus (an adenovirus) from chimpanzees to carry the code into cells.
When the first vaccine doses are given, it is possible that an immune response is raised not just against the spike protein created, but also against the carriers that are used to deliver the code for it. This is a known issue for treatments or vaccines that use viruses for delivery. If the second dose is then the same, the immunity developed against the carrier will react against the second dose, clearing some of it before robust, protective and long-lasting immunity develops.
This is why Russia’s Sputnik V vaccine – which is based on the same delivery method as the AstraZeneca vaccine – uses two different adenoviruses as carriers for its first and second doses, and has achieved impressive results.
There are additional benefits to mixing vaccine doses on top of improving protection. Logistical problems can arise when a second vaccine dose has to be identical to the first. Producing double the quantity of one vaccine takes time. Boosting with a different vaccine could allow the world’s population to be vaccinated quicker.
Second, if a person reacts badly to their first vaccination, they are more likely to get a second dose if they know it is a different one – and it’s clear that two are needed for good protection. Governments may also decide a certain type of vaccine is less suitable for different groups of people, as has been the case with the AstraZeneca vaccine in younger people in some countries. Having more potential vaccine combinations available may help overcome any public uncertainty in the wake of these sorts of decisions.
Supplying vaccines to some low- and middle-income countries can also be difficult, particularly if they do not have the necessary cold storage requirements for large batches of a vaccine that need to be kept at low temperatures. Including vaccines into the distribution plan that do not need storage at very low temperatures may make widespread vaccine delivery easier.
So there are clearly huge benefits to vaccine mixing. However, this study only looked at two vaccine types – in time, every combination will need to be tested, in every age group and in every ethnicity. Vaccines may also behave differently if mixed in different contexts, for example, against a backdrop of malnutrition or other infectious diseases. These factors will need to be included in future testing too. But for now, this study suggests that a mix-and-match approach to COVID-19 vaccines is an acceptable, useful option.
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