Long COVID is far more widespread than thought, a recent study shows, while another has found that a common symptom of the condition is linked to cognitive impairment. And a third believes it may stem from an overactive immune response in the lungs.
A large Dutch study recently showed that as many as one in every eight adults (12.7%) infected with SARS-CoV-2 experiences long term symptoms from the virus.
And one of the findings of a longitudinal study in Argentina is that persistent smell loss after SARS-CoV-2 infection predicted cognitive impairment in older adults, with the researchers saying loss of smell is often a signal of an inflammatory response in the brain: inflammation is part of the neurodegenerative process in diseases like Alzheimer’s.
One year after acute infection, anosmia, or loss of smell, was more strongly associated with cognitive impairment than severity of SARS-CoV-2 infection, said Gabriela Gonzalez-Aleman, MSc, PhD of Pontificia Universidad Católica Argentina in Buenos Aires.
“The more insight we have into what causes or at least predicts who will experience the significant long-term cognitive impact of COVID-19 infection, the better we can track it and begin to develop methods to prevent it,” she told MedPage Today.
Meanwhile, the Dutch study provides one of the first comparisons of long-term symptoms after SARS-CoV-2 infection, with symptoms in an uninfected population, as well as measuring symptoms in individuals both pre- and post-COVID-19 infection. The inclusion of uninfected populations enables a more accurate prediction of long-term COVID-19 symptom prevalence as well as improved identification of the core symptoms of long COVID.
“There is urgent need for data informing the scale and scope of the long-term symptoms experienced by some patients after COVID-19 illness,” says Professor Judith Rosmalen from the University of Groningen, lead author of the study. “However, most previous research into long COVID has not looked at the frequency of these symptoms in people who haven’t been diagnosed with COVID-19 or looked at individual patients’ symptoms before the diagnosis of COVID-19."
Her study team’s approach looked at the symptoms most often associated with long COVID, including breathing problems, fatigue and loss of taste and/or smell, both before a COVID-19 diagnosis and in people who have not been diagnosed with COVID-19.
“This method allows us to take pre-existing symptoms and symptoms in non-infected people into account to offer an improved working definition for long COVID and provide a reliable estimate at how likely long COVID-19 is to occur in the general population.”
In their study, reported in The Lancet, researchers collected data by asking participants of the population-based Lifelines COVID-19 Cohort (2) to regularly fill out digital questionnaires on 23 symptoms commonly associated with long COVID. The questionnaire was sent out 24 times to the same individuals between March 2020 and August 2021, meaning participants who had COVID-19 during this time were infected with the SARS-CoV-2 alpha-variant or earlier variants. Most of the data were collected before the COVID-19 vaccine roll-out in The Netherlands so the number of vaccinated participants was too small to analyse in this study.
Participants were recorded as COVID-19 positive if they had either a positive test or a doctor’s diagnosis of COVID-19. Of 76 422 participants, 4 231 (5.5%) participants who had COVID-19 were matched to 8 462 controls taking account of sex, age and time of completing questionnaires that indicated a COVID-19 diagnosis.
The researchers found that several symptoms were new or more severe three to five months after having COVID-19, compared to symptoms before a COVID-19 diagnosis and to the control group, suggesting these symptoms can be viewed as the core symptoms of long COVID.
The core symptoms recorded were chest pain, difficulties breathing, pain when breathing, painful muscles, loss of taste and/or smell, tingling hands/feet, a lump in throat, alternately feeling hot and cold, heavy arms and/or legs and general tiredness. The severity of these symptoms plateaued at three months after infection with no further decline. Other symptoms that did not significantly increase three to five months after a COVID-19 diagnosis included headache, itchy eyes, dizziness, back pain and nausea.
PhD candidate and first author of the study Aranka Ballering said: “These core symptoms have major implications for future research, as they can be used to distinguish between post COVID-19 condition and non-COVID-19-related symptoms.”
Of the study participants who had submitted pre-COVID symptom data, the researchers found that 21.4% (381/1 782) of COVID-19-positive participants, compared to 8.7% (361/4 130) of the control group, experienced at least one increased core symptom at moderate severity three months or more after SARs-CoV-2 infection. This implies that in 12.7% of COVID-19 patients their new or severely increased symptoms three months post-COVID can be attributed to SARS-CoV-2 infection.
Ballering added: “By looking at symptoms in an uninfected control group and in individuals both before and after SARS-CoV-2 infection, we were able to account for symptoms which may have been a result of non-infectious disease health aspects of the pandemic, such as stress caused by restrictions and uncertainty.
“Long COVID is an urgent problem with a mounting human toll. Understanding the core symptoms and the prevalence of post-COVID-19 in the general population represents a major step forward for our ability to design studies that can ultimately inform successful healthcare responses to the long-term symptoms of COVID-19.”
The authors acknowledge some limitations in the study. It included patients infected with the alpha variant or earlier variants of SARS-CoV-2 and has no data from people infected during the period when the Delta or Omicron variants were causing most infections.
Additionally, due to asymptomatic infection, the prevalence of COVID-19 in this study may be underestimated. Another limitation is that since the beginning of data collection, other symptoms, such as brain-fog, have been identified as potentially relevant for a definition of long COVID but this study did not look at these symptoms. Furthermore, the study was undertaken in one region and did not include an ethnically diverse population.
Rosmalen said: “Future research should include mental health symptoms (e.g. depression and anxiety symptoms), along with additional post-infectious symptoms that we could not assess in this study (such as brain fog, insomnia and post-exertional malaise). We were unable to investigate what might cause any of the symptoms observed after COVID-19 in this study, but we hope future research will be able to give insights into the mechanisms involved. Furthermore, due to the timing of this study we were unable to assess the effect of COVID-19 vaccination and different SARS-CoV-2 variants on long COVID symptoms. We hope future studies will provide answers on the impacts of these factors.” (1)
Writing in a linked comment, Professor Christopher Brightling and Dr Rachael Evans of the Institute for Lung Health, University of Leicester (who were not involved in the study) note: “This is a major advance on prior long COVID prevalence estimates as it includes a matched uninfected group and accounts for symptoms before COVID-19 infection.
“The pattern of symptomatology observed by Ballering and colleagues was similar to previous reports with fatigue and breathlessness among the commonest symptoms, but interestingly other symptoms such as chest pain were more a feature in those with long COVID versus uninfected controls. (…) Current evidence supports the view that long COVID is common and can persist for at least two years, although severe debilitating disease is present in a minority. The long COVID case definition needs to be further improved, potentially to describe different types of long COVID, for which better mechanistic understanding is critical.”
In the Argentinian study, the team’s findings form part of a global brain study of chronic neuropsychiatric sequelae of COVID, a consortium of researchers led by the Alzheimer’s Association and representatives from more than 25 countries, with technical guidance from the World Health Organisation (WHO).
“We’re learning more every day about the link between COVID-19 and the brain,” said Claire Sexton, PhD, senior director of scientific programmes and outreach at the Alzheimer’s Association. “Loss of smell is often a signal of an inflammatory response in the brain. We know inflammation is part of the neurodegenerative process in diseases like Alzheimer’s.”
She said with other viruses, like SARS and MERS, there have been similar associations between infection and cognition, “but there are still big questions about cause and effect”.
The Argentina study followed 865 people over 60 recruited from a provincial health registry that included all SARS-CoV-2 testing data for the region. Researchers randomly invited older adults with a positive PCR COVID test to participate between three and six months after acute SARS-CoV-2 infection.
Assessments followed the recommendations of the global consortium and included the WHO Schedules for Clinical Assessment in Neuropsychiatry (SCAN) scale, the Clinical Dementia Rating scale, neurocognitive and emotional reactivity assessments, and evaluations of semi-quantitative olfactory function, motor function, co-ordination and gait.
Among the 865 participants, 84.2% had COVID and 15.8% were controls with no history of a positive SARS-CoV-2 test. Median age was 67 and just more than half (56.5%) were female. Participants had a median of 10.35 years of education. Most participants with COVID did not have severe infection, with very few (2% or less) admitted to the ICU.
At one year, about a quarter of the study sample had no cognitive impairment; this group included control participants and about 20% of post-COVID patients, Gonzalez-Aleman said. Scores of remaining participants were normalised to the mean of the cognitively normal group, with impairment defined as z-scores below -2. Remaining participants were clustered into groups based on deficits in memory, attention, executive function and language, with some people showing impairment in multiple domains. PCR status and age predicted post-COVID cognitive problems, Gonzalez-Aleman said. Logistic regression analyses showed severity of anosmia, but not severity of SARS-CoV-2 infection, was significantly associated with cognitive impairment.
All anosmia was reported after acute SARS-CoV-2 infection, Gonzalez-Aleman noted. Some people in the control group also had anosmia, but their olfactory dysfunction was much less frequent – and less severe – than that of participants with COVID, she added.
The results are part of ongoing research about COVID among older Amerindian adults in Argentina. “It’s important to provide the most up-to-date research to the public so we can be aware of the evolving ways this virus affects us,” she said.
“But it’s also worth stressing that much more research is needed to paint a more complete picture of what COVID-19 is doing to our bodies and brains. We also need to study the direct impact that two years of pandemic-related isolation has had on our health.”
Meanwhile, in The Conversation, Harish Narasimhan, a doctoral student working in the Sun Lab at the University of Virginia, US, said why and how respiratory diseases can develop into conditions like long COVID-19 are still unclear, but it was becoming evident that it might not be an active viral infection causing long COVID-19 and similar conditions, but an overactive immune system. Keeping your immune system dormant when there isn’t an active infection is essential for your lungs to be able to function optimally.
Your respiratory tract is in constant contact with your external environment, sampling around five to eight litres air – and the toxins and micro-organisms in it – every minute, he wrote. Despite continuous exposure to potential pathogens and harmful substances, your body has evolved to keep the immune system dormant in the lungs. In fact, allergies and conditions such as asthma are byproducts of an overactive immune system. These excessive immune responses can cause your airways to constrict and make it difficult to breathe. Some severe cases may require treatment to suppress the immune system.
During an active infection, however, the immune system is absolutely essential. When viruses infect your respiratory tract, immune cells are recruited to your lungs to fight off the infection. Although these cells are crucial to eliminate the virus from your body, their activity often results in collateral damage to your lung tissue. After the virus is removed, your body dampens your immune system to give your lungs a chance to recover.
Over the past decade, researchers have identified a variety of specialised stem cells in the lungs that can help regenerate damaged tissue. These stem cells can turn into almost all the different types of cells in the lungs depending on the signals they receive from their surrounding environment. The immune system plays a significant role in providing signals that facilitate lung recovery.
But these signals can not only activate stem cells, they can also perpetuate damaging inflammatory processes in the lung.
Therefore, your body tightly regulates when, where and how strongly these signals are made, to prevent further damage.
While the reasons are still unclear, some people are unable to turn off their immune system after infection and continue to produce tissue-damaging molecules long after the virus has been flushed out. This not only further damages the lungs, but also interferes with regeneration via the lung’s resident stem cells. This phenomenon can result in chronic disease, as seen in several respiratory viral infections including COVID-19, Middle East Respiratory Syndrome (MERS), respiratory syncytial virus (RSV) and the common cold.
The immune system’s role in chronic disease
Many different types of immune cells are involved in the development of chronic disease after respiratory viral infections, including long COVID-19.
Scientists so far have identified one particular type of immune cells, killer T cells, as potential contributors to chronic disease. Also known as cytotoxic or CD8+ T cells, they specialise in killing infected cells either by interacting directly with them or by producing damaging molecules called cytokines.
Killer T cells are essential to curbing the virus from spreading in the body during an active infection. But their persistence in the lungs after the infection has resolved is linked to extended reduced respiratory function. Moreover, animal studies have shown that removing killer T cells from the lungs after infection may improve lung function and tissue repair.
Another type of immune cells called monocytes are also involved in fighting respiratory infections, serving among the first responders by producing virus- and tissue-damaging cytokines. Research has found these cells also continue to accumulate in the lungs of long COVID-19 patients and promote a pro-inflammatory environment that can cause further damage.
Understanding the immunological mechanisms underlying long COVID-19 is the first step to addressing a quickly worsening public health problem. Identifying the subtle differences in how the same immune cells that protect you during an active infection can later become harmful could lead to earlier diagnosis of long COVID-19.
We believe treatments that target the immune system could be an effective approach to manage long COVID-19 symptoms, that this strategy may turn out to be useful not only for COVID-19, but also for other respiratory viral infections leading to chronic disease as well.
Netherlands Study details
Persistence of somatic symptoms after COVID-19 in the Netherlands: an observational cohort study
Aranka V Ballering, Sander van Zon, Tim C olde Hartman, Judith Rosmalen, for theLifelines Corona Research Initiative
Published in The Lancet on 6 August 2022
Summary
Background
Patients often report various symptoms after recovery from acute COVID-19. Previous studies on post-COVID-19 condition have not corrected for the prevalence and severity of these common symptoms before COVID-19 and in populations without SARS-CoV-2 infection. We aimed to analyse the nature, prevalence, and severity of long-term symptoms related to COVID-19, while correcting for symptoms present before SARS-CoV-2 infection and controlling for the symptom dynamics in the population without infection.
Methods
This study is based on data collected within Lifelines, a multidisciplinary, prospective, population-based, observational cohort study examining the health and health-related behaviours of people living in the north of the Netherlands. All Lifelines participants aged 18 years or older received invitations to digital COVID-19 questionnaires. Longitudinal dynamics of 23 somatic symptoms surrounding COVID-19 diagnoses (due to SARS-CoV-2 alpha [B.1.1.7] variant or previous variants) were assessed using 24 repeated measurements between March 31, 2020, and Aug 2, 2021. Participants with COVID-19 (a positive SARS-CoV-2 test or a physician's diagnosis of COVID-19) were matched by age, sex, and time to COVID-19-negative controls. We recorded symptom severity before and after COVID-19 in participants with COVID-19 and compared that with matched controls.
Findings
76 422 participants (mean age 53·7 years [SD 12·9], 46 329 [60·8%] were female) completed a total of 883 973 questionnaires. Of these, 4231 (5·5%) participants had COVID-19 and were matched to 8462 controls. Persistent symptoms in COVID-19-positive participants at 90–150 days after COVID-19 compared with before COVID-19 and compared with matched controls included chest pain, difficulties with breathing, pain when breathing, painful muscles, ageusia or anosmia, tingling extremities, lump in throat, feeling hot and cold alternately, heavy arms or legs, and general tiredness. In 12·7% of patients, these symptoms could be attributed to COVID-19, as 381 (21·4%) of 1782 COVID-19-positive participants versus 361 (8·7%) of 4130 COVID-19-negative controls had at least one of these core symptoms substantially increased to at least moderate severity at 90–150 days after COVID-19 diagnosis or matched timepoint.
Interpretation
To our knowledge, this is the first study to report the nature and prevalence of post-COVID-19 condition, while correcting for individual symptoms present before COVID-19 and the symptom dynamics in the population without SARS-CoV-2 infection during the pandemic. Further research that distinguishes potential mechanisms driving post-COVID-19-related symptomatology is required.
Study 2
Global Brain Study of chronic neuropsychiatric sequelae of COVID-19: The need for a prospective study of viral impact on brain functioning
Gabriel A. de Erausquin, Heather Snyder, María Carrillo, Akram A. Hosseini, Traolach S. Brugha, Sudha Seshadri, the CNS SARS-CoV-2 Consortium
Published in Alzheimer’s & Dementia on 5 January 2021
Abstract
Introduction
The increasing evidence of SARS-CoV-2 impact on the central nervous system (CNS) raises key questions on its impact for risk of later life cognitive decline, Alzheimer's disease (AD), and other dementia.
Methods
The Alzheimer's Association and representatives from more than 30 countries – with technical guidance from the World Health Organization – have formed an international consortium to study the short-and long-term consequences of SARS-CoV-2 on the CNS, including the underlying biology that may contribute to AD and other dementias. This consortium will link teams from around the world covering more than 22 million COVID-19 cases to enroll two groups of individuals including people with disease, to be evaluated for follow-up evaluations at 6, 9, and 18 months, and people who are already enrolled in existing international research studies to add additional measures and markers of their underlying biology.
Conclusions
The increasing evidence and understanding of SARS-CoV-2’s impact on the CNS raises key questions on the impact for risk of later life cognitive decline, AD, and other dementia. This programme of studies aims to better understand the long-term consequences that may impact the brain, cognition, and functioning, including the underlying biology that may contribute to AD and other dementias.
Study 3
Olfactory dysfunction and chronic cognitive impairment following SARS‐CoV‐2 infection in a sample of older adults from the Andes mountains of Argentina
Gabriela Gonzalez Aleman, Hernan Zamponi, Gabriela Kukoc, Leonardo Juarez‐Aguaysol, Maria Eugenia Dominguez et al
Published in Alzheimers & Dementia in December 2021
Abstract
COVID‐19 has affected more than 150m people. The causal coronavirus, SARS‐CoV‐2 has infected twice as many individuals who have remained asymptomatic. COVID‐19 includes central nervous system (CNS) manifestations and may result in chronic neuropsychiatric sequelae. Risk factors for COVID‐19 sequelae overlap with those for Alzheimer’s disease (AD), particularly older age and ApoE4 status. The Alzheimer’s Association Consortium on Chronic Neuropsychiatric Sequelae of SARS‐CoV‐2 infection (CNS SC2) established harmonised definitions, ascertainment and assessment methodologies to evaluate and longitudinally follow up cohorts of older adults with variable exposure to COVID‐19. We present preliminary data from CNS SC2 in a prospective cohort of 234 older adult Amerindians from Argentina. Participants are ≥ 60 years recruited from the health registry of the Province of Jujuy containing all SARS‐CoV‐2 testing data (regardless of clinical status and of the result of the testing). We randomly invite older adults stratified by testing status regardless of symptom severity, a minimum of 3 months after clinical recovery (maximum 6 months); refusal to participate is <45%. Assessment includes interview with the Schedules for Clinical Assessment in Neuropsychiatry (SCAN) and Clinical Dementia Rating scale; neurocognitive assessment; emotional reactivity scale; and neurological assessment including semiquantitative olfactory function test, motor function, coordination and gait. We present here the results of olfactory testing and cognitive assessments. We assessed 233 infected participants and 64 controls. Average duration of formal learning is 9.35 ± 2.6 years and mean age is 66.7 ± 5.13 years. Normative data for the local population were available for Word list, Corsi Blocks, Oral Trails and Five Digit Tests and were used to normalise Z‐scores and categorize the sample in 3 groups: normal cognition (NC,44.6%); memory only impairment (MOI,21%); and multiple domain impairment (MDI,34.4%). Individuals with MDI presented severe alterations in short‐term memory; semantic memory; naming; executive function and attention compared to NC or MO groups. Severity of cognitive impairment was significantly correlated with severity of olfactory dysfunction (χ2 = 13.82; p= 0.003) but not severity of acute COVID‐19. Older adults frequently suffer persistent cognitive impairment after recovery from SARS‐CoV‐2 infection; cognitive impairment is correlated with persistent anosmia.
Study 4 details
Immune determinants of chronic sequelae after respiratory viral infection
Harish Narasimhan, Yue Wu, Nick Goplen, Jie Sun
Published in Science Immunology on 8 July 2022
Abstract
The acute effects of various respiratory viral infections have been well studied, with extensive characterisation of the clinical presentation as well as viral pathogenesis and host responses. However, over the course of the recent COVID-19 pandemic, the incidence and prevalence of chronic sequelae after acute viral infections have become increasingly appreciated as a serious health concern. Post-acute sequelae of COVID-19, alternatively described as “long COVID-19,” are characterized by symptoms that persist for longer than 28 days after recovery from acute illness. Although there exists substantial heterogeneity in the nature of the observed sequelae, this phenomenon has also been observed in the context of other respiratory viral infections including influenza virus, respiratory syncytial virus, rhinovirus, severe acute respiratory syndrome coronavirus, and Middle Eastern respiratory syndrome coronavirus. In this Review, we discuss the various sequelae observed following important human respiratory viral pathogens and our current understanding of the immunological mechanisms underlying the failure of restoration of homeostasis in the lung.
Science Immunology article – Immune determinants of chronic sequelae after respiratory viral infection (Open access)
https://www.science.org/doi/10.1126/sciimmunol.abm7996
Science Immunology article – Immune determinants of chronic sequelae after respiratory viral infection (Open access)
See more from MedicalBrief archives:
Newer COVID variants less likely to affect smell and taste – US study
COVID -19 may cause neurological tissue damage, grey matter loss – Oxford
30% of COVID-19 patients have lingering symptoms 6 months later — Washington study
Long COVID impacts heart, lung and kidney – Scottish study
Long COVID breathlessness: Novel scans uncover hidden lung damage