❦ ‘ Long Covid can manifest in people across the life span (from children to older adults ) and across race and ethnicity, sex, and baseline health status. It is a complex non-monolithic multisystemic disease with sequelae across almost all organ systems . The prototypical (classic) form of Long Covid (with brain fog [brain damage] , fatigue , dysautonomia *, and postexertional malaise ) is more common in younger adults and in females . Other forms of Long Covid, including those with cardiovascular and metabolic sequelae , are manifest more often in older adults and those with comorbidities . A common risk across all types of Long Covid is severity of acute infection; the risk – on the relative scale – increases according to the severity of the acute infection. However, despite the lower relative risk, more than 90% of [Long Covid] cases occur in people who had mild SARS-CoV-2 infection , owing to the much higher prevalence of mild cases. Because non-pharmaceutical interventions [ NPIs , such as respirator-wearing and air filtration ] to reduce the risk of SARS-CoV-2 transmission have largely been abandoned , vaccines are now the primary line of defense against both severe disease in the acute phase of the infection and Long Covid. Studies have consistently shown that vaccines reduce the risk of Long Covid by 15 to 75% , with a mean of ~40% reduction in risk . Yet vaccine policies in much of the world restrict boosters to older adults or those with risk factors for severe COVID-19, and with pandemic fatigue, the public’s appetite for boosters seems to be waning . Reinfection , which is now the dominant type of SARS-CoV-2 infection , is not inconsequential; it can trigger de novo Long Covid or exacerbate its severity . Each reinfection contributes additional risk of Long Covid : cumulatively, two infections yield a higher risk of Long Covid than one infection, and three infections yield a higher risk than two infections. Despite this cumulative knowledge on mechanisms, epidemiology, and prevention, there are several major challenges. Patients are often met with skepticism and dismissal of their symptoms as psychosomatic. The attribution of symptoms to psychological causes has no scientific support ; it perpetuates stigma and disenfranchises patients from accessing the care they need. The lack of consensus on terms , definitions , and clinical trial end points for Long Covid is slowing progress and hampering industry engagement in clinical trials. Evidence from multiple studies with 2 to 3 years of follow-up indicates prolonged risk for many sequelae and that spontaneous recovery or return to baseline status is uncommon . Extended follow-up of the 1918 influenza pandemic , poliomyelitis outbreaks, and Epstein-Barr virus infections has demonstrated that new, disabling sequelae of these infections can occur multiple decades later ; it is uncertain whether this will also occur with COVID-19. Tied with the antiscience , antivaccine movement , a tide of Long Covid denialism is rising . This movement sows doubt about the scale and urgency of Long Covid, conflates Long Covid with vaccine-adverse events, and seeks to hamper progress on addressing the care needs of people suffering from this condition. The pandemic has laid bare a blind spot in epidemiology and surveillance data systems for infectious diseases. Nearly all surveillance data systems are built on the archaic , and now obsolete , notion that accounting for cases, hospitalization, and death in the acute phase is sufficient to capture the health burden of the infection. This approach does not account for the burden of long-term health loss due to infectious illnesses, which obscures their true toll. Adding to this challenge are the absent , underdeveloped , or siloed healthcare data systems in much of the world. Long Covid will have wide-reaching effects that are yet to be fully appreciated. In addition to the prototypical form of Long Covid, SARS-CoV-2 infection increases the risk of a wide array of chronic diseases and will contribute to a rise in the burden of cardiovascular disease , diabetes , neurologic impairment , and autoimmune conditions . Long Covid affects the development and educational attainment of children and reduces labor participation and economic productivity in working-age adults . Both the direct effect of increased risk of death in people with Long Covid and the indirect effect on mortality through increased burden of chronic diseases caused by SARS-CoV-2 may contribute to further decline in life expectancy, potentially erasing decades of progress. Finding treatments for Long Covid must be prioritized. Preventing infections and reinfections is the best way to prevent Long Covid and should remain the foundation of public health policy. A greater commitment to non-pharmaceutical interventions , which include masking , especially in high-risk settings , and improved air quality through filtration and ventilation , are requisite . Updating building codes to require mitigation against airborne pathogens and ensure safer indoor air should be treated with the same seriousness afforded to mitigation of risks from earthquakes and other natural hazards. Reducing the risk of serious outcomes after COVID-19 and some prevention of Long Covid can be attained with vaccination of a wider spectrum of the population . Development of more durable , variant-proof vaccines that are not vulnerable to evasion by the ever-mutating virus needs to be accelerated. Nasally or orally administered vaccines that induce strong mucosal immunity to block infection and transmission should be pursued. It is also necessary to broaden the pipeline of SARS-CoV-2 antivirals , especially because of rising resistance.’ ❂ 📖 (22 Feb 2024 ~ Science) Solving the puzzle of Long Covid: Long Covid provides an opportunity to understand how acute infections cause chronic disease ➤ © 2024 Science .

❦ This study confirms everything that I have seen in the microscope over the last few years. The authors of the study use a technique called dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), an imaging technique that can measure the density, integrity, and leakiness of tissue vasculature. Comparing all individuals with previous COVID infection to unaffected controls revealed decreased general brain volume in patients with brain fog along with significantly reduced cerebral white matter volume in both hemispheres in the recovered and brain fog cohorts . Covid-19 induces brain volume loss and leaky blood-brain barrier in some patients. How can this be more clear? © 2024 Danielle Beckman. ➲ ❂ 📖 (22 Feb 2024 ~ Nature: Neuroscience) Blood–brain barrier disruption and sustained systemic inflammation in individuals with long COVID-associated cognitive impairment ➤ 📖 (22 Feb 2024 ~ Nature: Neuroscience) Leaky blood–brain barrier in long-COVID-associated brain fog ➤ ➲ Layperson overview: 📖 (February 2024 ~ Genetic Engineering and Biotechnology News) Leaky Blood Vessels in the Brain Linked to Brain Fog in Long COVID Patients ➤ Related: 📖 (7 Feb 2022 ~ Nature: Cardiovascular Research) Blood–brain barrier link to human cognitive impairment and Alzheimer’s disease ➤ ❂ © 2024 Nature .

❦ ‘The occurrences of respiratory disorders among patients who survived for 30 days after the COVID-19 diagnosis continued to rise consistently, including asthma, bronchiectasis, COPD, ILD, PVD, and lung cancer. With the severity of the acute phase of COVID-19, the risk of all respiratory diseases increases progressively. Besides, during the 24-months follow-up, we observed an increasing trend in the risks of asthma and bronchiectasis over time, which indicates that long-term monitoring and meticulous follow-up of these patients is essential. These findings contribute to a more complete understanding of the impact of COVID-19 on the respiratory system and highlight the importance of prevention and early intervention of these respiratory sequelae of COVID-19. In this study, several key findings have been further identified. Firstly, our research demonstrates a significant association between COVID-19 and an increased long-term risk of developing various respiratory diseases. Secondly, we found that the risk of respiratory disease increases with severity in patients with COVID-19, indicating that it is necessary to pay attention to respiratory COVID-19 sequelae in patients, especially those hospitalized during the acute stage of infection. This is consistent with the findings of Lam et al., who found that the risk of some respiratory diseases (including chronic pulmonary disease, acute respiratory distress syndrome and ILD) increased with the severity of COVID-19. Notably, however, our study found that asthma and COPD remained evident even in the non-hospitalized population. This emphasizes that even in cases of mild COVID-19, the healthcare system should remain vigilant. Thirdly, we investigated differences in risk across time periods, as well as the long-term effects of COVID-19 on respiratory disease. During the 2-years follow-up period, the risks of COPD, ILD, PVD and lung cancer decreased, while risks of asthma and bronchiectasis increased. Fourthly, our study showed a significant increase of the long-term risk of developing asthma, COPD, ILD, and lung cancer diseases among individuals who suffered SARS-CoV-2 reinfection. This finding emphasizes the importance of preventing reinfection of COVID-19 in order to protect public health and reduce the potential burden of SARS-CoV-2 reinfection. Interestingly, vaccination appears to have a potentially worsening effect on asthma morbidity compared with other outcomes. This observation aligns with some previous studies that have suggested a possible induction of asthma onset or exacerbation by COVID-19 vaccination. It suggests that more care may be necessary for patients with asthma on taking the COVID vaccines. The underlying mechanisms associated with COVID and respiratory outcomes are not fully understood, but several hypotheses have been proposed. First, SARS-CoV-2 can persist in tissues (including the respiratory tract), as well as the circulating system for an extended period of time after the initial infection. This prolonged presence of the virus could directly contribute to long-term damage of the respiratory tissues, consequently leading to the development of various respiratory diseases. Second, it has been observed that SARS-CoV-2 infection can lead to prolonged immunological dysfunctions, including highly activated innate immune cells, a deficiency in naive T and B cells, and increased expression of interferons and other pro-inflammatory cytokines. These immune system abnormalities are closely associated with common chronic respiratory diseases – asthma, bronchiectasis, COPD, as well as the development of lung cancer. Next, SARS-CoV-2 itself has been shown to drive cross-reactive antibody responses, and a range of autoantibodies were found in patients with COVID-19. In conclusion, our research adds to the existing knowledge regarding the effects of COVID-19 on the respiratory system. Specifically, it shows that the risk of respiratory illness increases with the severity of infection and reinfection. Our findings emphasize the importance of providing extended care and attention to patients previously infected with SARS-CoV-2.’ ❂ 📖 (17 Feb 2024 ~ The Lancet: eClinical Medicine) Long-term risks of respiratory diseases in patients infected with SARS-CoV-2: a longitudinal, population-based cohort study ➤ © 2024 The Lancet: eClinical Medicine .

❦ Chronic disease is like the perfect medical crime. The cause is usually long gone by the time the disease manifests, and nobody links the two until it’s much too late for most. ❂ © 2024 Henry Madison . ➲

❦ ‘Although some studies have shown neuroimaging and neuropsychological alterations in post-COVID-19 patients, fewer combined neuroimaging and neuropsychology evaluations of individuals who presented a mild acute infection. Here we investigated cognitive dysfunction and brain changes in a group of mildly infected individuals. We conducted a cross-sectional study of 97 consecutive subjects ( median age of 41 years ) without current or history of psychiatric symptoms (including anxiety and depression) after a mild infection , with a median of 79 days (and mean of 97 days ) after diagnosis of COVID-19. We performed semi-structured interviews, neurological examinations, 3T-MRI scans, and neuropsychological assessments. The patients reported memory loss ( 36% ), fatigue ( 31% ) and headache ( 29% ). The quantitative analyses confirmed symptoms of fatigue ( 83% of participants), excessive somnolence ( 35% ), impaired phonemic verbal fluency ( 21% ), impaired verbal categorical fluency ( 13% ) and impaired logical memory immediate recall ( 16% ). Our group… presented higher rates of impairments in processing speed ( 11.7% in FDT- Reading and 10% in FDT- Counting ). The white matter (WM) analyses with DTI * revealed higher axial diffusivity values in post-infected patients compared to controls. * Diffusion tensor imaging tractography , or DTI tractography, is an MRI (magnetic resonance imaging) technique most commonly used to provide imaging of the brain. Our results suggest persistent cognitive impairment and subtle white matter abnormalities in individuals mildly infected , without anxiety or depression symptoms. One intriguing fact is that we observed a high proportion of low average performance in our sample of patients (which has a high average level of education ), including immediate and late verbal episodic memory, phonological and semantic verbal fluency, immediate visuospatial episodic memory, processing speed, and inhibitory control . Although most subjects did not present significant impaired scores compared with the normative data, we speculate that the low average performance affecting different domains may result in a negative impact in everyday life , especially in individuals with high levels of education and cognitive demands .’ ❂ ❦ Note how these findings might negatively affect daily activities that demand sustained cognitive attention and fast reaction times – such as driving a car or motorbike, or piloting a plane. Consider air-traffic control. Consider the impact on healthcare workers whose occupations combine long periods of intense concentration with a need for critical precision. ❂ 📖 (19 Jan 2024 ~ Nature: Scientific Reports) Microstructural brain abnormalities, fatigue, and cognitive dysfunction after mild COVID-19 ➤ © 2024 Nature .

❦ ‘Acute infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cause a respiratory illness that can be associated with systemic immune cell activation and inflammation , widespread multi-organ dysfunction , and thrombosis . Not everyone fully recovers from COVID-19, leading to Long Covid, the treatment of which is a major unmet clinical need. Long Covid can affect people of all ages , follows severe as well as mild disease , and involves multiple organs . Patients with Long Covid display signs of immune dysfunction and exhaustion , persistent immune cell activation , and autoimmune antibody production , which are also pathological features of acute COVID-19. The complement system is crucial for innate immune defense by effecting lytic destruction of invading micro-organisms, but when uncontrolled, it causes cell and vascular damage . The complement cascade is activated by antigen–antibody complexes in the classical pathways or in the lectin pathway by multimeric proteins (lectins) that recognize specific carbohydrate structures, which are also found on the SARS-CoV-2 spike protein that facilitates host cell entry. Both pathways may contribute to the pronounced complement activation in acute COVID-19. Long Covid symptoms include a postexertional exhaustion reminiscent of other post-viral illnesses , such as myalgic encephalomyelitis ( ME ) – chronic fatigue syndrome ( MECFS ) with suspected latent viral reactivation . Antibody titer changes in Long Covid patients indicate an association of fatigue with reactivation of latent Epstein-Barr virus ( EBV ) infections , and Cervia-Hasler et al found that the severity of Long Covid symptoms is associated with cytomegalovirus ( CMV ) reactivation . A better understanding of the connections between viral reactivation, persistent interferon signaling, and autoimmune pathologies promises to yield new insights into the thromboinflammation associated with Long Covid. Although therapeutic interventions with coagulation and complement inhibitors in acute COVID-19 produced mixed results, the pathological features specific for Long Covid suggest potential interventions for clinical testing. Microclots are also observed in ME-CFS patients , indicating crucial interactions between complement, vWF, and coagulation-mediated fibrin formation in post-viral syndromes. A better definition of these interactions in preclinical and clinical settings will be crucial for the translation of new therapeutic concepts in chronic thromboinflammatory diseases .’ ❂ 📖 (18 Jan 2024 ~ Science) Immune damage in Long Covid ➤ © 2024 Wolfram Ruf / Science .

❦ ‘Alzheimer’s disease (AD) is acknowledged by the World Health Organisation (WHO) as a global public health concern. AD is the primary cause of dementia and accounts for 50–70% of cases. SARS-CoV-2 can damage the peripheral and the central nervous system (CNS) through both direct and indirect pathways, potentially leaving COVID-19 patients at higher risks for neurological difficulties, including depression, Parkinson’s disease, AD, etc., after recovering from severe symptoms. Patients who recovered from severe COVID-19 infection are more likely to acquire stable neuropsychiatric and neurocognitive conditions like depression, obsessive-compulsive disorder, psychosis, Parkinson’s disease, and Alzheimer’s disease. SARS-CoV-2 infection causes immune system dysfunction, which can lead to suppression of neurogenesis, synaptic damage, and neuronal death, all of which are associated with the aetiology of Alzheimer’s disease. Severe systemic inflammation caused by SARS-CoV-2 is predicted to have long-term negative consequences, such as cognitive impairment. Research has demonstrated that SARS-CoV-2-infected AD patients had a higher mortality rate. In a study from the Department of Neuroscience at the University of Madrid, 204 participants with Frontotemporal Dementia (FTD) and Alzheimer’s disease (AD) were enrolled. According to the study, 15.2% of these individuals had COVID-19 infection, and sadly, 41.9% of those who had the virus died as a result of their illness. COVID-19 causes a secondary effect on underlying brain pathologies, as SARS-CoV-2 has been shown to trigger or accelerate neurodegeneration processes that possibly explain long-term neurodegenerative effects in the elderly population. In response to the impact of COVID-19 in 2020, governments worldwide acted promptly by implementing various public health measures. During this period, people with cognitive impairments such as dementia or AD may have experienced greater stress and anxiety due to sudden changes in the environment and people’s behaviour. It is also significantly harder for AD patients to comprehend and execute defensive measures such as wearing face masks and sanitising frequently. ❂ COVID-19 has generated a worldwide outbreak, resulting in a slew of issues for humans, particularly those suffering from Alzheimer’s disease. Its ability to invade the central nervous system through the hematogenous and neural routes, besides attacking the respiratory system, has the potential to worsen cognitive decline in Alzheimer’s disease patients. The severity of this issue must be highlighted.’ ❂ 📖 (8 Jan 2024 ~ Frontiers in Aging Neuroscience) Unravelling the connection between COVID-19 and Alzheimer’s disease: a comprehensive review ➤ © 2024 Shajahan et al / Frontiers in Aging Neuroscience .

❦ ‘Al-Aly’s study undertook a comparative analysis of 94 pre-specified health outcomes and found that over 18 months of follow-up, COVID was associated with a “ significantly increased risk ” for 64 of them, or nearly 70% . The disease’s enhanced risk list includes everything from cardiac arrest , stroke , chronic kidney disease , and cognitive impairment to mental health and fatigue , characteristics often associated with long COVID. By comparison, the seasonal flu was associated with increased risk in only 6 of the 94 conditions specified. Further, while COVID increased the risks for almost all the organ systems studied, the flu heightened risk primarily for the pulmonary ( lung ) system . Those findings, Al-Aly says, suggest that “ COVID is really a multi-systemic disease , and flu is more a respiratory virus ”.’ ❂ 📖 (14 Dec 2023 ~ Fortune) COVID-19 v. Flu: A ‘much more serious threat,’ new study into long-term risks concludes ➤ 📖 (14 Dec 2023 ~ The Lancet) Long-term outcomes following hospital admission for COVID-19 versus seasonal influenza: a cohort study ➤ © 2023 Carolyn Barber / Fortune .

❦ As a consequence of their occupation, doctors and other healthcare workers were at higher risk of contracting coronavirus disease 2019 (COVID-19), and more likely to experience severe disease compared to the general population. Post-acute COVID (Long COVID) in UK doctors is a substantial burden. Insufficient respiratory protection could have contributed to occupational disease, with COVID-19 being contracted in the workplace , and resultant post-COVID complications. Although it may be too late to address the perceived determinants of inadequate protection for those already suffering with Long COVID, more investment is needed in rehabilitation and support of those afflicted . ❂ 📖 (11 Dec 2023 ~ Occupational Medicine) Post-acute COVID-19 complications in UK doctors: results of a cross-sectional survey ➤

❦ 'For middle-aged adults ( 50–64 ) in this period [June 2022 – June 2023 ], the relative excess for almost all causes of death examined was higher than that seen for all ages .' ➲ ‘Since July 2020, the Office for Health Improvement and Disparities (OHID) has published estimates of excess mortality. In the period from week ending 3rd June 2022 to 30th June 2023 , excess deaths for all causes were relatively greatest for 50–64 year olds ( 15% higher than expected ), compared with 11% higher for 25–49 and < 25 year olds , and about 9% higher for over 65 year old groups. Several causes, including cardiovascular diseases , show a relative excess greater than that seen in deaths from all-causes ( 9% ) over the same period (week ending 3rd June 2022–30th June 2023), namely: all cardiovascular diseases ( 12% ), heart failure ( 20% ), ischaemic heart diseases ( 15% ), liver diseases ( 19%) , acute respiratory infections ( 14% ), and diabetes ( 13% ). For middle-aged adults (50–64) in this 13-month period, the relative excess for almost all causes of death examined was higher than that seen for all ages . Deaths involving cardiovascular diseases were 33% higher than expected, while for specific cardiovascular diseases, deaths involving ischaemic heart diseases were 44% higher , cerebrovascular diseases 40% higher and heart failure 39% higher . Deaths involving acute respiratory infections were 43% higher than expected and for diabetes , deaths were 35% higher . Deaths involving liver diseases were 19% higher than expected for those aged 50–64 , the same as for deaths at all ages. Looking at place of death, from 3rd June 2022 to 30th June 2023 there were 22% more deaths in private homes than expected compared with 10% more in hospitals . The greatest numbers of excess deaths in the acute phase of the pandemic were in older adults. The pattern now is one of persisting excess deaths which are most prominent in relative terms in middle-aged and younger adults , with deaths from CVD [cardiovascular] causes and deaths in private homes being most affected.’ ❂ ➲ [C19.Life Note ] : Considering their findings and conclusion, I’m not sure why the authors would choose to use the term ‘post-pandemic’ in this title – when their evidence points to an on-going pandemic, fueled by continuing high rates of infection, that is now simply killing younger age-groups than previously seen.] ❂ 📖 (1 Dec 2023 ~ The Lancet (Regional Health Europe) Excess mortality in England post Covid-19 pandemic: implications for secondary prevention ➤ © 2023 Pearson-Stuttard et al / The Lancet (Regional Health Europe) .

❦ SARS-CoV-2 infection precipitates a molecular cascade that reactivates latent viral agents. Infection doesn’t just pass through the body’s defenses but rather reprograms them. It reactivates dormant pathogens and perpetuates a cycle of chronic immune activation. Long COVID sufferers are burdened with a significantly higher prevalence of immune responses to certain DNA viruses – namely, Epstein-Barr Virus (EBV)* and Parvovirus B19 – than those in good health. * Epstein-Barr Virus (EBV) is a common human virus that spreads primarily through saliva. It is a member of the herpes virus family and is found all over the world. Most people will get infected with EBV in their lifetime and will not have any symptoms. Elevated levels of antibodies against these viruses in Long COVID patients not only signal potential viral reactivations. It also suggests a reality where SARS-CoV-2 may be inciting a smoldering activation of chronic viral infections. ❂ 📖 (9 Nov 2023 ~ European Heart Journal) Sequential activation of DNA viruses by the RNA virus SARS-CoV-2 in patients with long COVID syndrome ➤ © 2023 Outbreak Updates ➲

❦ ‘It is now well established that post-COVID syndrome ( PCS ) represents a serious complication in a substantial number of patients following SARS-CoV-2 infection. PCS is diagnosed when COVID-19-related symptoms persist for more than 3 months. It can occur even after an initially mild to moderate course of infection , and comprise a large variety of symptoms . Around 30% of PCS patients show neurological and neuropsychiatric sequelae , such as fatigue , depressive symptoms , and cognitive dysfunction . These are experienced as particularly debilitating, as they have detrimental effects on daily functioning in PCS patients and hamper a successful return to their jobs. Fatigue is a frequent and one of the most debilitating symptoms in post-COVID syndrome (PCS). Recently, we proposed that fatigue is caused by hypoactivity of the brain’s arousal network and reflected by a reduction of cognitive processing speed . Eighty-eight PCS patients with cognitive complaints and 50 matched healthy controls underwent neuropsychological assessment. Seventy-seven patients were subsequently assessed at 6-month follow-up. Patients showed cognitive slowing indicated by longer reaction times compared to control participants in a simple-response tonic alertness task and in all more complex tasks requiring speeded performance . Reduced alertness correlated with higher fatigue . Alertness dysfunction remained unchanged at 6-month follow-up and the same was true for most attention tasks and cognitive domains .’ ❂ 📖 (7 Nov 2023 ~ Journal of Neurology) Persistent cognitive slowing in post-COVID patients: longitudinal study over 6 months ➤ © 2023 Journal of Neurology .

➲ A layperson-level overview from New Atlas on how all variants of SARS-CoV-2 – the virus that causes COVID-19 – are ‘neuroinvasive’ , meaning that all can infect or enter the brain and the nervous system . ❂ ❦ ‘... We know COVID is associated with a variety of neurological symptoms , both short- and long-term, but it still isn’t entirely clear whether these cognitive issues are the result of the virus directly infecting brain cells or simply due to a broader systemic inflammatory response. Studies looking at human brain tissue have yielded contradictory results. Some have found direct traces of SARS-CoV-2 , while others report only inflammatory damage . Animal models certainly demonstrate it is possible for the virus to infect the brain, but human tissue samples are obviously taken after a patient dies – meaning researchers can only hypothesize what happens during an acute infection. Using a hamster model, the research compared infection with the original SARS-CoV-2 virus from 2020 to several subsequent variants including Gamma, Delta and Omicron/BA.1 variants. Interestingly, the findings confirmed epidemiological observations showing acute disease severity is reduced in Omicron infections – however, all [SARS-CoV-2] variants demonstrated similar neuroinvasive capabilities. And, most strikingly, all variants infected the brain’s olfactory regions regardless of whether symptoms of anosmia (the loss of sense of smell) were present or not. “This suggests that anosmia and neuronal infection are two unrelated phenomena. If we follow this line of reasoning, it is quite possible that even an asymptomatic infection is characterized by the spread of the virus in the nervous system.” The researchers conclude this suggests all SARS-CoV-2 variants have the capacity to infect the brain, via the olfactory pathway, regardless of clinical disease presentations. This means it is possible even mild infections can lead to the virus infiltrating the brain. “The next step will be to understand... whether the virus is able to persist in the brain beyond the acute [initial, short-term] phase of infection, and whether the presence of the virus can induce persistent inflammation and the symptoms described in cases of long COVID, such as anxiety, depression and brain fog” [brain damage].’ © 2023 Rich Haridy / New Atlas. ➲ Source © 2023 Institut Pasteur .

❦ Your brain is a vast city. The roads (myelin) in this city let cars move efficiently. Oligodendrocytes are the construction workers who maintain these roads. As we age, these workers slow down, causing traffic jams and slower thoughts. Enter SARS-CoV-2, the destructive rioter. It doesn’t just disrupt traffic; it damages the roads and chases away the construction crews. Weeks after the riot, the city still struggles to function, with long-lasting road damages and traffic jams. This is the ‘brain fog’ of post-COVID life. ❂ 📖 (24 Sep 2023 ~ Aging and Disease) Role of Microglia, Decreased Neurogenesis and Oligodendrocyte Depletion in Long COVID-Mediated Brain Impairments ➤ © 2023 Outbreak Updates ➲

❦ Your lungs are balloons made of the finest silk, allowing them to expand and contract effortlessly with each breath. SARS-CoV-2 is as a needle, puncturing and tearing this delicate fabric. In an attempt to heal, the body patches up the punctures, but instead of the original silk, it uses rough patches. These patches – scarring or fibrosis – make parts of the lung rigid, restricting its once flawless expansion. With each subsequent infection, more patches appear, further suffocating the lung’s true function. The virus doesn’t just infect. It sabotages the very essence of our breath. ❂ 📖 (6 Apr 2022 ~ Annals of Medicine and Surgery) Post COVID-19 pulmonary fibrosis; a meta-analysis study ➤ © 2023 Outbreak Updates ➲

❦ ‘The most common causes of acquired lymphocytopenia include: ➲ Protein-energy undernutrition. ➲ HIV infection. ➲ COVID-19 . ➲ Certain other viral infections. Patients with HIV infection routinely have lymphocytopenia, which arises from destruction of CD4+ T cells infected with the HIV virus. Patients with COVID-19 also frequently have lymphocytopenia ( 35% to 83% of patients ) . Lower lymphocyte counts portend a poor prognosis and an increased likelihood of requiring ICU admission and of dying from the disease. The cause of the lymphocytopenia is not completely understood, but COVID-19 can directly infect lymphocytes, and a cytokine-related apoptosis of the cells is likely. ➲ Lymphocytopenia is most often due to AIDS , and recently COVID-19 , or undernutrition, but it also may be inherited or caused by various infections, drugs, or autoimmune disorders. ➲ Patients have recurrent viral , bacterial , fungal , or parasitic infections .’ ❂ 📖 (Accessed 16 Sep 2023 ~ Merck & Co.) Entry for 'Lymphocytopenia' in Merck Manual ➤ © 2023 Merck & Co .

❦ ‘We have recently demonstrated a causal link between loss of gonadotropin-releasing hormone ( GnRH ), the master molecule regulating reproduction , and cognitive deficits during pathological aging , including Down syndrome and Alzheimer’s disease. Olfactory and cognitive alterations , which persist in some COVID-19 patients, and long-term hypotestosteronaemia in SARS-CoV-2-infected men are also reminiscent of the consequences of deficient GnRH, suggesting that GnRH system neuroinvasion could underlie certain post-COVID symptoms and thus lead to accelerated or exacerbated cognitive decline . We explored the hormonal profile of COVID-19 patients and targets of SARS-CoV-2 infection in post-mortem patient brains and human fetal tissue. We found that persistent hypotestosteronaemia in some men could indeed be of hypothalamic origin , favouring post-COVID cognitive or neurological symptoms , and that changes in testosterone levels and body weight over time were inversely correlated. Infection of olfactory sensory neurons and multifunctional hypothalamic glia called tanycytes highlighted at least two viable neuroinvasion routes . Furthermore, GnRH neurons themselves were dying in all patient brains studied , dramatically reducing GnRH expression. Human fetal olfactory and vomeronasal epithelia , from which GnRH neurons arise, and fetal GnRH neurons also appeared susceptible to infection . Putative GnRH neuron and tanycyte dysfunction following SARS-CoV-2 neuroinvasion could be responsible for serious reproductive , metabolic , and mental health consequences in long-COVID and lead to an increased risk of neurodevelopmental and neurodegenerative pathologies over time in all age groups .’ ❂ 📖 (12 Sep 2023 ~ eBioMedicine: Lancet Discovery Science) Long-COVID cognitive impairments and reproductive hormone deficits in men may stem from GnRH neuronal death ➤ © 2023 eBioMedicine: Lancet Discovery Science .

❦ — “I don’t know anyone with Long Covid.” — “Everyone I know is tired.” ❂ © 2023 Antiviral Marketing . ➲

❦ Children have largely been unaffected by severe COVID-19 compared to adults, but data suggest that they may have experienced new conditions after developing the disease. We compared 1656 exposed and 1656 unexposed children from 1 February 2020 to 30 November 2021. We found significantly higher risks for some new conditions in exposed children, including mental health issues and neurological problems . The overall excess risk for new-onset conditions after COVID-19 was 78% higher in the exposed than unexposed children. ❂ 📖 (9 Sep 2023 ~ Acta Paediatrica) Comparative study showed that children faced a 78% higher risk of new-onset conditions after they had COVID-19 ➤ © 2023 Di Chiara et al / Acta Paediatrica.

❦ ‘Individuals with SARS-CoV-2 infection can develop symptoms that persist well beyond the acute phase of COVID-19 or emerge after the acute phase, lasting for weeks or months after the initial acute illness. The post-acute sequelae of COVID-19 (PASC) , which include physical, cognitive, and mental health impairments, are known collectively as long COVID or post-COVID-19 condition (PCC) . The proportion of patients affected by post-COVID-19 condition might be in the range of 10–30% of those infected with SARS-CoV-2, although understanding of this condition is still evolving. Socio-economic factors are fundamental determinants of health after COVID-19. Individuals from low-income and middle-income countries, those from marginalised communities, and those who are socially disadvantaged are probably disproportionately affected. The post-COVID-19 condition is systemic, affecting various organ systems. PCC results in: an increased use of healthcare resources ; a decreased quality of life ; an increased susceptibility to subsequent viral or bacterial infection ; and leads to heightened vulnerability to perioperative morbidity and mortality for individuals who require a surgical procedure for any (unrelated) indication. With a large and growing global population of survivors of COVID-19, the impact on individuals, healthcare systems, communities, and society is likely to be substantial. At present, there are no specific treatments for post-COVID-19-condition.’ ❂ 📖 (17 July 2023 ~ The Lancet) Post-acute sequelae of COVID-19: understanding and addressing the burden of multisystem manifestations ➤ © 2023 Parotto et al / The Lancet.

❦ ‘Long COVID is the patient-coined term for the disease entity whereby persistent symptoms ensue in a significant proportion of those who have had COVID-19, whether asymptomatic, mild or severe. The disease burden spans from mild symptoms to profound disability, the scale making this a huge, new healthcare challenge. Long COVID will likely be stratified into several more or less discrete entities with potentially distinct pathogenic pathways. The evolving symptom list is extensive, multi-organ, multisystem and relapsing–remitting, including fatigue, breathlessness, neurocognitive effects and dysautonomia. A range of radiological abnormalities in the olfactory bulb, brain, heart, lung and other sites have been observed in individuals with Long COVID. Some body sites indicate the presence of microclots; these and other blood markers of hypercoagulation implicate a likely role of endothelial activation and clotting abnormalities. Diverse auto-antibody (AAB) specificities have been found, as yet without a clear consensus or correlation with symptom clusters. There is support for a role of persistent SARS-CoV-2 reservoirs and/or an effect of Epstein-Barr virus reactivation, and evidence from immune subset changes for broad immune perturbation. The oncoming burden of Long COVID faced by patients, healthcare providers, governments and economies is so large as to be unfathomable, which is possibly why minimal high-level planning is currently allocated to it.’ ❂ 📖 (11 July 2023 ~ Nature Reviews: Immunology) The immunology of long COVID ➤ © 2023 Altmann et al / Nature.

❦ From the start of this pandemic, UK healthcare workers have been risking their lives and health caring for Covid patients without adequate protection. A significant number are now disabled following preventable occupational exposure to SARS-CoV-2, and are being managed out of the door with no support system in place, and without means to financially support themselves and their families. Not only have they lost their health and independence; they have lost their careers and livelihoods, with many now facing financial destitution. One would think – given the circumstances under which we fell ill, and with current workforce shortages – that NHS employers would be eager to do everything to facilitate the return to work of healthcare workers with Long Covid. However, NHS employers are legally required to implement only ‘reasonable adjustments’ – and so things such as extended-phased-return, or adjustments to shift patterns, are not always being facilitated. Instead, an increasing number of employers are choosing to terminate contracts. We feel betrayed and completely abandoned. Infection control guidelines are fundamentally flawed: SARS-CoV-2 is airborne. It is outrageous that three-and-a-half years into this pandemic, staff and patients are still, knowingly and repeatedly, being exposed to a level-3 biohazard – a virus known to cause brain damage and significantly increased risk of life-threatening blood complications even in those recovered. Healthcare workers must be provided with respiratory protection and the air quality in hospitals be monitored and improved through the installation of ventilation systems and air filter units. © 2023 Dr. Kelly Fearnley . ➲ NHS Doctor, Chair & Co-Founder of Long Covid Doctors for Action (LCDA). ➲ ❂ 📖 (The Guardian ~ 6 Jul 2022) Who's clapping now? UK healthcare workers with Long Covid have been abandoned ➤ 📖 (PDF): (BMA ~ 4 July 2023) Over-exposed and under-protected: the long-term impact of COVID-19 on doctors ➤ 📖 Related: (BMJ ~ 29 Jan 2021) Up the line to death: Covid-19 has revealed a mortal betrayal of the world's healthcare workers ➤ 📖 Related: (Industrial Injuries Advisory Council ~ November 2022) Covid-19 and occupational impacts ➤

❦ Feeling validated that life is ‘back to normal’ as you see all of those unmasked people around you in restaurants, shops and cinemas? I’ll let you in on a little secret. Those who recognise the risk and who would be masked up aren’t even there. They are busy elsewhere staying healthy. More than 400 million now have Long Covid; a disease from Covid that can impact any organ system, and is proven to cause damage to the brain, heart, lung, kidney, gut, immune and multiple other systems. That’s one in 20 globally. How come you don’t know anyone with it? It’s one of three likely reasons… 1. They have been sick so long that they do what most chronically ill people do when they are asked, “How are you?” They say, “I’m fine”. 2. They don’t recognise the relation of their recent heart attack/memory impairment/new diabetes to their Covid illness in the last year. 3. It’s because they aren’t at that restaurant, movie, theatre, work night out as they don’t fancy worsening their already awful situation with a further infection. Out of sight, out of mind. Even those who know someone with Long Covid will minimise it, as it doesn’t fit with the general narrative that Covid is over. It’s too much cognitive dissonance for most people to handle. Easier to believe that everything’s OK, and it must ‘just be them being anxious’. It’s not over. I’ll let you in on another special secret; it’s not anxiety. It’s a calm determination to maintain health, in the full knowledge of what Covid can do. © 2023 NHS Palliative Care Medicine Consultant . ➲

❦ I have seen a disproportionate number of young patients with advanced cancer over the last two years. They used to stand out: now it’s every week. The evidence points to direct Covid-driven mechanisms for rises in cancer risk. Will you hear about it in the news? Of course not. Covid’s over. It’s just anxiety now if you’re thinking about it. Except it’s not. It’ll take years for people to accept this. It’ll be too late. A number of my oncology colleagues have been commenting on how they’ve never seen such aggressively-progressive cancers in all their careers since Covid arrived. I’ve been seeing it as all these patients come to me. It isn’t normal. Alarm bells should be ringing loudly. The evidence: 📖 (22 Mar 2023 ~ Global Journal of Life Sciences and Biological Research) Cancer Related-Genes Enriched in Peripheral Blood Mononuclear Cells (PBMCs) of COVID-19 Patients: A Bioinformatics Study ➤ ‘SARS-CoV-2 can be considered a potential risk factor for increasing the probability of developing cancer.’ Study 1: 📖 (7 Jun 2022 ~ Frontiers in Oncology) SARS-CoV-2 M Protein Facilitates Malignant Transformation of Breast Cancer Cells ➤ ‘Coronavirus disease 2019 (COVID-19) has spread faster due to the emergence of SARS-CoV-2 variants, which carry an increased risk of infecting patients with comorbidities, such as breast cancer.’ Study 2: 📖 (9 Aug 2022 ~ Journal of Infection ) Is SARS-CoV-2 an oncogenic virus? ➤ ‘Gene expression of p53 [tumour suppressor] is downregulated in blood of COVID-19 patients. Downregulation persists at least 24 weeks after infection in long COVID-19 patients. Long-term reduction of p53 could have impact on carcinogenesis.’ 📖 (9 Aug 2022 ~ Journal of Infection) Letter to the editor: Is SARS-CoV-2 an oncogenic virus? ➤ Study 3: 📖 (22 Mar 2023 ~ Global Journal of Life Sciences and Biological Research) Cancer related-genes enriched in peripheral blood mononuclear cells (PBMCs) of COVID-19 patients. A bioinformatics study ➤ ‘Numerous cancer-related genes up-regulated in SARS-CoV-2-infected patients, particularly those genes participating in the cell-cycle regulation or engaged in cellular senescence processes.’ Study 4: 📖 (2 Jun 2023 ~ Biochimie) Possible cancer-causing capacity of COVID-19: Is SARS-CoV-2 an oncogenic agent? ➤ ‘One of the most worrying long-term effects of infection is the potential to induce malignant neoplasms, which will be a major health concern over the coming decades. SARS-CoV-2 infection affects many mechanisms that play a crucial role in cancer onset and progression including cell-cycle regulation, the RAAS system and inflammation / proliferation signaling pathways.’ ❂ Related reading : 📖 (9 Aug 2021 ~ Nature: Scientific Reports) More than 50 Long-term effects of COVID-19: a systematic review and meta-analysis ➤ 📖 (21 Jun 2021 ~ Nature: Scientific Reports) The risk of pancreatic adenocarcinoma following SARS-CoV family infection ➤ 📖 (4 Mar 2021 ~ Nature: Scientific Reports) COVID-19 engages clinical markers for the management of cancer and cancer-relevant regulators of cell proliferation, death, migration, and immune response ➤ 📖 (28 Jan 2021 ~ Nature: Scientific Reports) Meta-analysis of host transcriptional responses to SARS-CoV-2 infection reveals their manifestation in human tumors ➤ 📖 (25 Jan 2010 ~ Nature: Oncogene) Viral epigenome in human tumorigenesis ➤ 📖 (Dec 2006 ~ Yale Journal of Biology and Medicine) Viruses and human cancer ➤ ❂ © 2023 NHS Medical Consultant .

❦ Researchers at The University of Queensland have discovered viruses such as SARS-CoV-2 can cause brain cells to fuse, initiating malfunctions that lead to chronic neurological symptoms. SARS-CoV-2, the virus that causes COVID-19, has been detected in the brains of people with 'Long COVID' months after their initial infection. "We discovered COVID-19 causes neurons to undergo a cell fusion process, which has not been seen before," Professor Hilliard said. "After neuronal infection with SARS-CoV-2, the spike S protein becomes present in neurons, and once neurons fuse, they don't die." "They either start firing synchronously, or they stop functioning altogether." As an analogy, Professor Hilliard likened the role of neurons to that of wires connecting switches to the lights in a kitchen and a bathroom. "Once fusion takes place, each switch either turns on both the kitchen and bathroom lights at the same time, or neither of them," he said. "It's bad news for the two independent circuits." The discovery offers a potential explanation for persistent neurological effects after a viral infection.  "In the current understanding of what happens when a virus enters the brain, there are two outcomes – either cell death or inflammation," Dr Martinez-Marmol said. "But we've shown a third possible outcome, which is neuronal fusion." Dr Martinez-Marmol said numerous viruses cause cell fusion in other tissues, but also infect the nervous system and could be causing the same problem there. "These viruses include HIV, rabies, Japanese encephalitis, measles, herpes simplex virus and Zika virus," he said. “Our research reveals a new mechanism for the neurological events that happen during a viral infection. “This is potentially a major cause of neurological diseases and clinical symptoms that is still unexplored.” ❂ 📖 (7 June 2023 ~ Science Advances) SARS-CoV-2 infection and viral fusogens cause neuronal and glial fusion that compromises neuronal activity ➤ 📖 (8 June 2023 ~ Queensland Brain Institute) COVID-19 can cause brain cells to 'fuse' ➤ © 2023 Martinez-Marmol & Hilliard / Queensland Brain Institute / University of Queensland.

❦ What if Covid has been causing mass cognitive impairment and we are all living in an increasingly stupid society? Mad things could happen with that: imagine if hospitals got rid of masks or people started to believe Covid was just a cold? I know that’s far-fetched, but imagine! ❂ © 2023 NHS Medical Consultant . ➲

❦ ‘Long COVID or post-COVID-19 condition (PCC) can affect anyone exposed to SARS-CoV-2, regardless of age or severity of the original symptoms, characterised by long-term health problems persisting or appearing after the typical recovery period of COVID-19. The presented evidence suggests that the duration of SARS-CoV-2 infection in patients can persist considerably longer than suggested by PCR-negative tests on nasopharyngeal swabs or bronchoalveolar lavage fluids. A US study including 40,947 participants with SARS-CoV-2 reinfection (two or more infections) indicated that reinfection further increases risks of death, hospitalisation, and sequelae in multiple organ systems in the acute and post-acute phases.’ ❂ 📖 (10 May 2023 ~ The Lancet: Respiratory Medicine) Association of SARS-CoV-2 infection and persistence with long COVID ➤ © 2023 Yang et al / The Lancet: Respiratory Medicine.

❦ ‘Some viruses are known to be associated with the onset of specific cancers. These micro-organisms – oncogenic viruses or oncoviruses – can convert normal cells into cancer cells. Seven oncogenic viruses are known to promote tumorigenesis [tumour creation] in humans: Human papillomavirus (HPV) Hepatitis B and C viruses (HBV, HCV) Epstein-Barr virus (EBV) Human T-cell leukemia virus 1 (HTLV-1) Kaposi sarcoma-associated herpesvirus (KSHV) Merkel cell polyomavirus (MCPyV) Recent research indicates that SARS-CoV-2 infection and COVID-19 progression may predispose recovered patients to cancer onset and accelerate cancer development . This hypothesis is based on the growing evidence regarding the ability of SARS-CoV-2 to modulate oncogenic pathways, promoting chronic low-grade inflammation and causing tissue damage.’ ❂ 📖 (25 Apr 2023 ~ International Journal of Molecular Sciences) Deciphering the Relationship between SARS-CoV-2 and Cancer ➤ © 2023 Costanzo et al / International Journal of Molecular Sciences.

❦ Critically ill COVID-19 patients are highly susceptible to opportunistic fungal infection due to many factors, including virus-induced immune dysregulation , host-related comorbidities, overuse and misuse of antibiotics or corticosteroids, immune modulator drugs, and the emergencies caused by the pandemic. Fungal coinfection is a common complication of critically ill COVID-19 patients admitted to the ICU. Candidiasis , aspergillosis , and mucormycosis are the most common COVID-19-associated fungal infections and have a great impact on mortality rates . ❂ 📖 (18 Apr 2023 ~ BMC Infectious Diseases) Fungal infection profile in critically ill COVID-19 patients: a prospective study at a large teaching hospital in a middle-income country ➤ © 2023 Negm et al / BMC Infectious Diseases.

❦ The results presented here reveal that at least 85% [of the 214 patients with post COVID-19 syndrome] exhibit deficits in one neuropsychological test . Also, the youngest patients were those who showed the most marked and heterogeneous cognitive impairment , while the oldest patients maintained their cognitive functions preserved to a greater extent with only a mild impairment in attention and speed processing. ❂ 📖 (19 Apr 2023 ~ Nature: Scientific Reports) Cognitive impairment in young adults with post COVID-19 syndrome ➤ © 2023 Herrera et al / Nature.

❦ ‘COVID-19 patients have a hypercoagulability state, and thrombosis is a life-threatening complication of them.’ ✻ Hypercoagulability , also known as thrombophilia , is a condition in which there is an abnormally increased tendency towards blood clotting . ‘From the early days of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) outbreak to the present, clinical and basic studies have indicated that coronavirus disease 2019 (COVID-19) may be associated with coagulopathy ( CAC ), which is involved in its related morbidity and mortality. Deep vein thrombosis ( DVT ) and pulmonary embolism ( PE ) are common in COVID-19 patients and are remarkably high in the intensive care unit (ICU)–admitted patients. CAC can lead to the formation of circulating microthrombi and macrothrombi which can involve multiple sites, including the lungs , brain , heart , and visceral organs like kidneys and spleen . There is a close relationship between the immune system and coagulation. The components of the hemostatic system play a role in the body’s immunity, and the activation of the immune system strongly influences the hemostatic system. Abnormal activation of the immune system may promote the growth of pathologies associated with thrombosis. COVID-19 is accompanied by an immune-cell hyperactivation and excessive production of proinflammatory cytokines , known as “ cytokine storm ”. CAC is theorized to result from dysregulated interactions between the immune and coagulation systems .’ ❂ 📖 (19 Apr 2023 ~ Annals of Hematology) Status of major hemostatic components in the setting of COVID-19: the effect on endothelium, platelets, coagulation factors, fibrinolytic system, and complement ➤ © 2023 Annals of Hematology .

❦ 'The risk of herpes zoster (HZ) ( Shingles ) remained significantly [+60%] higher in patients with COVID-19 compared with those without COVID-19. The higher risk of HZ in the COVID-19 cohort compared with that in the non-COVID-19 cohort remained consistent across subgroup analyses regardless of vaccine status, age, or sex. The risk of HZ within a 12-month follow-up period was significantly higher in patients who had recovered from COVID-19 compared with that in the control group. ❂ 📖 (18 Apr 2023 ~ Journal of Medical Virology) Long-term risk of herpes zoster following COVID-19: A retrospective cohort study of 2 442 686 patients ➤ © 2023 Journal of Medical Virology.

❦ ‘Pulmonary arterial hypertension (PAH) is a pulmonary vascular disease characterized by the progressive elevation of pulmonary arterial pressures.’ Pulmonary Arterial Hypertension ( PAH ) is a progressive lung disease that affects the heart and lungs . It is caused when the tiny arteries in the lungs become thickened and narrowed , causing abnormally high blood pressure in the pulmonary artery . Symptoms include shortness of breath during exercise, fainting spells , dizziness , swelling of the ankles or legs , chest pain , and a racing pulse . ‘It is becoming increasingly apparent that inflammation contributes to the pathogenesis and progression of PAH. Several viruses are known to cause pulmonary arterial hypertension (PAH) , such as SARS-CoV-2 , Human Endogenous Retrovirus K (HERV-K), and Human Immunodeficiency Virus ( HIV ), in part due to acute and chronic inflammation .’ ❂ 📖 (18 Apr 2023 ~ International Journal of Molecular Sciences) Human Endogenous Retrovirus, SARS-CoV-2, and HIV Promote PAH via Inflammation and Growth Stimulation ➤ © 2023 International Journal of Molecular Sciences .

❦ The full picture of post-COVID-19 autoimmune diseases and their prevalence is lacking despite numerous case reports and small series. Two studies that use large cohorts now highlight that SARS-CoV-2 infection is linked to a substantially increased risk of developing a diverse spectrum of new-onset autoimmune diseases . The reports by Chang et al and Tesch et al provide a comprehensive overview of diverse new-onset autoimmune conditions after COVID-19. In addition, an earlier preprint of a retrospective matched cohort analysis using data from the Clinical Practice Research Datalink Aurum database of 458,147 SARS-CoV-2-infected and 1,818,929 uninfected adults across England between 31 January 2020 and 30 June 2021 reported that the incidence of type 1 diabetes mellitus , inflammatory bowel disease and psoriasis are significantly associated with SARS-CoV-2 infection. Some of the earliest evidence that SARS-CoV-2 infection leads to dysregulated immune responses came from paediatric patients who presented with multisystem inflammatory syndrome in children (MIS-C) , which, as the name indicates, involves diffuse organ system involvement and a clinical spectrum that overlaps with other hyperinflammatory syndromes , such as Kawasaki disease , toxic-shock syndrome , and macrophage activation syndrome . Since the start of the pandemic, many researchers have also reported isolated cases of adults with various post-COVID-19 autoimmune conditions. ❂ 📖 (12 Apr 2023 ~ Nature Reviews: Rheumatology) High risk of autoimmune diseases after COVID-19 ➤ © 2023 Sharma & Jagadeesh / Nature.

❦ The Linseman Laboratory is studying the long-term brain health effects of COVID-19 in individuals with and without traumatic brain injury (TBI). Preliminary data suggest that those with a history of both COVID-19 and TBI experience more severe Long COVID symptoms, a higher symptom burden , and more frequent symptoms . Those who reported having COVID-19 and TBI reported worse depressive symptoms , worse functional outcomes , and increased fatigue . ❂ 📖 (4 Apr 2023 ~ SciTechDaily) Researchers Discover Connection Between Traumatic Brain Injury and Long COVID ➤ © 2023 Linesman Laboratory / University of Denver / SciTechDaily.

❦ The possible neurological consequences of SARS-CoV-2 infection, associated with physical and cognitive frailty, could lead to a worsening of Parkinson’s disease (PD) in infected patients or – more rarely – to an increase in the Parkinsonian symptomatology . Parkinson’s disease (PD) or Parkinsonism has been described after infections with viruses , such as the Epstein-Barr virus , hepatitis C virus , HIV , influenza A virus , Japanese encephalitis virus , varicella zoster virus , or West Nile virus . Therefore, the hypothesis that SARS-CoV-2 may have even longer-term effects on the brain and lead to an increase in cases of Parkinson’s disease, as occurred in the years following the Spanish flu , has been put forward. ❂ 📖 (23 Mar 2023 ~ Brain Science) Parkinson’s Disease, SARS-CoV-2, and Frailty: Is There a Vicious Cycle Related to Hypovitaminosis D? ➤ © 2023 Palermo et al / Brain Science.

❦ ‘Dr. Kashyap Patel (MD), CEO of Carolina Blood & Cancer Care Associates, sees something different in his practice since the onset of the COVID-19 pandemic – not just with cancer care, but with cancer itself. — “The trend is getting more and more alarming. We are noticing trends in hematological malignancies, breast cancer, colorectal carcinoma and pancreatic cancer.” With COVID-19 added to the mix, Patel now fears a “perfect storm” of factors will trigger inflammatory responses in some patients, causing cancer to arrive years earlier than normal and making it deadlier once it is diagnosed.’ ❂ 📖 (22 Mar 2023 ~ Evidence-Based Oncology) Kashyap Patel, MD, Sees Link Between COVID-19 and Cancer Progression, Calls for More Biomarker Testing ➤ © 2023 Hayden Klein / Evidence-Based Oncology.

❦ It's no wonder that depression and PTSD rates ✢ are up in people living with Long COVID. ✢ Long COVID: major findings, mechanisms and recommendations ➤ There are no approved therapies for the physical or cognitive disabilities that now plague 65 million people around the world, a conservative estimate given the degree of undocumented cases. It is now clear from US and UK investigations of approximately 2,000 previously hospitalized Covid patients that six months later more than half have problems managing finances and paying bills as well as completing everyday activities like preparing meals, bathing, getting dressed, or walking across a room. But what exactly is going on inside the brains of these people from a biological and pathological perspective? Autopsy studies show that the virus can persist ✢ in some people for many months even though they have no symptoms and test negative for the virus. ✢ Persistent SARS-CoV-2 infection in patients seemingly recoveredfrom COVID-19 ➤ Brains donated by people who died of Covid-19 also show widespread problems in the cells lining the blood vessels and exaggerated clotting, supporting the idea of Covid-19 as a blood flow disorder ✢ that brings on brain disease. ✢ Neurovascular injury with complement activation and inflammation in COVID-19 ➤ Perhaps the most harrowing thing I have done in 30 years as a physician-scientist has been to ask family members I'd never met, often in the middle of the night via telephone during the height of the Covid surges, if I and my colleagues could study their loved one's brain. In a study we conducted of 20 of these priceless brain donations ✢ , we found brain swelling due to decreased blood flow and heightened activity in microglial cells, the so-called 'white matter' in brains that support the neurons that transmit thoughts and help store information. We saw this even in young previously healthy individuals. ✢ Brain autopsies of critically ill COVID-19 patients demonstrate heterogeneous profile of acute vascular injury, inflammation and age-linked chronic brain diseases ➤ A study from the National Institutes of Health of 44 complete autopsies ✢ mapped and quantified the distribution of SARS-CoV-2 and showed it was widely distributed throughout the body, including in the hypothalamus and cerebellum in the brain and neurons in the spinal cord. ✢ SARS-CoV-2 infection and persistence in the human body and brain at autopsy ➤ Especially relevant to Long Covid, viral fragments were detected in some of the brains of people who died many months after symptom onset. In Their Own Words Barbara Nivens, who retired from retail management at age 59, has been diagnosed by her neurologist as having rapid onset dementia due to Covid-19. An incredibly thorough medical work-up found no plausible causes for this dementia other than its onset following her Covid infection, which she contracted before the vaccine was available. Matt Fitzgerald, age 26, is a mechanical engineer who worked for Tesla and now designs surgical devices – when he can. Since recovering from his initial bout with Covid-19, he's developed a condition characteristic of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) known as post-exertional malaise, which is why even slight exertion leaves him and millions like him inexplicably incapacitated. ❦ Barbara Nivens: — “I walk down the hall and see dozens of pictures of family trips and feel like a ghost because I don't remember any of them. Now I'm trying to figure out who Barbara 2.0 is going to be.” (Her husband, tearing up as he listened to her, said softly, “I just want my wife back.”) ❦ Matt Fitzgerald: — “I feel like I'm underwater. When you talk to me, I can hear you, but my brain does not understand the words. I can't comprehend what you're saying. I have no intellectual capacity or energy to digest data. At work my brain is just begging for rest. I struggle with finding words and completing tasks in a timely manner. It's the worst. I'll be in a meeting and know exactly what I want to say before I say it. I'll start saying it and I'll get to a word, and I just cannot think of the word. I'll just be like, ‘Give me a moment,’ and I'll go through my brain cycling through words. This week it was 'consistent'. I couldn't think of the word 'consistent'. I kept thinking it was 'coincident' or 'concentric' or 'constant'.” Such problems in executive function, memory, and processing speed are what many people complain about in the Long COVID support groups. Science validates their injuries. A picture is emerging from animal models showing how on-going inflammation of glial cells disrupts the electrical conduction highways in the brain's white matter that link to and support the neurons in gray matter. It's as if the bridges (white matter) linking different territories of the brain have been blown up and the land itself (nerves in the cerebral cortex and hippocampus) becomes scorched, leaving people with Long COVID plagued by thinking and memory deficits. ❂ 📖 (16 Feb 2023 ~ Stat) The haunting brain science of Long COVID ➤ © 2023 E. Wesley Ely / Stat.

❦ ‘A new comprehensive study of organ impairment in long COVID patients over twelve months shows organ damage persisted in 59% of patients a year after initial symptoms , even in those not severely affected when first diagnosed with the virus. The study, published in the Journal of the Royal Society of Medicine, focused on patients reporting extreme breathlessness , cognitive dysfunction and poor health-related quality of life . 536 long COVID patients were included in the study. 13% were hospitalised when first diagnosed with COVID-19. 32% of people taking part in the study were healthcare workers . Of the 536 patients, 331 (62%) were identified with organ impairment six months after their initial diagnosis. These patients were followed up six months later with a 40-minute multi-organ MRI scan (Perspectum’s CoverScan), analysed in Oxford. The findings confirmed that 29% of patients with long COVID had multi-organ impairment , with persistent symptoms and reduced function at six and twelve months . 59% of long COVID patients had single organ impairment twelve months after initial diagnosis . A member of the research group, Professor Amitava Banerjee, Professor of Clinical Data Science at the UCL Institute of Health Informatics, said: “Symptoms were common at six and twelve months and associated with female gender , younger age and single organ impairment .” The study reported a reduction in symptoms between six and twelve months (extreme breathlessness from 38% to 30% of patients, cognitive dysfunction from 48% to 38% of patients and poor health-related quality of life from 57% to 45% of patients). Professor Banerjee added: “Several studies confirm persistence of symptoms in individuals with long COVID up to one year . We now add that three in five people with long COVID have impairment in at least one organ , and one in four have impairment in two or more organs , in some cases without symptoms .” He said: “ Impact on quality of life and time off work, particularly in healthcare workers , is a major concern for individuals, health systems and economies . Many healthcare workers in our study had no prior illness, but of 172 such participants, 19 were still symptomatic at follow-up and off work at a median of 180 days.” The underlying mechanisms of long COVID remain elusive, say the researchers, who did not find evidence by symptoms, blood investigations or MRI to clearly define long COVID subtypes. They say that future research must consider associations between symptoms, multi-organ impairment and function in larger cohorts. Prof Banerjee concluded: “Organ impairment in long COVID has implications for symptoms, quality of life and longer-term health, signalling the need for prevention and integrated care for long COVID patients.” ❂ 📖 (15 Feb 2023 ~ The Royal Society of Medicine) Organ damage for 59% of patients with long COVID continues a year after initial symptoms ➤ © 2023 The Royal Society of Medicine .

❦ Cognitive postscripts of COVID-19 , codenamed as ‘cognitive COVID' or ‘brain fog’, characterized by multi-domain cognitive impairments, are now being reckoned as the most devastating sequelae of COVID-19 . The rapid progression of dementia , the addition of further impairments/deterioration of cognitive abilities , and the increase or new appearance of white matter lesion burden suggest that previously compromised brains have little defense to withstand a new insult (i.e., a ‘second hit’-like infection/dysregulated immune response, and inflammation). ❂ 📖 Related: (4 Apr 2023 ~ Eurekalert) New study shows SARS-CoV-2 infection accelerates the progression of dementia ➤ ‘ All subtypes of dementia , irrespective of patients' previous dementia types, behaved like rapidly-progressive dementia following COVID-19 .’ 📖 Related: (4 Apr 2023 ~ NeuroscienceNews) COVID-19 Infection Accelerates the Progression of Dementia ➤ ‘A rapidly and aggressively deteriorating course was observed in patients having insidious-onset, slowly-progressive dementia, and who were previously cognitively stable .’ ❂ 📖 (14 Feb 2023 ~ Journal of Alzheimer's Disease Reports) The Effects of SARS-CoV-2 Infection on the Cognitive Functioning of Patients with Pre-Existing Dementia ➤ © 2023 Dubey et al / Journal of Alzheimer’s Disease Reports.

❦ Lymphopenia , particularly when restricted to the T-cell compartment, has been described as one of the major clinical hallmarks in patients with coronavirus disease 2019 ( COVID-19 ) and proposed as an indicator of disease severity. Although several mechanisms fostering COVID-19-related lymphopenia have been described, including cell apoptosis and tissue homing, the underlying causes of the decline in T-cell count and function are still not completely understood. Patients with COVID-19 had reduced thymic function that was inversely associated with the severity of the disease. Our data demonstrate that the human thymus is a target of SARS-CoV-2 and thymic function is altered following infection . Note: Lymphopenia (also called lymphocytopenia) is a disorder in which your blood doesn't have enough white blood cells called lymphocytes. Lymphocytes play a protective role in your immune system. ❂ 📖 (7 Feb 2023 ~ Journal of Allergy and Clinical Immunology) SARS-CoV-2 infection of thymus induces loss of function that correlates with disease severity ➤ © 2023 Rosichini e t al / Journal of Allergy and Clinical Immunology.

❦ ‘Acute ischemic stroke (AIS) is a fearful complication of Coronavirus Disease-2019 (COVID-19). SARS-CoV-2 infection seems to play a major role in endothelium activation and infarct volume extension during AIS.’ ❂ 📖 (10 Jan 2023 ~ Frontiers in Cardiovascular Medicine) SARS-CoV-2 infection predicts larger infarct volume in patients with acute ischemic stroke ➤ © 2023 Frontiers in Cardiovascular Medicine .

❦ Strikingly, the [foetal brain] haemorrhages are predominately found in the late first and early second trimester of gestation , a period of development in which the effect of the COVID-19 pandemic has not been thoroughly investigated. Specifically, the majority were between 12 and 14 pcw, a critical window of human foetal brain development when the endothelial tight junctions increase to form the blood-brain barrier . Our observations of disrupted foetal cerebral vasculature are consistent with reports of damage to the microvasculature of the adult brain in SARS-CoV-2 infected patients . ❂ 📖 (16 Jan 2023 ~ Brain) Haemorrhage of human foetal cortex associated with SARS-CoV-2 infection ➤ © 2023 Massimo et al / Brain.

❦ ‘The narrative that COVID-19 had only respiratory sequelae led to a delayed realization of the neurological, cardiovascular and other multi-system impacts of COVID-19. Long COVID is a multi-systemic illness encompassing ME / CFS , dysautonomia , impacts on multiple organ systems , and vascular and clotting abnormalities . Circulatory system disruption includes endothelial dysfunction and subsequent downstream effects, and increased risks of deep vein thrombosis , pulmonary embolism and bleeding events . Microclots detected in both acute COVID-19 and long COVID contribute to thrombosis.’ ✻ Endothelial dysfunction precedes atherosclerosis and is an independent predictor of cardiovascular events. Atherosclerosis is a condition where plaque , a sticky substance made up of fat, cholesterol, calcium, and other substances found in the blood, hardens and narrows the arteries , limiting the flow of oxygen-rich blood to the body . Deep vein thrombosis ( DVT ) is a blood clot that forms in a deep vein , usually in the pelvis , calf , or thigh . A pulmonary embolism [ PE ] is a blood clot that blocks and stops blood flow to an artery in the lung . Often the clot starts in a leg and travels to the lung. ‘Long-term changes to the size and stiffness of blood cells have also been found in long COVID, with the potential to affect oxygen delivery. A long-lasting reduction in vascular density , specifically affecting small capillaries, was found in patients with long COVID 18 months after infection . Long COVID has already debilitated millions of individuals worldwide, and that number is continuing to grow. On the basis of more than two years of research on Long COVID and decades of research on conditions such as ME/CFS, a significant proportion of individuals with Long COVID may have lifelong disabilities if no action is taken. Diagnostic and treatment options are currently insufficient , and many clinical trials are urgently needed to rigorously test treatments that address hypothesized underlying biological mechanisms, including viral persistence, neuroinflammation, excessive blood clotting and autoimmunity.’ ❂ 📖 (13 Jan 2023 ~ Nature Reviews: Microbiology) Long COVID: major findings, mechanisms and recommendations ➤ © 2023 Davis et al / Nature .

❦ ‘Long COVID impacts children of all ages . Children with Long COVID experience fatigue, post-exertional malaise (PEM), cognitive dysfunction, memory loss, headaches, orthostatic intolerance, sleep difficulty and shortness of breath. ❦ Post-exertional malaise (PEM) = The worsening of symptoms following even minor physical or mental exertion, with symptoms typically worsening 12 to 48 hours after activity and lasting for days or even weeks. ❦ Cognitive dysfunction = deficits in attention, verbal and non-verbal learning, short-term and working memory, visual and auditory processing, problem solving, processing speed, and motor functioning. ❦ Orthostatic intolerance = The inability to remain upright without symptoms. Liver injury has been recorded in children who were not hospitalized during acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections, and although rare, children who had COVID-19 have increased risks of acute pulmonary embolism, myocarditis and cardiomyopathy, venous thromboembolic events, acute and unspecified renal failure, and type 1 diabetes. Infants born to women who had COVID-19 during pregnancy were more likely to receive a neurodevelopmental diagnosis in the first year after delivery. A paediatric Long COVID centre’s experience treating patients suggests that adolescents with a moderate to severe form of Long COVID have features consistent with myalgic encephalomyelitis (ME) / chronic fatigue syndrome (CFS) . ❦ Myalgic encephalomyelitis / Chronic fatigue syndrome = (ME/CFS) is a condition that causes extreme tiredness and a range of other symptoms. Other symptoms of ME/CFS may include: ⊙ Tender lymph nodes in the neck or armpits. ⊙ A sore throat that happens often. ⊙ Digestive issues, like irritable bowel syndrome. ⊙ Chills and night sweats. ⊙ Allergies and sensitivities to foods, odors, chemicals, light, or noise. ⊙ Muscle weakness. ⊙ Shortness of breath. ⊙ Irregular heartbeat. Children experiencing Long COVID have hypometabolism in the brain similar to the patterns found in adults with Long COVID. ❦ Hypometabolism in the brain = Characterized by decreased brain glucose consumption, is a common feature of many neurodegenerative diseases . The initial hypometabolic brain state created by characteristic risk factors may predispose the brain to acquired epilepsy and sporadic Alzheimer's and Parkinson's diseases . Long-term pulmonary [lung] dysfunction is found in children with Long COVID, and in those who have recovered from COVID-19. Children with Long COVID were more likely to have had attention deficit hyperactivity disorder, chronic urticaria and allergic rhinitis before being infected. Fatigue, headache, dizziness, dyspnoea, chest pain, dysosmia, dysgeusia, reduced appetite, concentration difficulties, memory issues, mental exhaustion, physical exhaustion and sleep issues were between 2 and 36 times more likely in individuals with Long COVID aged 15-19 .’ ❦ Dyspnoea = shortness of breath, or breathlessness. ❦ Dysosmia = a change in the ability to smell. ❦ Dysgeusia = a change in perception of taste. ❂ 📖 (13 Jan 2023 ~ Nature Reviews: Microbiology) Long COVID in children ➤ 📖 (13 Jan 2023 ~ Nature Reviews: Microbiology) Long COVID: major findings, mechanisms and recommendations ➤ © 2023 Nature.

❦ Globally, millions of people have contracted COVID-19 over the past few years, and some have even caught the virus two or more times. Of more than 665 million cases worldwide, nearly one in two people with COVID-19 is at risk of developing Post-COVID-19 Neurological Syndrome (PCNS). Symptoms of Post-COVID-19 Neurological Syndrome (PCNS) mimic some of the symptoms we see after a stroke, and younger adults seem to be at particular risk. It’s worth noting that a link between brain health and Coronavirus infections has been known since 2006, so in this context the long-term impact of COVID-19 on the brain may arguably be the expectation rather than the exception. Nearly one in two people who have reportedly recovered from acute COVID-19 cite disabling fatigue – that is, fatigue lasting more than twelve weeks – coupled with a series of attention and cognitive deficits similar to persistent post-stroke neurological symptoms. We have already reported on the shared pathobiology between stroke and COVID-19 at a cellular level. So, it should not be surprising to see the long-term impact on the brain with a persistent inflammatory response (potentially due to viral persistence, immune dysregulation or autoimmunity). ❂ 📖 Related: (1 Jan 2023 ~ The Lancet) The prevalence and long-term health effects of Long Covid among hospitalised and non-hospitalised populations: A systematic review and meta-analysis ➤ 📖 Related: (7 Mar 2022 ~ Nature) SARS-CoV-2 is associated with changes in brain structure in UK Biobank ➤ 📖 Related: (12 Jan 2021 ~ Australian Journal of General Practice) COVID-19 and long-term neurological problems: Challenges ahead with Post-COVID-19 Neurological Syndrome ➤ 📖 Related: (1 Feb 2006 ~ Nature Reviews Microbiology) Coronavirus infection of the central nervous system: host-virus stand-off ➤ 📖 Related: (28 Jan 2021~ Frontiers in Neurology) COVID-19 Pathophysiology Predicts That Ischemic Stroke Occurrence Is an Expectation, Not an Exception - A Systematic Review ➤ ❂ 📖 (6 Jan 2023 ~ University of Melbourne) What we now know about long COVID and our brains ➤ © 2023 Wijeratne et al / University of Melbourne.

❦ ‘In the most comprehensive autopsy tissue study conducted to date, researchers have found traces of the SARS-CoV-2 virus throughout the entire body, from the brain and the heart to the eyes. The findings indicate the virus can cause persistent infections in many parts of the body, months past an initial illness, and support the argument for further research into antiviral drugs as possible treatment for long COVID. The findings revealed SARS-CoV-2 RNA could be detected in 84 different locations in the body. The highest burden of viral RNA was found in airway and lung tissue – however, the virus was also detected in the brain, gut, heart, kidney, eye, adrenal gland and lymph nodes.’ ❂ 📖(4 Jan 2023 ~ New Atlas) Large COVID autopsy study finds SARS-CoV-2 all over the human body ➤ 📖 (14 Dec 2022 ~ Nature) SARS-CoV-2 infection and persistence in the human body and brain at autopsy ➤ © 2023 Rich Haridy / New Atlas.

❦ ‘In 2021, SARS-CoV-2-related severe neurologic involvement in US hospitalized children and adolescents showed a potential increase in diagnoses of acute central nervous system infections / demyelination. In this case series of 2168 US patients younger than 21 years hospitalized for acute COVID-19 (34%) or multisystem inflammatory syndrome in children (66%), 476 (22%) had neurologic involvement. Of these, 42 (9%) had life-threatening conditions, with 23 (55%) having acute central nervous system (CNS) infections / demyelination; 18 of 42 (43%) died or had new neurologic deficits; and most vaccine-eligible patients were unvaccinated.’ ❂ 📖 (1 Jan 2023 ~ JAMA Network / Neurology) Changes in Distribution of Severe Neurologic Involvement in US Pediatric Inpatients With COVID-19 or Multisystem Inflammatory Syndrome in Children in 2021 vs 2020 ➤ 📖 Related: (5 Jan 2023 ~ Neurology Today) Nearly One-Fifth of Hospitalized Children and Adolescents with SARS-CoV-2 or MIS-C Have Persistent Neurologic Complications ➤ © 2023 LaRovere et al / JAMA: Neurology.

❦ COVID-19 causes lung fibrosis. It affects the immune system, and it causes liver fibrosis * . * 📖 (11 Oct 2021 ~ BMC Gastroenterology) Intriguing findings of liver fibrosis following COVID-19 ➤ COVID-19 causes brain inflammation and heart inflammation, strokes, heart attacks and large blood clots. COVID-19 causes diabetes. * 📖(18 Mar 2022 ~ NewsGP) Diabe tes ris k could be 28% higher after COVID infection ➤ COVID-19 can cause kidney failure. I could go on... and on. Bone necrosis, joint pain, hair and teeth falling out. Do you normally expect a cold to make your teeth fall out? * 📖 (10 Feb 2022 ~ Frontiers in Oral Health) Impa ct of COVID-19 on Periodontitis and Peri-Implantitis: A Narrative Review ➤ Look up ‘lung fibrosis’ and ‘liver fibrosis’. Google them, and read about the complications. Read how patients that have these progressive diseases die. (Apologies to patients that already know.) Time and again, these patients have said to me (particularly when I was a young medical student): “Don’t do what I did.” “Don’t smoke.” “Alcohol is...” “I wish I had never...” “Save yourself...” Of those dying of infectious causes of lung and liver fibrosis: “Why me...?” “I wish I could have avoided that infection...” Stop. Stop as many COVID infections as you can. Stop now. Now is your chance to avoid treading these terrible paths. Once COVID has weakened your organs and immune system, every other pathogen – and even some environmental/commensal bugs – can move in... You will feel nothing wrong, nothing wrong, nothing wrong... then... the cascade of deterioration will snowball. Stop now while you are still in the “I feel nothing wrong” phase. There may well already be stuff wrong, but it’s better to try to stay in this phase than accelerate towards death any faster than is avoidable. No, not everyone will get every effect to the same extent, but macrophages do get activated by COVID (as well as other immune pathways and cells). Some of the inflammation in the body has been observed for months. That is a recipe for damage and fibrosis. I wrote this after hearing – again and again – “I have a cough, it just won’t budge, and it’s not COVID”. I don’t know what's causing all the coughing. Could be anything... but this is one of the ways I would expect widespread prevalence of lung damage to present. It’s also one of the ways I would expect chronic infections with slow-growing pathogens (like TB or atypical pneumonias) to present... Chronic coughs can also have other malignant or serious causes. These should be assessed and monitored by a GP if it’s not budging. Please... try to look after yourselves.. . © 2023 Dr. Noor Bari . ➲