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Year : 2020  |  Volume : 8  |  Issue : 2  |  Page : 173-185

Gaps in knowledge: Unmasking post-(Acute) COVID-19 syndrome and potential long-term complications in COVID-19 survivors

Department of Neurology, Yenepoya Medical College, Yenepoya (Deemed to be) University, Mangalore, Karnataka, India

Date of Submission20-Nov-2020
Date of Decision28-Nov-2020
Date of Acceptance29-Nov-2020
Date of Web Publication23-Dec-2020

Correspondence Address:
Prof. Bhaskara P Shelley
Department of Neurology, Yenepoya Medical College, Yenepoya (Deemed to be) University, Mangalore-575 018, Karnataka
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/amhs.amhs_324_20

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How to cite this article:
Shelley BP. Gaps in knowledge: Unmasking post-(Acute) COVID-19 syndrome and potential long-term complications in COVID-19 survivors. Arch Med Health Sci 2020;8:173-85

How to cite this URL:
Shelley BP. Gaps in knowledge: Unmasking post-(Acute) COVID-19 syndrome and potential long-term complications in COVID-19 survivors. Arch Med Health Sci [serial online] 2020 [cited 2021 Dec 5];8:173-85. Available from: https://www.amhsjournal.org/text.asp?2020/8/2/173/304734

What's true of all the evils in the world is true of plague as well. It helps men [sic] to rise above themselves.Albert Camus,The Plague

”Each individual is an expression of the collective consciousness of humanity, and the collective consciousness of humanity is an expression of the one universal consciousness.”Eckhart Tolle

Man in his entirety has been governed by his own created philosophy based on the orthodoxy of scientism and the empirical knowledge from the tangible scientific methodology. Thus, the phenomenal progress of Man's Science and the Industrial Revolution has impacted on the multitude facets of humanity, where man has become the master of destiny of the human species and the collective life of humanity on our Terra Madre (Mother Earth). Perhaps as a deluge of my naive (pseudoscience) thoughts through the lens of Greek mythology of Goddess Gaia (Earth Goddess) and James Lovelock's Gaia hypothesis, I ask “Is Nature's mother God sending us a message with the COVID-19 storm?” “Is COVID-19 a symptom of Gaia's sickness?”[1] On the 50th anniversary of the Earth Day, 22nd April 2020, the Pope Francis reiterated the need to protect “our garden-home, our Mother Earth”, that creation must be protected and not exploited, and that nature will not forgive our trespasses. He recounted a Spanish proverb “God always forgives, man sometimes forgives but nature never forgives” in the context of COVID-19 and made a proclamation for Environmental stewardship. It is my steadfast conviction that coronavirus 2019 (COVID-19) is perhaps one such reality of a catastrophe stemming from Man's ideology of Anthropocentrism, an absolute decry of Biospheric egalitarianism and Planetary health, and Man's dereliction of moral responsibility for an Earth-Environmental Stewardship strategy.

Humankind should envision “One Nature” Post-COVID-19 Planetary health governance. This will certainly transcend our current astigmatism of 'false binaries' i.e. Humans versus Nature, and Humans versus Non-Humans. This co-existentialism and harmony of different species of living creatures, including plants and animals is notably embraced in the Indian tradition, the concept of Vasudhaiva Kutumbakam that originated initially from ancient Sanskrit text of Maha Upanishad and later in the literary works of Hitopadesha. To my soulful mind, this renewed philosophical view, would be pivotal in paving the way for Environmental justice and Biospheric egalitarianism. Such a post-anthropocentric conceptualization would be a progressive and transformative futuristic policy to prevent zoonotic spillover emerging infectious disorders, and future ecological crisis. The humanity of Humans must be re-awakened so as to avert a dystopian future and possible human and biological annihilation on Planet Earth. The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic is undoubtedly a cataclysmic health crisis, but its ripple effects have traumatized and fractured almost all the pillars of our dynamic and thriving human society. To “hit the nail on the head,” I would only reiterate that the COVID-19 pandemic is indeed a grim “SOS signal for the human enterprise” on Planet Earth for a “One Health” concept (rethinking health at the Human- Animal-Environmental-Ecosystem Interface). The 'One Health' Perspective was in fact a key focus session as part of the COVID-19 Summit in November 2020 by Cornell University researchers in the United States. I would state that the future of Mankind and Earth systems needs an exit from the Anthropocene and an entry to an era of Symbiocene that resonates with the mindset of Ernest Hemingway, “The Earth is a fine place and worth fighting for.” It has been my steadfast philosophy that science and technology alone cannot solve the panoply of challenges imposed by COVID-19 pandemic, but pluralistic approaches, most importantly humanities and behavioral and social sciences, must help and be on the top of the COVID-19 research agenda. This notion resonates with the affirmations made by Viktor Frankl, i.e., “When we are no longer able to change a situation, we are challenged to change ourselves. Everything can be taken from a man but one thing: the last of the human freedoms–to choose one's attitude in any given set of circumstances, to choose one's own way. Between stimulus and response there is a space. In that space is our power to choose our response. In our response lie our growth and our freedom.”

The acute COVID-19 illness, human sufferings, and the catastrophic loss of lives unequivocally do represent large collective wreckage in human history. COVID-19 pandemic underscores how emerging infectious diseases are presenting an existential threat to humanity. At the time of writing, the rapidly evolving SARS-CoV-2 pandemic has spread across 217 countries that have led to a cumulative total of 52,454,684 confirmed cases with over 1,289,983 global deaths and a recovery of 36,685,543 cases. After a dip in new cases during June–August, Europe and the United Kingdom are now reporting a second wave with a far higher number of cases than during its previous peak. The United States, too, is going through resurgence. As the tragedy of acute COVID-19 infectious disease is ravaging across the globe, the world now seems to be pinning all of its hopes on the COVID-19 vaccine race. Scientists around the world are working at an unprecedented pace to develop safe and effective vaccines that could generate long-lasting protective immunity against SARS-CoV-2 and provide population immunity, thus reducing the transmission of SARS-CoV-2 infection. Not sounding too Pollyannaish, I would now like to draw attention to the two dark sides of the prevailing COVIDomics. (i) the acute illness of COVID-19 and (ii) the hidden (unexpected) long-term health complications among COVID-19 survivors. COVID-19 has spread worldwide since first being recognized in Wuhan, a city in Central China, in December 2019. Even though the number of COVID-19 cases worldwide now has approached astronomical numbers, we are still amazed how little we know about this very complex disease. The clinical spectrum varies widely. Up to 40% of people infected with SARS-CoV-2 never develop symptoms. About 80% of those who do become symptomatic have a mild illness that does not require hospitalization; about 15% are sick enough to require hospitalization; however, only 5% require care in an intensive care unit (ICU), usually for mechanical ventilation to treat respiratory insufficiency.

Early in the pandemic, many people believed that COVID-19 was a short-term illness. With the acute COVID-19 infection, there was no sense of what was coming next in the first few months. There is now emerging preliminary knowledge of subacute and long-term health worrisome and grave consequences in the post–acute-COVID-19 phase, a COVID-19 survivorship syndrome. The prevalence of post–COVID-19 long-term complications is not yet fully known and may only become apparent in the months and years to come. An article in the November issue of JAMA has suggested a proposed framework and timeline of the spectrum of SARS-CoV-2 infection.[2] The timeline for the spectrum of COVID-19 illness could be categorized into (i) acute COVID-19 infection, (ii) postacute hyperinflammatory illness, and (iii) late inflammatory and virological sequelae. It is possible that the late sequelae of COVID-19 represent multiple syndromes resulting from distinct pathophysiological processes along the spectrum of disease. Such a framework would have important implications for public health surveillance, clinical research, future treatments, and health services planning.

The relevance of this Editorial is to encapsulate the long-term health consequences (i.e., the third illness period of the proposed framework) that are now adding to the ever-emerging landscape of medical knowledge on COVID-19. I would reiterate that the health problem does not stop with the first (acute) COVID-19 illness. I would not hesitate to state that it seems to be a dangerous illusion that survivors could be discharged home COVID-free without further medical attention. The end of a clinical acute COVID-19 disease may seem to be the beginning of a silent wave of under-recognized long-term sequelae, a second wave of challenges, the aftermath of COVID-19 survivor syndrome, namely the post–(acute) COVID-19 syndrome. This post–COVID-19 recovery phase does seem to be a longer and harder aftermath, does indeed mark the onset of a broader challenge, certainly not the end of the crisis, and does portray a Sisyphean challenge. The war on COVID-19 pandemic is far from over akin to the adage, “It's not over until it's over.” This sets alarm bells for the entire healthcare fraternity to recalibrate our healthcare environment and health teams to be able to effectively provide patient-centric, team-based multidisciplinary care and rehabilitation ensuring a good quality of life (QoL) in such post–COVID-19 survivors. The quote cited above by Albert Camus in his fictional novel “The Plague” symbolizes a way of overcoming nihilism exemplified through the fight against an epidemic. Therefore, global healthcare community will need to summon the collective Hercules ethos as a collective solidarity of the human spirit, commitment, empathy, and collective innate human resilience not only to transcend the first wave of acute COVID-19 crisis but also to recognize and effectively establish protocols for battling the emerging second wave of “post–acute-COVID-19 syndrome” and other long-term health-related sequelae.

  My Journey with COVID-19 and Post-COVID Syndrome Top

Allow me to share my self-reflective narrative of my COVID-19 illness behavior. My positive nasopharyngeal RT-PCR COVID-19 journey began in September 2020 where I became unwell with a symptom complex of a persistent raging fever for 2 weeks, during which time I developed olfactory disturbances, dysgeusia, watery diarrhea, cough with mucoid sputum, chest pressure, mild dyspnea, headache, malaise, and musculoskeletal aches. These were hellish days where I was literally hit with a wave of extreme fatigue, had fever with rigors, and had lost appetite. I had lost 5 kg of my body weight during this illness period. I was virtually bed-bound for about 2 weeks with acute COVID-19. I had fairly deep restful sleep but was colored by “emotionally intense” vivid movie-like dreams, often negatively-toned dreams (fever dreams). The 21 days of self-quarantine caused anxiety symptoms and a sense of helplessness in me. I became afebrile by the end of 2 weeks and resumed my work by the end of the 3rd week. By the end of the 3rd week, my rapid antigen test was negative, and as I rejoined my work, I found myself to be vexed by lingering rollercoaster symptoms comprising malaise and exhaustion, diffuse myalgia, joint pains, physical fatigue, dry cough, smell and taste disturbances, anorexia, insomnia (COVID-somina) with nonrestorative sleep, lethargy, and subtle neurocognitive difficulties (”brain fog”), all of which caused difficulty to engage fully in day-to-day activities. I currently feel that I am living in a “COVID cycle” of symptoms that are present to this day. Intrigued and perplexed by these constellation of new symptoms after I have recovered from COVID-19, my innate curiosity, self-inquiry, and self-directed temperament of seeking answers to my new-found persistent symptom complex led me to the newly emerging diagnosis of Post–COVID-19 syndrome. I do feel that I am now beginning to see the light at the end of this spiraling “COVID tunnel” as I feel I am not alone and there seems to be evidence of post–COVID syndrome (PCS) from across the world. This undoubtedly was indeed reassuring to me and that I was not suffering from a health anxiety and/or illness anxiety disorder. I don't know what's in store for me. It's never easy and it's never over, but for sure I will get through this Post COVID-19 syndrome.

  Decoding Post-COVID-19 Syndrome Top

COVID-19 is a complex disease with a wide spectrum of clinical patterns. COVID-19 clinical spectrum does range from asymptomatic or paucisymptomatic to severe clinical presentations with life-threatening outcomes. Although predominantly a respiratory illness, emerging data suggest that multiorgan injury is common, particularly in those with moderate-to-severe infections. Most of the infections are not severe, but 81% are mild (no or mild pneumonia), 14% manifest themselves through a severe disease (with dyspnea, hypoxia, or >50% lung involvement on imaging within 24–48 h), and 5% develop a critical illness (e.g., with respiratory failure, shock, or multiorgan dysfunction). It is interesting to note that seven different forms of mild COVID-19 were published in November by a team of MedUni Vienna scientists led by immunologist Winfried F. Pickl. The research showed the seven symptom cluster groups of symptoms in mild COVID-19: (1) “flu-like symptoms” (with fever, chills, fatigue, and cough), (2) “common cold-like symptoms” (with rhinitis, sneezing, dry throat, and nasal congestion), (3) “joint and muscle pain,” (4) “eye and mucosal inflammation,” (5) “lung problems” (with pneumonia and shortness of breath), (6) “gastrointestinal (GI) problems” (including diarrhea, nausea, and headache), and (7) “loss of sense of smell and taste and other symptoms.”

PCS is a collection of symptoms that persist for 2 or more months following the initial infection with the SARS-CoV-2 virus. PCS is defined as post–acute-COVID-19 as extending beyond 3 weeks from the onset of first symptoms and chronic COVID-19 (otherwise called as “Long COVID” or post–COVID “Long Haulers” or “Long Haul COVID”) as extending beyond 12 weeks.[3] In another word, “Long COVID” is a term being used to describe a multisystem disease in people who have either recovered from a relatively mild acute COVID-19 illness but are still report lasting effects of the infection or have had the usual symptoms for far longer than would be expected. Long COVID is a patient-made term, first used by Elisa Perego (a research associate at the University College London) in May 2020 to describe her own COVID-19 experience. The most noticeable finding to date about PCS or Long COVID syndrome is that one does not need to have suffered from severe COVID to get this condition. Previously healthy adults who had mild symptoms and recovered from COVID-19 without ever-needing intensive care are also reporting subacute to long-lasting, debilitating symptoms even 2–3 months later.

The kaleidoscopic array of lingering, fluctuating, bedeviling, and multisystem symptom complex reported in COVID-19 survivors includes fatigue, exhaustion and anergia, dyspnea, dry cough, chest pain, musculoskeletal aches, joint pains, headaches, myalgias, protracted loss of taste or smell, loss of appetite, gastrointestinal symptoms, diarrhea, sleep disturbances, cognitive impairment-forgetfulness and memory disturbances (”brain fog”), and mental health disturbances, all of which affect the QoL and delay the return to usual health. The wide range of rollercoaster persistent symptoms among COVID-19 survivors does occur not only among the hospitalized and critically ill patients but sadly also reported in nonhospitalized asymptomatic or mild COVID-19 patients. As the magnitude of COVID-19 pandemic is ravaging at an unprecedented scale, and considering the high number of people affected by COVID-19 infection worldwide, it can be expected that there will be a significant influx of patients with lingering and significant post–(acute) COVID-19 syndrome and other subacute and long-term health consequences. Therefore, this underestimated silent wave of PCS and “unexpected” medium- to long-term multiorgan health consequences in COVID-19 survivors would need to be more fully anticipated and addressed. A COVID-19 survivor registry and a long-term healthcare map are absolutely quintessential to study the long-term health complications impacting QoL in COVID-19 survivors.

  Post-COVID Syndrome - What Does the Evidence Say? Top

Prolonged symptom duration and disability are common in adults hospitalized with severe COVID-19. However, relatively little is known about the clinical course of COVID-19 and return to baseline health for persons with milder, outpatient illness. What do we know so far about PCS? What does the evidence say about this less known, hidden subacute to chronic “unsuspected” PCS associated with posthospitalized and nonhospitalized COVID-19 survivorship? As yet, there is little research into the number of people at risk of developing ongoing PCS and/or Long COVID. Early attention has been on the acute illness generated by the virus, but it is becoming clear that, drawing on some COVID 19 survivor experiences, the post–acute-COVID-19 infection is a long-term illness. As yet PCS and Long COVID are not a well-defined term, with a lack of empirical diagnostic tests, there is no strict diagnostic code for PCS and/or “Long COVID.” Although it is too early to give a precise definition, guidance on reaching a working diagnosis and a code for clinical datasets is needed. This is imperative to envisage clinical care models and rehabilitation programs to address and mitigate the physical, social, and psychological consequences of PCS and/or “Long COVID” syndrome.

A recent Medscape article in October alluded facts from a dynamic themed review of the evidence around ongoing COVID-19 symptoms (often called Long COVID) published by Dr. Elaine Maxwell of the United Kingdom's National Institute for Health Research. This review suggested that the term “Long COVID' does not represent a single illness phenomenon and maybe a “Catch-All Term” for a wide range of recurring symptoms among people who had been hospitalized because of COVID-19, as well as those who had COVID-19 in the community. In their review, the term “Long COVID” (review preferred the term phrases “ongoing COVID-19” and “living with COVID-19”) is being used as a catch-all for more than one syndrome and perhaps did actually represent four different syndromes. These different clinical phenotypes are best described and categorized as (i) postintensive care syndrome (PICU) in ICU survivors, (ii) postviral PCS that resembles a postviral fatigue syndrome or akin to chronic fatigue syndrome (CFS)/myalgic encephalomyelitis, (iii) long-term multisystem illness spectrum of Long COVID, and (iv) potential long-term organ-specific complications such as long-term post-acute respiratory distress syndrome (ARDS) pulmonary sequelae, long-term cardiovascular sequelae, post–COVID-19 emerging sequelae in children, long-term liver and kidney sequelae, long-term neuropsychiatric sequelae, post-COVID neurological syndromes (PCNSs), and post–acute-COVID-19 vulnerability to neurodegenerative and neuroimmunological disorders. It is worthwhile to note that some COVID survivors may be suffering with more than one syndrome at the same time.

The UK COVID Symptom Study, an epidemiological research mobile app-driven data, has shown that there are six distinct “types” of acute COVID-19, each distinguished by a cluster of symptoms. The six clusters were categorized as (1) “flu-like” with no fever, (2) “flu-like” with fever (3) GI, (4) severe level 1, fatigue, (5) severe level 2, confusion, and (6) severe level 3, abdominal and respiratory. This categorization did help to predict the symptom cluster that would require hospitalization. This study predicted that patients in the three “severe” clusters were more likely to require oxygen or ventilation in a hospital. Researchers discovered that only 1.5% of people with cluster 1, 4.4% of people with cluster 2, and 3.3% of people with cluster 3 COVID-19 symptoms required breathing support. These figures were considerably higher for the remaining clusters, with 8.6%, 9.9%, and 19.8% for clusters 4, 5, and 6, respectively. About half of the patients in cluster 6 ended up in the hospital when compared with 16% of those in cluster 1. The UK COVID-19 study data do show that one in 10 people with COVID-19 continue to be sick and suffer from lingering and debilitating symptoms for 3 weeks or more and a smaller proportion for months. Furthermore, the COVID Symptom Study also revealed that Long COVID could be predicted in their model if patients were experiencing more than five moderate symptoms of fatigue, headache, cough, dyspnea, hoarseness of voice, and myalgia during the 1st week of illness, and was more likely with increasing age (elderly), body mass index, and female sex.

Another study published in the August JAMA 2020 issue, a team of researchers (Angelo Carfi et al.) from Italy reported that nearly nine in 10 patients (87%) discharged from a Rome hospital after recovering from COVID-19 were still experiencing at least one symptom, particularly fatigue and dyspnea, 60 days after onset. They found that 13% of the 143 people were completely free of any symptoms, while 32% had one or two symptoms, and 55% had three or more. Many still reported fatigue (53%), dyspnea (43%), joint pain (27%), and chest pain (22%). Two-fifths of patients reported a worsened QoL. Yet, another large published study in September 2020 from Belgium and the Netherlands involving 112 hospitalized and 2001 nonhospitalized COVID-19–positive patients has noted that even among a large number of asymptomatic or very mildly symptomatic patients, prolonged symptoms such as muscle pain, dizziness, headaches, fatigue, and anosmia continued to experience for months. This undoubtedly reinforces that previously hospitalized and nonhospitalized COVID-19 patients can still have multiple persistent symptoms 3 months after the onset of infection-related symptoms. This suggests the presence of a “post-COVID-19 syndrome” and highlights the unmet healthcare needs in a subgroup of patients with “mild” or “severe” COVID-19.

The Influenza Vaccine Effectiveness in the Critically Ill Network Investigators; CDC COVID-19 Response Team Study from the United States is another study in July 2020 that did confirm the validity of a “post-COVID-19 syndrome” and documented the delayed return to usual health. Among the 292 telephonic interview respondents, 94% (274) reported experiencing one or more symptoms at the time of testing; 35% of these symptomatic respondents reported not having returned to their usual state of health by the date of the interview (median = 16 days from testing date), including 26% among those aged 18–34 years, 32% among those aged 35–49 years, and 47% among those aged =50 years. Among respondents reporting cough, fatigue, or shortness of breath at the time of testing, 43%, 35%, and 29%, respectively, continued to experience these symptoms at the time of the telephonic interview. These findings indicate that COVID-19 can result in prolonged illness even among persons with milder outpatient illness, including young adults even without underlying chronic medical conditions. Older age and the presence of multiple chronic medical conditions and possibly chronic psychiatric conditions are thought to be plausible risk factors for the delayed return to usual health.

Albeit these studies described, the evidence is far from complete on the long-term effects of COVID-19 partly because it has not been possible to fully research them this early in the pandemic. It is becoming increasingly clear that, for some people, COVID-19 infection is not a discrete single entity but one that marks the start of ongoing, often debilitating symptoms life-changing experiences affecting normal functional capacities and QoL. The narrative of COVID survivorship real experiences is captured and evident from members of the Long COVID Facebook group, a discussion and support group for patients with Long COVID. The PCS and Long COVID illness are likely to become a permanent demand for health and social care services, as the COVID-confirmed cases are rising and even after the pandemic subsides. The awareness and recognition of PCS and Long COVID would need research thrust on the postinfectious pathogenesis and immune mechanisms that may contribute to these lingering long-term health sequelae. There is a need for multinational longitudinal research to explore the prevalence, risk factors, and whether it would be possible to predict a protracted course early in the acute COVID-19 disease. In conclusion, these studies do indeed endorse the presence of a “post-COVID-19 syndrome.” Long-lasting and debilitating symptoms could affect people of all ages, including those with paucisymptomatic acute COVID-19 illness who did not require hospitalization.

  Post-Intensive Care Syndrome: Survivorship after COVID-19 Intensive Care Unit Stay Top

To many of us, a common assumption around the world is that once a critical COVID-19 ICU patient is discharged from the hospital, the critical illness has been resolved and that would be the end of the matter. However, most of us are caught unaware of what happens to the COVID-19 survivors after they are discharged from critical care.

Survival of critically unwell patients, in general, has improved in the last decade due to advances in critical care medicine. Millions of people worldwide have survived an admission to the ICU, and the number of survivors is growing. While the patients with critical COVID-19 have, many a times, have survived a life-threatening illness, it is prudent to take note that most survivors of severe COVID-19 would experience postintensive care syndrome (PICS) and suffer important long-term complications. This has the potential to be the next significant public health crisis when patients are discharged from the hospital.[4] Patients who survived COVID-19 may have to face another battle. This subacute to long-term crisis of patient survivorship after the severe, life-threatening crisis of critically-ill patients with COVID-19 is marred by a combination of long-lasting physical disability, neuropsychological and cognitive impairments, sleep difficulties, and/or disturbances in emotional well-being affecting the mental health, mainly in terms of anxiety, depression, and posttraumatic stress disorder (PTSD). PICS is a term that describes new or worsening cognitive, psychological, physical, and other consequences that plague ICU survivors. With the rising of COVID-19 and second wave of infection in Europe and the United States, critical COVID-19 would surpass the ICU capacity in most of these countries. On the flipside, this upsurge of acute COVID-19 would likely result in many more patients with PICS and its associated health and economic challenges. It is crucial to note that the impairments from PICS could possibly persist beyond the ICU hospitalization for as long as 5–15 years. The major risk factors for the development of PICS in acute COVID-19 survivors are ARDS, sepsis, delirium and the duration of delirium, prolonged mechanical ventilation with exposure to higher amount of sedatives and systemic corticosteroids, multiorgan failure, and metabolic aberrations [hypoglycemia, hyperglycemia, hypoxemia, hypotension].

The physical impairments in post–COVID PICS are prevalent to a figure of 80% and include muscular weakness, critical illness neuromyopathies, fatigue, dyspnea, impaired pulmonary function, sleep-disordered breathing, and decreased exercise tolerance, all of which frequently lead to a reduction in activities of daily living (ADLs) and QoL. Emotional well-being and mental health impairments have a higher prevalence of post-ICU psychological sequelae with predictive risk factors such as patients who are younger, were female, have poor recall of the ICU stay, and had a longer duration of ICU sedation. The neuropsychiatric sequelae of such an ICU stay include anxiety, depression, and PTSD and are said to occur in 8%–57% of patients with PICS. The cognitive domain is affected by vexing symptoms of forgetfulness, memory loss and difficulty with concentration, attentional span, comprehension, and critical thinking. The ICU patient's experiences of isolation and the reduction in human interactions cause a “domino effect” of reduced cognitive stimulation, reorientation, and reassurance to patients with tell-tale effects on the cognitive and emotional well-being of the COVID-19 survivors.

The multidomain PICS impairments do indeed have a profound impact on patients' QoL, as well as that of their family members, known as PICS-F. It is also prudent to realize that the limited visitation policies due to the risk of transmission also increase the risk of PICS-F. Individuals with PICS-F are most commonly affected in the domain of mental health. It is sad to note that as many as 40% of patients with PICS are unable to return to their former level of function that could potentially result in job loss and financial difficulties.

I would highlight that in the wake of the acute COVID-19 life-threatening ICU scenario, the current emphasis is overwhelmingly on the acute treatment of complications and in-hospital management. In another words, PICS highlights a largely neglected but important issue in the wake of the COVID-19 pandemic. PICS is indeed one of the long-term complications of post-ICU COVID-19 survivors, and it is quintessential for early mobilization and integration of multidisciplinary rehabilitation teams for the prevention of PICS-associated complications. Now, another question is what can we do about it? Therefore, it is crucial that all ICU staff and multidomain rehabilitation team be aware and skillfully trained to evaluate the extent of physical, emotional, and cognitive impairments with ongoing assessment of patients' need for physical and occupational therapy. Efforts should be directed toward preventing PICS by minimizing sedation and early mobilization during ICU. I will not be able to dwell on the nitty–gritty evidence-based management of PICS but suffice for me to reiterate that there must be an absolute need to utilize the daily ICU checklist and the ABCDEF bundle (daily assessment of pain, analgesia, sedation, liberation from mechanical ventilation, delirium, mobility, and family engagement), early respiratory rehabilitation in post–COVID-19 ARDS survivors, a skillful neuromotor rehabilitation protocol, in addition to the diligent assessment of nutrition and sleep. It is highly recommended that both rehabilitation programs and recovery are executed at the bedside with healthcare workers in personal protective equipment (PPE).

I would underscore the need for a heightened awareness of how to identify PICS as an entity, identify risk predictors, evaluate, manage, and prevent PICS among the clinicians who evaluate ICU survivors. Post–acute-COVID-19 survivors, undoubtedly and justifiably, are vulnerable people who would need a compassionate “whole-patient-centered” mental health support. After discharge, these patients should be referred to post-ICU recovery/rehabilitation clinic (as a telerehabilitation/virtual service or in person visits), which is an interdisciplinary clinic with a critical care physician, a physician, a mental health professional, a physical therapist, an occupational therapist, a psychologist, and a respiratory therapist taking into confidence the COVID-19 survivor as well as the family caregivers for ongoing continuity of rehabilitative care and counseling. Since COVID-19–related PICS is rather neglected, I would underscore the dire need for an educational strategy to implement opportunities for multinational and international teleconferences and telerehabilitation conferences that would not only heighten the awareness of PICS but also empower the training skills and competence for multidisciplinary and rehabilitation professionals. This entire integrated well-knit care continuum, with a multidisciplinary team approach along with an ICU survivor peer support groups, would indeed pave the way forward in mitigating the PICS impairments, thus guaranteeing a return to ADLs, ensuring a good QoL, and setting vital foundations for improving patients' overall long-term post-ICU survivorship experience. Such endeavors would certainly help survivors of acute COVID-19 to attain an all-encompassing, successful, and meaningful life.

  Long-Term Multiorgan Sequelae AND Coronavirus 2019 – What We Know So Far Top

Long-term consequences were observed in survivors of SARS, but it is unknown whether lessons from SARS are applicable to COVID-19. We are still in the first 10 months of the COVID-19 pandemic, and we do not know what to tell our patients with certainty when they are asking about the course and prognosis of their subacute to long-term ongoing health consequences. Data is emerging about the medium-to-long term effects that occur; particularly multiorgan damage from COVID-19 in moderate-to-severe SARS-CoV-2 infections.[5] I would say that some of these burgeoning studies and evidence on the long-term health consequences/complications are indeed quite worrying. The COVERSCAN study investigators (Dennis et al.) did reveal distressing facts that almost 70% of low-risk young patients with Long COVID to have impairment in one or more organs 4 months after initial symptoms of SARS-CoV-2 infection. There is accumulating evidence for chronic multiorgan health effects such as cardiopulmonary/lung health, PCNS and brain health, post–COVID neuropsychiatric sequelae affecting mental health, myocardial/cardiac health, liver health, glucometabolic complications, and kidney health as far as risk for new chronic kidney disease is concerned in patients who have recovered from COVID-19. The emerging data and anecdotal evidence of long-term recovery and persistent debilitating symptoms highlight the need for robust and standardized studies to assess the risk factors for sequelae after COVID-19.

A recent Oxford University study published this October did elucidate the medium-term effects (at 2–3 months from disease onset) in 58 prospective posthospital discharged moderate-to-severe COVID-19 with comorbidity-matched controls. The study explored medium-term health consequences by explicating multiorgan structural (brain, lungs, heart, liver, and kidneys) magnetic resonance imaging (MRI), coupled with functional assessments such as spirometry, 6-min walk test (6MWT), and cardiopulmonary exercise test (CPET). The QoL, cognitive, and mental health outcomes were assessed by self-questionnaires using patient health questionnaire depression module (PHQ-9), Montreal cognitive assessment, general anxiety disorder questionnaire-7, and short form-36 survey.

It is quite revealing that a significant proportion of COVID-19 patients discharged from hospital experience ongoing symptoms of persistent breathlessness (64%), fatigue (55%), anxiety, depression, and exercise limitation at 2–3 months from disease onset. At 3 months of follow-up, the lung MRI revealed persistent parenchymal abnormalities and significantly FEV1 and FVC and higher FEV1/FVC ratio which did correlate well with poor exercise tolerance during CPET as evident by high VE/VCO2 slope, a marker of ventilatory efficiency. Persistent fibro-inflammatory changes were evident on high-resolution pulmonary computed tomography (CT) in about 70% of COVID-19 pneumonia survivors at 3 months of postdischarge. These indices of lung health and exercise tolerance (6MWT) did show positive correlations with markers of inflammation (C-reactive protein, procalcitonin). It is interesting to note that patients with initial cardiac injury at admission with elevated troponin had fairly normal left ventricular function on follow-up. However, the grim fact was that of underlying “subclinical” cardiac sequelae as evident by the significant abnormalities on cardiac MRI reflective of fibrosis and/or persistent inflammation that again correlated with markers of ongoing inflammation. In acute liver injury related to acute COVID, a similar trend for persistent MRI evidence of hepatic fibro-inflammation was observed at the 2–3 months of the follow-up period. In the follow-up of patients with acute kidney injury, the surrogate biological markers of persistent renal injury/fibro-inflammation were evident by a significantly higher renal cortical T1 and lower corticomedullary differentiation. The finding of the Oxford study does indeed highlight the subclinical (occult) persistent fibro-inflammation of various target organs, drawing a correlation between the severity of initial COVID infection, markers of inflammation, and ultimately persistent inflammation at 2–3 months of follow-up that subsequently results in multiorgan (lungs, brain, heart, liver, and kidneys) structural and functional sequelae. These structural imaging findings underscore the need to further understand the pathophysiological mechanisms underpinning multiorgan MRI tissue abnormalities. Another intriguing question is whether these imaging biomarkers could be surrogate markers to ongoing immune-mediated inflammation and an autonomous maladaptive immune response to incite permanent and long-term detrimental effects of COVID-19–related organ damage in the future.

The number of people affected by COVID-19 is unprecedented, and the only way I see as the way forward to comprehend post–(acute) COVID-19 sequelae would be to put in place a multinational COVID-19 Survivor Registry for the meticulous longitudinal follow-up of these patients. Such surveillance programs would enable healthcare professionals and researchers to be vigilant and look out for these long-term “unsuspected” complications in people who have had and recovered from COVID-19. Not only will the registry be able to keep a trajectory of long-term health complications of COVID-19 survivors, but this also would set an ideal and constructive platform for ongoing research needs. The research imperatives would envisage answering several questions. Are the mechanisms underlying the long-term consequences of COVID-19 immunological? Or caused by new or relapsing inflammation, ongoing (persistent SARS-CoV-2) infection, SARS-CoV-2 autoimmunity, downstream effects of the hyperinflammatory cytokine storm, or side effects of immunomodulatory treatment? Such data can serve to point at candidate management strategies to be tested in trials. Whether these late manifestations are related to nonresolving inflammation or a low-grade immune process driven by molecular mimicry or dysregulated adaptive immunity remains to be established.

With the discussion thus far, the global medical community has recognized the possible clinical sequelae that may persist after resolution of the acute COVID-19. To lend further credence to the possible long-term health consequences post–acute-COVID-19, a global harmonized longitudinal observational study across 42 countries has been launched as of July 2020 under the Aegis of the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) COVID-19 follow-up working group. This innovative global study would certainly inform strategies to prevent sequelae and to inform clinical management, rehabilitation, and public health management strategies to reduce morbidity and improve outcomes in post-COVID survivors with long-term health complications.

  Post-COVID-19 Pulmonary Sequelae Top

The available clinical, radiographic, and autopsy data have indicated that pulmonary fibrosis is central to severe acute respiratory distress syndrome (SARS) and Middle East respiratory syndrome (MERS) pathology, in approximately 30% of survivors after rehabilitation. The current evidence suggests that pulmonary fibrosis could also complicate infection by SARS-CoV-2. The extent and severity of the post–acute-COVID-19 long-term pulmonary complications enlightened by the emerging data indicate that many patients experience persistent respiratory symptoms several months after their initial illness. The potential respiratory problems in post–COVID-19 survivors do include chronic cough, architectural distortion and interlobar septal thickening, traction bronchiectasis, fibrotic lung disease, honey-combing fibrosis, and pulmonary vascular disease. These structural changes and the subsequent pulmonary dysfunction do indeed lead to worsening pulmonary symptoms, poor exercise endurance, psychosocial dysfunction, poor QoL, and early mortality.

Pulmonary fibrosis is a recognized sequela of ARDS and post–COVID-19 pneumonia and does pose a nightmarish long-term complication in the aftermath of the COVID-19. Available data indicate that about 40% of patients with COVID-19 develop ARDS and 20% of ARDS cases are severe. Given these observations, the burden of pulmonary fibrosis after COVID-19 recovery could indeed be substantial. The pathomechanisms through which severe SARS-CoV-2 ARDS causes lung damage are only partly known, but plausible contributors include a cytokine release syndrome triggered by the viral antigen, drug-induced pulmonary toxicity, hypersensitivity pneumonitis, autoimmunity triggered progressive, fibrotic irreversible interstitial lung disease, and high airway pressure and hyperoxia-induced acute lung injury secondary to mechanical ventilation. The virus triggered immune hyperreaction and combined effect of the virus-induced cell injury and inflammatory mediators induce alveolar epithelial damage and pulmonary injury. After the initial phase of inflammatory lung injury, there is an attempt at repair through angiogenesis, fibroproliferation, and lung remodeling to restore pulmonary architecture. However, this attempt at lung repair in the milieu of dysregulated release of growth factors and chemokines unfortunately promotes and leads to a potential increase in the risk of pulmonary fibrosis occurring as a sequela of COVID-19. Apart from these, additional factors could predispose individuals to severe lung injury and lead to an increased risk of mortality or pulmonary fibrosis in survivors. The evidence suggests that the predictors of pulmonary fibrosis in COVID-19 infection were advanced age, illness severity, length of ICU stay and mechanical ventilation, smoking, and chronic alcoholism. Lung transplantation is the only treatment option with demonstrably increased survival in selected patients with idiopathic pulmonary fibrosis. It is to be noted that post-COVID lung fibrosis affects even young survivors. There are reports of resorting to lung transplantation in a 20-year-old COVID-19 survivor in Chicago and another two survivors from China and Vienna.

The awareness of the post–COVID-19 fibrotic pulmonary complications mandates the need for a longer follow-up in convalescent patients with pulmonary function tests and high-resolution CT (HRCT) scans to monitor changes in the lung architecture to detect persistent lung damage and long-term pulmonary dysfunction. Such long-term surveillance of post–COVID-19 ARDS/COVID-19 pneumonia survivors by spirometric assessment of FVC, FEV1, total lung capacity, and diffusion capacity of the lung for carbon monoxide measured by means of the single-breath test that needs to be complemented with HRCT chest. At present, the long-term pulmonary consequences of COVID-19 remain speculative with some accumulating evidence, but this mandates the absolute research and surveillance needs with the design of multisite, multinational prospective longitudinal studies to explicate clinical and laboratory biomarkers of progression as a predictive modeling tool to rapidly identify the subgroup of patients that are going to deteriorate or develop post–ARDS/COVID-19 pneumonia lung fibrosis in the survivor population. There is a tremendous need for identifying potent predictors of mortality as well as the discovery of biomarkers early in the disease course to identify likely progression of COVIDARDS to pulmonary fibrosis. Such endeavors are quintessential for larger purpose of implementing effective therapies and answering whether potential antifibrotic intervention within the 1st week of COVID-19 ARDS-onset or stem cell/mesenchymal stem cell therapies could be considered. Until the discovery of an effective vaccine, apart from protective lung ventilation during the critical ICU phase, it is highly recommended to have a close follow-up by a team of physical medicine and rehabilitation and to provide a customized, personalized intervention with effective respiratory and physical rehabilitative interventions. Such programs of care would go a long way to ameliorate long-term respiratory symptoms in COVID-19-ARDS survivors.

  Post-COVID-19 Emerging Cardiac Disease in Children Top

Previous reports suggest that children infected with COVID-19 are highly resilient and commonly present with a mild upper respiratory illness. However, as of late April 2020, first being reported from the United Kingdom, a new, dangerous, and potentially life-threatening syndrome known as multisystem inflammatory syndrome in children (MIS-C), also interchangeably known as pediatric inflammatory, multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS), has caught medical attention globally. Early in the COVID-19 pandemic, epidemiological data offered reassuring evidence that children are largely spared of severe sequelae of SARS-CoV-2. Most children have had minor symptoms or an asymptomatic SARS-CoV-2 infection that unfortunately leads to the diagnosis of clinically silent or mild cases. Case studies also show MIS-C can strike seemingly healthy children without warning 3 or 4 weeks after asymptomatic infections. Therefore, the more concerning findings of this post–COVID-19 nightmare were that children could still develop MIS-C despite an asymptomatic course of COVID-19. This new hyperinflammatory disease that is temporally associated with SARS-CoV-2 infection has a clinical phenotype with overlapping features of Kawasaki disease and toxic shock syndrome and is complicated by significant cardiac involvement. MIS-C is rare, but the potential long-term sequelae from this disease are currently unknown.

According to the literature, children did not need to exhibit the classic upper respiratory symptoms of COVID-19 to develop MIS-C, which is frightening. Most reports were 4–6 weeks after the peak of COVID-19 infections. Therefore, an intriguing question for this potentially life-threatening cardiac involvement would be: Is MIS-C a postinfectious syndrome or reflective of underlying persistent viral infection? The literature reports that MIS-C typically manifests 3–4 weeks after SARS-CoV-2 infection. This does explain why as many as 90% of children had positive antibodies to SARS-CoV-2, but many have a negative RT-PCR at the time of MIS-C evaluation. The US CDC case definition is based on clinical presentation, evidence of severe illness and multisystem (two or more) organ involvement, no plausible alternative diagnoses, and a positive test for current or recent SARS-CoV-2 infection or COVID-19 exposure within 4 weeks before the onset of symptoms (i.e., positivity for current or recent SARS-CoV-2 infection by RT-PCR, serology, or antigen test, or exposure to a suspected or confirmed COVID-19 case within the 4 weeks before the onset of symptoms). Symptoms of MIS-C are reported to show up several weeks to a month after exposure to the virus and generally do not include the typical respiratory symptoms associated with COVID-19. MIS-C is a postviral syndrome or an overreaction by the body's immune system to COVID-19.

MIS-C is a dangerous systemic infection characterized by extreme systemic inflammation, hyperinflammatory shock fever, cervical lymphadenopathy, abdominal symptoms, conjunctivitis, and rash with multiorgan involvement. In this emerging dangerous childhood disease, the affected children were critically ill and had extraordinary inflammation with the predominance of cardiac manifestations characterized by inflammatory myocarditis, myocardial stunning, arrhythmias, cardiogenic shock or acute left ventricular dysfunction, and acute heart failure, and some developed coronary artery dilation or aneurysms. Persistent infection with SARS-CoV-2/chronic infection-robust T-cell response may be plausible factors that efficaciously clear infection in the lung preventing severe respiratory disease in children, and a low-level, persistent infection in other sites may build up over time in some children, resulting in MIS-C. MIS-C could well be a postinfectious-immune inflammatory disorder where SARS-CoV-2 could act as a direct trigger of autoimmune and/or autoinflammatory conditions either by molecular mimicry or other, unknown mechanisms. It is suggested that there are two different patterns of T-cell differentiation which are called “antigen mode” and “inflammation mode,” and it is the latter mode that incites the slightly higher and delayed peak values of inflammatory cytokines during the subsequent course of the disease that may be responsible for the MIS-C phenotype. The dysregulated or maladaptive immune-mediated hyperinflammatory responses superimposed on a susceptible genetic predisposition (immunogenetic link) could be an additional plausible factor. More research is needed to understand why some children may be more susceptible to developing MIS-C.

Most children with COVID-19 seem to have mild illness, and serious cases remain rare among children. Though uncommon, MIS-C is still a serious complication, and some children may become very sick. Clinical teams should be alert during the weeks after COVID-19 pediatric to be on the lookout to detect the clinical syndrome of MIS-C. Although intensive care was needed, favorable clinical outcomes with aspirin, corticosteroids, and immunoglobulin treatment were achieved with an overall mortality rate of 2%. Will there be long-term cardiac complications in MIS-C is currently unknown. However, there is evidence of long-term cardiovascular consequences in adult counterparts of COVID-19 patients. A study (Rajpal et al.) from Ohio State University, United States, published in JAMA Cardiology in September, documented cardiac MRI markers of myocardial inflammation in about 45% of the enrolled study group of 26 athletes who have recovered from nonhospitalized asymptomatic or mildly symptomatic COVID-19 illness. An earlier study (Puntmann et al.) in July did also provide credible evidence of long-term cardiovascular consequences of COVID-19 in a cohort of German patients who had recently recovered from COVID-19 infection. In this study, cardiovascular MRI did reveal cardiac involvement in 78% and ongoing myocardial inflammation in 60% of post–COVID-19-recovered patients, independent of preexisting conditions, severity and overall course of the acute illness, and time from the original diagnosis. It is important to be cognizant of unusual cases (Nicol et al.) of a delayed subclinical or fulminant myocarditis after the initial SARS-CoV-2 infection, detected by cardiac MRI studies and endomyocardial biopsy.

Extrapolating from the cardiac long-term consequences in adult post–COVID-19 patients, there is emerging preliminary evidence that reveals that post–MIS-C syndrome could potentially severely damage children's hearts. The use of cardiac MRI studies including three-dimensional speckle-tracking echocardiographic strain analysis, as used in the Children's Hospital of Philadelphia (CHOP)-MIS-C study (Matsubara et al.), would be novel tools in elucidating myocardial mechanics and evaluating myocardial scarring and other tell-tale evidence possible lingering long-term effects of MIS-C myocarditis–related myocardial scarring after the episode of MIS-C. This novel strain imaging cardiac MRI protocol for assessing cardiac function detected subtle myocardial changes that were not possible by conventional echocardiography. This would entail the need for long-term monitoring and follow-up as essential surveillance program to fully understand this new postviral inflammatory disease. Such a systematic follow-up of post–MIS-C patients and adult subclinical “post-COVID-19 cardiac syndrome” would be instrumental in the early detection of long-term cardiovascular consequences, which would direct the need for cardiac rehabilitation.

  Post-COVID-19 Neurological and Neuropsychiatric Long-Term Sequelae Top

What are the potential long-term neurological and neuropsychiatric threats in survivors of the acute COVID-19 illness? Data from the previous human coronavirus pandemics of SARS coronavirus and MERS coronavirus infections have revealed a high prevalence of a long-term neurological impact. The entire spectrum of acute neurological involvement in SARS-CoV-2 is rapidly coming to the forefront. However, as we are still experiencing multiple waves of the acute COVID-19 pandemic, it will be too early to describe the full clinical picture of the potential neurological long-term sequelae.

The effects of COVID-19 on the human nervous system have been inadequately explored. It is essential and urgent to elucidate the degree of nervous system involvement in COVID-19, as well as determine the neural circuits, if any, that are potentially affected by SARS-CoV-2. The SARS-CoV-2 virus does gain entry to the brain through various routes. These include retrograde axonal transport along axons (nasal epithelium, olfactory nerve, trigeminal nerve, vagus nerve, glossopharyngeal nerves, lung-brain axis – via vagus neural pathway, enterocytes, submucosal plexus and/or myenteric plexus neurons of the enteric nervous system, and glymplatic routes), hematogenous spread via the blood–brain barrier (BBB), blood–cerebrospinal fluid barrier, meningeal–cerebrospinal fluid barrier, via direct infection of endothelial cells and/or through spreading of infected leukocytes (Trojan Horse mechanism) to the brain across the BBB. The neurolocalization and neurological target sites of involvement do correlate with the high ACE2 expression in specific regions such as piriform cortex, entorhinal cortex, amygdala, hippocampus, orbitofrontal cortex, dopamine neurons of striatum/substantia nigra, middle temporal gyrus, posterior cingulate cortex, the hypothalamus, cardiorespiratory centers in the pontomedullary region, and other brainstem structures such as nucleus tractus solitaries/nucleus ambiguus, trigeminal ganglia, dorsal motor nuclei of the vagus nerve, and the dorsal raphe nuclei. The enteric nervous system via the submucosal plexus and/or myenteric plexus neurons and the GI epithelium having a relatively higher expression of ACE2 receptor than in the lungs do seem to be an alternative entrance door in SARS-CoV-2 neuroinvasion taking advantage of the complex neural pathways of the brain–lung axis and gut–brain interconnections.

Once in the brain, these viruses disrupt the complex organization of neural circuits either directly by neuronal damage (virus-induced central nervous system [CNS] damage; virus-induced neuropathology) or indirectly through host immune response pathways (virus-induced neuro-immunopathology). The multitude of neuromechanisms that probably contributes to COVID-19–related brain involvement with consequent neurological manifestations includes cytokine-triggered neuro-inflammatory, thrombo-inflammatory, ACE-2 receptor autoimmunity, SARS-CoV-2 endotheliopathy driven by molecular mimicry or dysregulated adaptive immunity, inflammo-proteomics, and “inflamm-aging.”

As a neurologist, several intriguing questions do arise in my mind as to the neuromechanism of brain target organ involvement in a long-term continuum of SARS-CoV-2 as far as the neurocognitive and neuropsychiatric perspective is concerned. Can SARS-CoV-2 directly infect resident brain cells via a direct viral effect? After gaining entry to target brain sites, can they remain latent where neural and immune cells serve as reservoirs for coronaviruses latency? Can the latent viruses reactivate and become infective again when the immune system is less vigilant to induce a low-grade chronic persistent infection? Can SARS-CoV-2 cause indirect deleterious effects on resident brain cells via neuro-inflammation, and immune dysregulation triggered altered neuroglial activity, alter the neurochemical landscape, activate the hypothalamic neurohumoural pathways, and remodel the dynamics of psychoneuro-immunological networks? From a study published in the September issue of Neurology (Gisslen et al.), there is first-ever data from mild to moderate COVID-19 survivors to have evidence for astrocyte activation triggered neuronal injury in otherwise neurologically asymptomatic patients. Elevated plasma levels of neurofilament light chain and glial fibrillary acidic protein [markers of astrocyte activation] were elevated in these asymptomatic COVID-19 survivors. Could these represent biomarkers for neurochemical evidence of under-appreciated or occult CNS injury? Will there be long-term effect in these patients? Could indirect maladapative immune host response and the virus-induced neuro-immunopathology be potential downstream effects to cause a pathological remodeling of the brain's distributed neuronal networks? Whether there is a potential for setting off neurodegenerative disorders as a sequela of COVID-19 to produce disorders at the brain–mind interface? These are all important questions for me, as a neurologist, as well as to the world community of neuroscience researchers. The answers to these questions may explicate the post–COVID-19 long-term neurological complications, cognitive dysfunction, immunopsychiatry, and its consequent long-term psychopathologies/neuropsychiatric sequelae.

Lessons learned from 1918 H1N1 spanish flu

Looking back to history, after the “Spanish” influenza pandemic in the 20th century, an outbreak of encephalitis lethargica (EL), a neurological syndrome with neuropsychiatric features spread across Europe and then the world beginning in the winter of 1916–1917 and continuing into the 1930s. Essentially, EL was a postinfectious autoimmune disorder where the chronic phase that typically developed 1–5 years after the acute phase was marked by postencephalitic  Parkinsonism More Details, akinesia paradox, oculogyric crises, sleep disturbances, oculomotor abnormalities, in addition to abnormal involuntary movements including chorea, torsion spasms, myoclonus, and tics affecting the jaw, lips, tongue, and palate. Chronic EL was also associated with neuropsychiatric manifestations, which included changes in mood, feelings of euphoria, increased sexual drive, hallucinations, and psychosis. Having witnessed the post-H1N1 long-term neuropsychiatric consequences in EL, it would not be wrong or unwise to expect long-term neurological and neuropsychiatric complications in COVID-19 survivors. These long-term neurological and neuropsychiatric consequences of COVID-19 may indeed be a “silent wave” and could potentially be underestimated. I would reiterate the need to have a global consensus guideline for a meticulous system-based approach to the assessment, reporting, and management of COVID-19 survivors including a COVID-19 Survivor Registry which would aid in the exploration of the key clinical features of any consequential long-term PCNS. This would also pave the strategies in formulating potential management algorithms and multidisciplinary rehabilitation programs.

The lesson that we could learn from chronic EL, and a question I would like to pose, is whether the downstream effects of dysregulated adaptive immunity, neuro-immune inflammation, inflammo-proteomics, and “inflamm-aging” could trigger neurodegenerative process in the brain of genetically vulnerable human beings. Conceptually, neuro-inflammation and immune system dysregulation do contribute to the pathological development of neurodegeneration and often are considered as a common, even unifying feature of neurodegeneration, while brain infection and ischemic insults by themselves could potentially trigger neurodegenerative process and instigate mild cognitive impairment and dementia. SARS-CoV-2 proteins could interact with host proteins triggering alterations in pathways involved with aging, including mitochondrial dysfunction, loss of proteostasis, autophagy dysfunction, and endoplasmic reticulum stress, all of which make it possible for SARS-CoV-2 infection to prompt protein misfolding and aggregation, which underpins neurodegenerative disease processes such as Parkinson's disease (PD) and Alzheimer's disease (AD). It has been postulated that the SARS-CoV-2 localization to the substantia nigra does promote cellular pathways of proteostasis, promoting the accumulation of the alpha-synuclein (α-Syn), the major protein component of Lewy bodies in the brain. The presence of olfactory involvement at the outset suggests a striking similarity with alpha synucleinopathies such as PD in which olfactory dysfunction is a premotor feature.

Post-COVID-19 De Novo neurodegeneration and Parkinsonism

In the context of postinfectious neurodegeneration, there are emerging reports of a post–COVID-19 Parkinsonian syndrome drawing again a correlation between SARS-CoV-2 neurotropicity, H1N1 postencephalitic parkinsonism (PEP), and the triggering of a post infectious autoimmune sequelae or perhaps induce de novo neurodegeneration as a long term complication. The high prevalence of COVID-19–related anosmia combined with a strong historical account of a link between an EL-type association with a historic influenza pandemic leads us to this important question whether history is repeating with the current COVID-19 pandemic. At this juncture, it will not be right of me to ignore the epidemiologic and clinical debate regarding the association of EL and the influenza epidemic. The influenza hypothesis is prima facie, and not conclusive but I felt the need to avoid complacency and keep my mind open to post viral epidemic related long-term neurologic sequelae like PEP. In a similar vein, COVID-19 triggered Parkinsonism could remain formally possible. Whether the SARS-CoV-2 infection might trigger neurodegeneration, starting in the olfactory bulb, in predisposed patients is unknown. Keeping in mind the historical account of EL-PEP, it may be unwise or premature, to underestimate the potential long-term neurological Parkinsonian sequelae of the SARS-CoV-2 virus.

There are three case reports that have been published of relatively young COVID-19 patients who developed clinical parkinsonism, either in isolation or with other neurologic deficits, within 2–5 weeks of contracting the disease. Three recent case reports in September–October 2020 by Méndez-Guerrero et al. from Spain; Cohen et al. from Israel; and Faber et al. from Brazil describe the development of acute parkinsonism following COVID-19, possibly representing a post or para-infectious Parkinsonian syndrome.

They reported that the three patients in the published cases were aged 35, 45, and 58 years. All had severe respiratory infection that required hospitalization. For two of three patients, symptoms of parkinsonism diminished upon administration of traditional dopaminergic medication. The third patient recovered spontaneously. In all cases, brain imaging revealed reduced function of the nigrostriatal dopamine system as is seen in PD. None of them did have a family history of PD or any history of signs of prodromal Parkinson's. One patient underwent genetic testing and was not found to carry any Parkinson's risk variants. These patients possibly seemed to be destined to develop PD, when the COVID-19 infection only accelerated an ongoing neurodegenerative process and drop out of nigral dopamine neurons around a critical time point. Such reports do lend evidence to support that SARS-CoV-2 can gain access to the CNS, affecting midbrain structures and leading to neurologic signs and symptoms. The midbrain dopaminergic neurons express high level of ACE2 receptors possibly making these cells selectively vulnerable to SARS-CoV-2 attack. The neuroinvasion of SARS-CoV-2–related neuro-inflammation leads to an upregulation of intraneuronal a-Syn (Synuclein), leading to the formation of aggregates, similar to the PD brain, possibly followed by neuronal death.

Although acute parkinsonism in conjunction with COVID-19 appears to be rare, spread of SARS-CoV-2 widely in the society might lead to a high proportion of patients being predisposed to developing PD later in life, especially because they will also be affected by normal aging processes. Therefore, I would underscore the importance of careful follow-up of large cohorts of patients affected by COVID-19 and monitor them for manifestations of PD, especially in those with initial olfactory disturbances. Clinicians should watch for other early warning signs of PD (using screening tools for prodromal PD detection) for neuroprotective therapy or disease-modifying treatments among COVID-19 patients who lose their sense of smell that is persistent, as the symptom could be linked to neurodegeneration later on. The acute onset and the association with SARS-CoV-2 infection raise the possibility that the three cases might represent a post or para-infectious auto-immune triggered parkinsonian syndrome. Alternatively, other plausible mechanisms could be the unmasking of underlying pre-clinical (pre-symptomatic/prodromal) Parkinson's disease, long-term development of PD in individuals with genetic susceptibility,SARS-CoV-2 triggered a-synucleinopathies upon a background of the bioenergetic stress of SARS-CoV-2 neuroinvasion, neuroinflammation and ageing process. It is worth drawing a historical parallel with the postencephalitic lethargica parkinsonism that took place in the 1920s. In my opinion, it would not be wise to completely cast aside the long-lasting impacts that the growing COVID-19 pandemic on the incidence of a post COVID-19 Parkinsonism in the years to come. However, as a cautionary note, the causal association of SARS-CoV-2 infection with the development of Parkinson's disease is not supported by robust evidence yet. Therefore, it will be important to strategize a multi-national coordinated long term surveillance to monitor COVID-19 survivors, particularly for those with persisting hyposmia. Finally, I would state that the current COVID-19 pandemic does provide a unique opportunity to investigate the hypothesis of post–acute COVID-19 vulnerability to neurodegenerative (AD/PD), neuroimmunological, and immunopsychiatric disorders.

Post-COVID-19 cognitive complications - collateral


One long-term impact of COVID-19 that is becoming increasingly apparent is its effect on cognitive function, even in those with mild symptoms. The long-term cognitive sequelae in COVID-19 survivors could be multifactorial. The cognitive dysfunction is usually attributed to a combination of pathophysiological events such as non-CNS systemic impairment related to ARDS, hypoxia, multiorgan dysfunction, and sepsis and also related to the underlying psychological distress such as anxiety, depression, and PTSD. Cognitive impairment may also ensue from the synergistic interaction of COVID–related acute cerebrovascular disease (including silent infarcts), necrotizing encephalopathy, delirium, other CNS involvement, sedating and anesthetic drugs, mechanical ventilation, medical complications, medical comorbidities (hypertension, diabetes mellitus, obesity), secondary effects of medications used to treat COVID-19, dysfunction of peripheral organs, and advanced aging as well as due to preexisting conditions such as cognitive impairment or dementia. The cytokine storm triggered hyperinflammation and “sickness behavior” are certainly plausible biological factors that cause pathological changes of neuronal networks and brain connectomics, and the brain's neurochemical milieu could lead to induction of neurodegeneration, brain dysfunction, neurocognitive fragility, executive dysfunction, dementia, and neuropsychiatric complications. Patients with ARDS of any cause experience a high prevalence of cognitive impairment, and up to 20% of them do show long-term deficits. In summary, three mechanisms are proposed to explain cognitive dysfunction during the infection by SARS-CoV-2: (i) direct CNS damage induced by the virus, (ii) non-CNS complications that affect the brain, and (iii) psychological distress due to social isolation and a severe medical illness. The hippocampus appears to be particularly vulnerable to coronavirus infections, thus increasing the probability of postinfection memory impairment and acceleration of neurodegenerative disorders such as AD. The extreme levels of proinflammatory cytokines observed in COVID-19 patients are likely to induce neurotoxicity. The systemic hyperinflammation could compound existing chronic BBB dysfunction from Alzheimer's-type pathophysiology and render the brain vulnerable to both amyloid-beta accumulation and cytokine-mediated hippocampal damage. The SARS-CoV-2–related sustained hyperinflammatory cytokine storm, microglial activation, and neuro-immune activation are postulated to trigger AD pathology by accelerated amyloid fibrillization and hyperphosphorylation of Tau protein. In particular, the NLRP3 inflammasome-mediated inflammation adversely affects beneficial immune functions in the brain and thereby causes the pathological accumulation of neurodegeneration-associated peptides such as fibrillar amyloid-β. This would indeed be responsible for acceleration or aggravation of preexisting cognitive deficits or de novo induction of an Alzheimer's neurodegenerative pathogenesis in the aftermath of COVID-19 illness. It is critical to assess and monitor COVID-19 survivors for cognitive impairment, poor psychosocial outcomes, and functional decline. It will be absolutely crucial to offer neuropsychological rehabilitation to those who need it. It is essential and urgent to minimize the potential negative effects on cognitive and psychosocial functioning and QoL of COVID-19 survivors.

Long-term neuropsychiatric complications

The pandemic of Spanish flu in 1918–1920 instigated speculation of the causative role of viral infection in the pathogenetic mechanism of behavioral disorders in bipolar and schizophrenic subjects. COVID-19 is likely to have important neuropsychiatric effects in both the short and longer term. As far as emotional and mental health well-being is concerned, a question that comes to my mind is “How COVID-19–associated immune-inflammatory changes influence the risk, progression, and outcomes of psychiatric conditions?” Well, the answer to post COVID-19 neuropsychiatric complications could be explicated from the field of immunopsychiatry (brain, behavior, and immunity axis) and psychoneuroimmunology. The plausible multitude of covering and synergistic biological mechanisms involves neuro-immune-inflammatory status, immune system dysregulation, postinfectious autoimmunity (similar to PANDAS/PANS), whole-brain connectome functional alterations, aberrations of the hypothalamo–pituitary axis and neuro–endocrine–immunologic networks, and cytokine network dysregulation. The neuropsychiatric long-term consequences that are postulated to occur in the aftermath of acute COVID-19 illness do include anxiety, stress-related disorders, depression, bipolar disorder, PTSD, obsessive–compulsive disorder, new-onset psychoses, somatoform pain disorder, panic disorder, chronic pain disorder, and CFS. There has been worsening of preexisting psychiatric conditions, namely mood and bipolar disorders, especially in the vulnerable populations. Careful monitoring, robust mental health screening, and treatment programs are absolutely essential to mitigate these subacute to chronic post–COVID-19 neuropsychiatric sequelae.

  The Aftermath of Acute COVID-19: The Way Forward Top

During the COVID-19 pandemic it has now become clear that the SARS-CoV-2 causes not just respiratory disease, but can affect multiple organs and tissues. The occurrence of multiorgan complications is not unexpected given the fact that SARS CoV-2 'gateway receptor' ACE2 and TMPRSS2 is invariably highly expressed in multiple human tissues. Undoubtedly, this will dictate the multipronged SARS-CoV-2 pathogenesis wrecking the body from the head to toe. The current COVID-19 pandemic has thus given rise to many surprises, including the appearance of long term health consequences, post acute COVID-19 multi-organ damage related persistent symptoms and resulting functional disabilities to disrupt HRQoL. The world was caught off guard by the first wave of COVID-19, and we should not lose sight of a 'hidden or unexpected' silent wave of Post COVID-19 long term multi-organ health consequences. While the current focus is on acute disease management, in the near future, attention will need to turn to the long-term consequences of COVID-19 infection and their mitigation. As the magnitude of COVID-19 pandemic is at an unprecedented scale, we can anticipate a far higher surge in the various multiorgan dysfunctions and neurocognitive/psychiatric sequelae in the survivors of this highly pathogenic novel coronavirus. It is of utmost importance to fathom the potential long-term complications of this novel virus so that healthcare systems are geared up to meet up such challenges in a not so distant future. It will be important to elucidate if anti-IL-6 (tocilizumab) treatments, neuroprotective therapy, disease-modifying treatment, or prolonged antiviral treatment in moderate-to-severe COVID-19 cases would show benefit in arresting, minimizing, or mitigating the future subacute, medium, to long-term multiorgan consequences described in this Editorial. There should be thrust in research needs in basic sciences to further deliver insights into potential mechanistic relationships between viral infections and immune-inflammation, immunogenetics, and the genesis of potential long-term multiorgan complications for better understanding of these associations, and potential and novel therapeutic targets in our pharmacological armamentarium.

The rollercoaster multiorgan long-term health consequences indeed do represent a post–acute COVID-19 nightmare, indeed a crisis after a crisis. It is quintessential to have heightened awareness to recognize the possibility of a whole host of multiorgan long-term complications. An international robust prospective “patient-centric” surveillance and clinical registry for long-term health consequences alluded to in this Editorial is mandatory. There is indeed a need for a holistic integrated multidisciplinary model of clinical care for COVID-19 patients posthospital discharge. It is necessary to formulate rehabilitation programs for these patients, to help them restore physical and respiratory function, and to reduce anxiety and depression, particularly patients with comorbidities and those who live alone or in rural settings. Timely preparation and thoughtful planning and delivery of whole person-centered, continuing interdisciplinary rehabilitation are absolutely essential to restore a good QoL.

Given the paucity of evidence that no long-term data of substantial numbers of COVID-19 survivor symptoms (PCS, Long COVID, PICS, and the various multiorgan long-term sequelae), it is paramount and urgent that systematic longitudinal observational studies, COVID-19 Survivor Registry, and clinical trials would be critical to elucidate the durability and depth of health consequences attributable to COVID-19. In this respect, the right strides have been taken by the ISARIC COVID-19 follow-up working group to systematically characterize risk of long-term consequences and immune responses over time in different populations globally and to facilitate standardized data collection globally to enable combined analysis. This study will inform strategies to prevent risk of consequences; clinical management, rehabilitation, and public health management need to reduce morbidity and improve outcomes. The Post-hospitalization COVID-19 study (PHOSP-COVID) is yet another research study in the UK to understand and improve long-term health outcomes in COVID-19 survivors. The INSPIRE COVID study in the United States (Innovative Support for Patients with SARS-CoV-2 Infections Registry) is tracking 4800 individuals to assess the outcomes of infections on various age groups over a 2-year period to understand the long-term effects of COVID-19. The participation of an international, multinational, and interdisciplinary group of researchers will be the only prudent step to fully understand post–COVID-19 syndromes and to improving the care of our patients with long-term consequences of COVID-19 survivorship.

”The proper use of science is not to conquer nature but to live in it.”

Barry Commoner

  References Top

Gatti RC. Coronavirus outbreak is a symptom of Gaia's sickness. Ecol Modell. 2020 Jun 15; 426:109075. [doi: 10.1016/j.ecolmodel.2020.109075].  Back to cited text no. 1
Datta SD, Talwar A, Lee JT. A proposed framework and timeline of the spectrum of disease due to SARS-CoV-2 infection: Illness beyond acute infection and public health implications. JAMA 2020; November 18, 2020. [doi:10.1001/jama.2020.22717].  Back to cited text no. 2
Greenhalgh T, Knight M, A'Court C, Buxton M, Husain L. Management of post-acute COVID-19 in primary care. BMJ 2020;370:m3026.  Back to cited text no. 3
Jaffri A, Jaffri UA. Post-intensive care syndrome and COVID-19: Crisis after a crisis? Heart Lung 2020;49:883-4.  Back to cited text no. 4
Del Rio C, Collins LF, Malani P. Long-term health consequences of COVID-19. JAMA 2020;324:1723-1724. [Doi: 10.1001/jama. 2020.19719].  Back to cited text no. 5


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