The ‘third wave’: impending cognitive and functional decline in COVID-19 survivors

Abstract

The novel coronavirus, severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2), was initially discovered in November 2019 in Wuhan, China. The associated human disease, coronavirus disease 2019 (COVID-19), rapidly became a global pandemic.1Peng P.W.H. Ho P.L. Hota S.S. Outbreak of a new coronavirus: what anaesthetists should know.Br J Anaesth. 2020; 124: 497-501Abstract Full Text Full Text PDF PubMed Scopus (245) Google Scholar By March 2020, the USA began to experience its first wave of infections, with New York City at the epicentre. In the hardest hit areas, healthcare facilities were overwhelmed. Critically ill patients exceeded the capacity of ICUs, operating rooms were converted to makeshift ICUs, and temporary satellite hospitals were erected to divert care for non-critically ill patients.2Jotwani R. Cheung C.A. Hoyler M.M. et al.Trial under fire: one New York City anaesthesiology residency programme's redesign for the COVID-19 surge.Br J Anaesth. 2020; 125: e386-e388Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar With the introduction of social distancing, contact tracing, mandatory masks, and similar public health measures, New York City and the surrounding area were ultimately able to ‘flatten the curve’.3Harris J.E. The coronavirus epidemic curve is already flattening in New York city. National Bureau of Economic Research, Inc., 2020Crossref Google Scholar Months later, as other US cities and states began to relax their stay-at-home restrictions and people across the USA optimistically prepared to resume their former lives, cases began to increase again at an alarming rate, especially in southern and western states.4Tanne J.H. Covid-19 cases increase steeply in US south and west.BMJ. 2020; 369: m2616Crossref PubMed Scopus (3) Google Scholar Although there is debate among epidemiologists whether the recent increase in cases constitutes a ‘second wave’ or an ongoing first wave, the overriding consensus is that the COVID-19 pandemic is far from over.5Hazem Y. Natarajan S. Berikaa E. Hasty reduction of COVID-19 lockdown measures leads to the second wave of infection.medRxiv. 2020; https://doi.org/10.1101/2020.05.23.20111526Crossref Scopus (0) Google Scholar Thus, we have become accustomed to social distancing, mask regulations, and quarantine measures, the ‘new normal’. These measures will likely remain in place until the development and widespread administration of a SARS-CoV-2 vaccine. Several companies including Moderna and the National Institute of Allergy and Infectious Diseases in the USA and University of Oxford and AstraZeneca in the UK have entered phase 3 trials for a SARS-CoV-2 vaccine and plan on having results by early 2021. With the growing number of infected people there is a simultaneous increase in the number of recovered patients with chronic needs, so-called ‘long-haulers’. People who have cleared their SARS-CoV-2 infections are not all symptom-free. Many report continued fatigue, joint and bone pain, palpitations, headaches, dizziness, and insomnia. There is also concern for irreversible pulmonary scarring and dysfunction, especially in patients with severe pulmonary disease.6Spagnolo P. Balestro E. Aliberti S. et al.Pulmonary fibrosis secondary to COVID-19: a call to arms?.Lancet Respir Med. 2020; 8: 750-752Abstract Full Text Full Text PDF PubMed Scopus (300) Google Scholar Given that the virus has only been known for a matter of months, long-term studies simply do not exist yet, and the outlook for these patients remains completely unknown. There are likely to be many chronic consequences of COVID-19 beyond the initial wave of acute infections that will be uncovered in the coming months and years. One long-term impact of COVID-19 that is becoming increasingly apparent is its effect on cognitive function, even in those with mild symptoms. One-third of COVID-19 patients report neurological symptoms, and there have been anecdotal accounts of ‘COVID-19 delirium’, manifesting as paranoid hallucinations, confusion, and agitation in more than 20% of hospitalised patients.7Mao L. Jin H. Wang M. et al.Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China.JAMA Neurol. 2020; 77: 683-690Crossref PubMed Scopus (3941) Google Scholar,8Helms J. Kremer S. Merdji H. et al.Neurologic features in severe SARS-CoV-2 infection.N Engl J Med. 2020; 382: 2268-2270Crossref PubMed Scopus (1517) Google Scholar A small study from the UK reported delirium in 42% of COVID-19 patients.9Mcloughlin B.C. Miles A. Webb T.E. et al.Functional and cognitive outcomes after COVID-19 delirium.Eur Geriatr Med. 2020; 11: 857-862Crossref PubMed Scopus (95) Google Scholar One of the highest-risk groups for severe manifestations of COVID-19, patients more than 65 yr old, often have underlying mild cognitive impairment (MCI) and are already at increased risk of delirium as a result of underlying ‘neurocognitive frailty’.10Safavynia S.A. Arora S. Pryor K.O. García P.S. An update on postoperative delirium: clinical features, neuropathogenesis, and perioperative management.Curr Anesthesiol Rep. 2018; 8: 252-262Crossref PubMed Google Scholar,11Safavynia S.A. Goldstein P.A. The role of neuroinflammation in postoperative cognitive dysfunction: moving from hypothesis to treatment.Front Psychiatry. 2019; 9: 752Crossref PubMed Scopus (117) Google Scholar COVID-19-related inflammation also increases susceptibility to silent infarcts, blood–brain barrier (BBB) permeability, thrombosis, and coagulopathy, all of which may further propagate neurological injury.12Girard T.D. Ware L.B. Bernard G.R. et al.Associations of markers of inflammation and coagulation with delirium during critical illness.Intensive Care Med. 2012; 38: 1965-1973Crossref PubMed Scopus (77) Google Scholar Moreover, the clinical management of these patients, including patient isolation, lack of personal protective equipment (PPE) resulting in reduced staff contact, lack of family/visitors, and long-term ventilation/sedation, not only places them at high risk for delirium and subsequent cognitive deficits, but also likely under-diagnosis of delirium. Taken together, there is growing evidence that a patient's COVID-19 risk factors, pathology, and treatment course can independently and synergistically contribute to development of long-term cognitive and functional decline (Fig. 1). In addition to poor outcomes for patients, the severe agitation associated with delirium in many COVID-19 patients in the ICU creates difficulties for staff and compounds the stress of caring for these extremely sick patients. Risk factors for severe COVID-19 infection include advanced age,13Garg S. Kim L. Whitaker M. et al.Hospitalization rates and characteristics of patients hospitalized with laboratory-confirmed coronavirus disease 2019—COVID-NET, 14 States, March 1–30, 2020.MMWR Morb Mortal Weekly Rep. 2020; 69: 458-464Crossref PubMed Scopus (0) Google Scholar medical comorbidities, most commonly hypertension (40–60%), diabetes mellitus (20–40%), obesity (40–50%),14Cummings M.J. Baldwin M.R. Abrams D. et al.Epidemiology, clinical course, and outcomes of critically ill adults with COVID-19 in New York City: a prospective cohort study.Lancet. 2020; 395: 1763-1770Abstract Full Text Full Text PDF PubMed Scopus (1216) Google Scholar and smoking.15Reddy R.K. Charles W.N. Sklavounos A. Dutt A. Seed P.T. Khajuria A. The effect of smoking on COVID-19 severity: a systematic review and meta-analysis.J Med Virol Adv. 2020; (Access published on August 4)https://doi.org/10.1002/jmv.26389Crossref Scopus (160) Google Scholar This population overlaps significantly with at-risk groups for MCI and cognitive decline, which include advanced age, traumatic brain injury, obesity, hypertension, current smoking, and diabetes mellitus.16Baumgart M. Snyder H.M. Carrillo M.C. et al.Summary of the evidence on modifiable risk factors for cognitive decline and dementia: a population-based perspective.Alzheimers Dement. 2015; 11: 718-726Abstract Full Text Full Text PDF PubMed Scopus (889) Google Scholar Together, such risk factors represent a baseline neurocognitive frailty that can increase susceptibility to cognitive complications during and after inflammatory states,17Robertson D.A. Savva G.M. Kenny R.A.J. Frailty and cognitive impairment—a review of the evidence and causal mechanisms.Ageing Res Rev. 2013; 12: 840-851Crossref PubMed Scopus (436) Google Scholar similar to perioperative neurocognitive disorders associated with surgery and anaesthesia.11Safavynia S.A. Goldstein P.A. The role of neuroinflammation in postoperative cognitive dysfunction: moving from hypothesis to treatment.Front Psychiatry. 2019; 9: 752Crossref PubMed Scopus (117) Google Scholar Thus, the highest risk individuals for severe COVID-19 infection may also represent the most inherently susceptible population for cognitive decline in the setting of COVID-19 inflammation. Pulmonary dysfunction in COVID-19 is propagated by SARS-CoV-2 infection of ciliated bronchial epithelial cells and type-II pneumocytes. The virus gains entry into these cells by binding to the angiotensin-converting enzyme 2 (ACE2) receptor, triggering viral endocytosis. Subsequently, the viral surface spike (S) glycoprotein is cleaved by the transmembrane protease serine 2 (TMPRSS2) causing release of viral contents and propagation of the infection.18Hoffmann M. Kleine-Weber H. Schroeder S. et al.SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor.Cell. 2020; 181 (e8): 271-280Abstract Full Text Full Text PDF PubMed Scopus (10847) Google Scholar The lung damage and resulting hypoxaemia caused by COVID-19 likely contribute indirectly to neuronal injury and subsequent cognitive decline. Cognitive impairment is frequently seen in patients with chronic hypoxaemia, including chronic obstructive pulmonary disease (COPD) and obstructive sleep apnoea.19Thakur N. Blanc P.D. Julian L.J. et al.COPD and cognitive impairment: the role of hypoxemia and oxygen therapy.Int J Chron Obstruct Pulmon Dis. 2010; 5: 263-269PubMed Google Scholar,20Yerlikaya D. Emek-Savaş D.D. Kurşun B.B. Öztura İ. Yener G.G. Electrophysiological and neuropsychological outcomes of severe obstructive sleep apnea: effects of hypoxemia on cognitive performance.Cogn Neurodyn. 2018; 12: 471-480Crossref PubMed Scopus (8) Google Scholar Similarly, patients with COVID-19 acute respiratory distress syndrome (ARDS) can exhibit severe hypoxaemia despite relatively well-preserved lung mechanics.21Gattinoni L. Chiumello D. Rossi S. COVID-19 pneumonia: ARDS or not?.Crit Care. 2020; 24: 154Crossref PubMed Scopus (358) Google Scholar This ‘silent hypoxaemia’ has been described in COVID-19 patients as ‘oxygen levels incompatible with life without dyspnoea’.22Tobin M.J. Laghi F. Jubran A. Why COVID-19 silent hypoxemia is baffling to physicians.Am J Respir Crit Care Med. 2020; 202: 356-360Crossref PubMed Scopus (291) Google Scholar In critically ill patients with COVID-19, the resulting hypoxaemia has largely necessitated tracheal intubation and prolonged mechanical ventilation to address the ensuing chronic hypoxaemic state. SARS-CoV-2 has also been found to invade endothelial cells, leading to vascular inflammation and a high rate of superimposed arteriovenous thrombotic complications.23Varga Z. Flammer A.J. Steiger P. et al.Endothelial cell infection and endotheliitis in COVID-19.Lancet. 2020; 395: 1417-1418Abstract Full Text Full Text PDF PubMed Scopus (3670) Google Scholar SARS-CoV-2 can also cause a systemic vasculitis and cytokine storm that can damage a range of organ systems, with renal, hepatic, dermatological, and cardiac manifestations. Cardiac complications are among the most severe in COVID-19 infection, ranging from fulminant myocarditis to heart failure and cardiac arrest.24Mehra M.R. Ruschitzka F.J.J.H.F. COVID-19 illness and heart failure: a missing link?.JACC Heart Fail. 2020; 8: 512-514Crossref PubMed Scopus (99) Google Scholar The hypercoagulable and hyperinflammatory states seen in severe COVID-19 may contribute to delirium and future cognitive decline, as inflammation and coagulopathy are independently associated with an increased risk of delirium and poor outcomes in critically-ill patients.12Girard T.D. Ware L.B. Bernard G.R. et al.Associations of markers of inflammation and coagulation with delirium during critical illness.Intensive Care Med. 2012; 38: 1965-1973Crossref PubMed Scopus (77) Google Scholar Moreover, SARS-CoV-2 infection can cause susceptibility to silent infarcts and thromboses via microemboli. Neuroinflammation can cause cognitive dysfunction by compromising the BBB.10Safavynia S.A. Arora S. Pryor K.O. García P.S. An update on postoperative delirium: clinical features, neuropathogenesis, and perioperative management.Curr Anesthesiol Rep. 2018; 8: 252-262Crossref PubMed Google Scholar In both animals and humans, inflammatory insults can cause upregulation of pro-inflammatory cytokines and inflammatory mediators in the serum and CNS.11Safavynia S.A. Goldstein P.A. The role of neuroinflammation in postoperative cognitive dysfunction: moving from hypothesis to treatment.Front Psychiatry. 2019; 9: 752Crossref PubMed Scopus (117) Google Scholar Peripheral pro-inflammatory cytokines such as interleukin-1 (IL-1), IL-6, and tumour necrosis factor alpha (TNF-α) compromise BBB permeability via cyclooxygenase-2 (COX-2) upregulation and matrix metalloprotease (MMP) activation. Once the BBB is disrupted, cytokines can enter the CNS and cause microglial activation and oxidative stress, leading to synergistic cognitive impairment. The resulting neuroinflammation can contribute to delirium in the short term and severe long-term cognitive deficits.25Cunningham C. Systemic inflammation and delirium: important co-factors in the progression of dementia.Biochem Soc Trans. 2011; 39: 945-953Crossref PubMed Scopus (100) Google Scholar In addition to the baseline cognitive susceptibility of high-risk patients and the neurological effects of COVID-19 inflammation, patients affected with COVID-19 often have hospital courses that can further contribute to cognitive decline. Acute mental status changes, such as delirium, are common in hospitalised COVID-19 patients. Delirium itself is associated with subsequent cognitive decline,26Davis D.H. Muniz-Terrera G. Keage H.A. et al.Association of delirium with cognitive decline in late life: a neuropathologic study of 3 population-based cohort studies.JAMA Psychiatry. 2017; 74: 244-251Crossref PubMed Scopus (158) Google Scholar and is a common occurrence in ICU patients, as observed in ARDS.27Hsieh S.J. Soto G.J. Hope A.A. Ponea A. Gong M.N. The association between acute respiratory distress syndrome, delirium, and in-hospital mortality in intensive care unit patients.Am J Respir Crit Care Med. 2015; 191: 71-78Crossref PubMed Scopus (50) Google Scholar Despite the known iatrogenic contributors to cognitive decline in COVID-19 patients, many COVID-19 patients were denied typical precautions and interventions for cognitive health because of the transmissibility of SARS-CoV-2 and the increased load of critically ill patients in the first wave. Our experience in a New York City hospital reflects this course: patients were intubated early in their disease progression, often with limited family contact. These mechanically ventilated patients experienced prolonged periods of ‘iatrogenic hypoxaemia’, as it is common to maintain Pao2 values as low as 55 mm Hg (7.3 kPa) or Sao2 concentrations as low as 88% in ARDS management.28Bein T. Grasso S. Moerer O. et al.The standard of care of patients with ARDS: ventilatory settings and rescue therapies for refractory hypoxemia.Intensive Care Med. 2016; 42: 699-711Crossref PubMed Scopus (140) Google Scholar Ventilated patients were commonly agitated and required prolonged sedation with multiple agents to prevent self or staff harm. Although arousal and auditory functions, such as a patient hearing their name spoken by a familiar voice, are some of the most effective measures for emergence from disorders of consciousness,29Lee H.Y. Park J.H. Kim A.R. Park M. Kim T.-W. Neurobehavioral recovery in patients who emerged from prolonged disorder of consciousness: a retrospective study.BMC Neurol. 2020; 20: 1-11Crossref PubMed Scopus (9) Google Scholar simple measures such as this are difficult to implement because of pandemic precautions. Both short- and medium-term neurological deficits are already being observed in both critically ill and non-critically ill COVID-19 survivors, although long-term studies are yet to be completed. In fact, the fourth most common presenting symptom of COVID-19 is confusion or altered consciousness, suggesting both direct and indirect early neurological consequences. These data raise serious concerns regarding subsequent development of cognitive and functional decline in these patients, as cognitive decline is largely an insidious process after a heralding neurological or neurocognitive insult. Moreover, cognitive decline does not occur in isolation; rather it manifests in reduced quality of life and impaired ability to perform activities of daily living (ADLs) and instrumental ADLs (IADLs). Cognitive decline is often undiagnosed until it is more advanced and accompanied by moderate to severe functional deficits. It may benefit our cumulative research efforts to consider the long-term effects of COVID-19 in alignment with anaesthesia and surgery, which are known precipitants of inflammation-related cognitive and functional decline. Given the overlapping inflammatory response to injury for both, this may allow us to pre-empt poor cognitive and functional outcomes for COVID-19 patients, and work to implement preventive interventions or treatments that may alleviate long-term consequences of COVID-19. Drawing on the vast body of literature addressing perioperative neurocognitive disorders, which have a similar inflammatory component, may facilitate advances in strategies for both, and other neurological injuries, in a relatively short timeframe. In summary, COVID-19 risk factors, pathology, hospital course, and patient factors comprise multiple neurological insults that likely predispose patients to long-term cognitive dysfunction and functional decline. It is critical that we assess and monitor COVID-19 survivors for cognitive impairment, poor psychosocial outcomes, and functional decline. Research addressing the neurological sequelae of COVID-19, anaesthesia, and surgery, and other inflammatory disorders are imperative to reduce or prevent these poor outcomes for COVID-19 survivors, as well as for other inflammatory disease-related neurological insults. Wrote the first draft of the manuscript and prepared the figure: HAB Co-wrote the manuscript, provided accounts of clinical care for COVID-19 survivors, and assisted in figure preparation: SAS Conceived the idea and edited the manuscript: LAE