Long-Term Sequelae of COVID-19

Clinical Question

Long-Term Sequelae of COVID-19

Key Findings

  • Long-term sequelae following SARS-CoV-2 infection are not well established.
  • Recovered COVID-19 patients surviving prolonged period of time in intensive care and mechanical ventilation are susceptible to post intensive care syndrome.[1]
  • Studies of past respiratory viral pandemics suggest that diverse types of neuropsychiatric symptoms may arise from acute viral infection or after variable periods of time post-infection.[2]
  • Lung CT scan images of COVID-19 patients show extensive abnormalities,[3] and lung autopsy from deceased COVID-19 patients show vascular disease[4]; the lung injury associated with COVID-19 may have long term effects for survivors.

Summary of Findings

Post Intensive Care Syndrome (PICS)

SARS-CoV-2 infection causes severe lung injury that leads some patients to spend prolonged periods of time in intensive care and on ventilators. As COVID-19 patients recover, they don’t just recover from severe respiratory illness but also from post intensive care syndrome (PICS).[1]

Among non-COVID patients with PICS, cognitive impairments, acute brain dysfunction, hypoxia, hypotension, and glucose dysregulation are among the major risk factors.[5] Muscle atrophy, physical weakness, and post-traumatic stress are also observed. Between 30%-80% of post-ICU patients have reported to experience cognitive impairment such as delirium, with severity and duration depending on pre-existing cognitive deficits and age.[6] One study reported one-year outcomes of PICS to include new symptoms such as dyspnea, pain, sexual dysfunction, impaired pulmonary function and impaired exercise tolerance with the most common sequelae being neuromuscular resulting in poor mobility, frequent falls, and even quadriparesis.[1][7]

As part of PICS, critical illness polyneuropathy (CIP) and critical illness myopathy (CIM) is seen in approximately 25-45% of patients during and after intensive care treatment on mechanical ventilation.[8] These patients exhibit more severe neurodegenerative complications including flaccid and symmetric paralysis, limb and respiratory muscle weakness, systemic inflammatory response syndrome, or multiple organ failure.[8]

The long-term impacts of prolonged periods in ICU is also disruptive to the patient in other aspects of life. Close to one third of patients who suffer from PICS do not go back to work, another third do not go back to their pre-ICU job, or a job with a pre-ICU salary.[1] At least 25% of these patients experience a dramatic loss of independence and require assistance in daily living one year after ICU admission.[9]

Potential Long-term Neuropsychiatric Sequelae

Studies of past respiratory viral pandemics suggest that long-term neuropsychiatric symptoms can arise following acute viral infection or after variable periods of time post-infection.[2] Neuropsychiatric sequelae such as narcolepsy, seizures, encephalitis, encephalopathy, Guillain-Barre Syndrome (GBS), and other neuromuscular and demyelinating syndromes were reported from the 2009 influenza (H1N1) pandemic and coronavirus outbreak (SARS-CoV-1 in 2003 and MERS-CoV in 2012.[10][11][12][13] In a report of 217 hospitalized COVID-19 patients in Wuhan, China, neurologic symptoms of cerebrovascular complications, encephalopathies, and muscle injuries was seen in 40 out of 88 patients with severe infections.[14]

Encephalopathies

Encephalopathy or persistent (>24 h) alterations in consciousness was seen in approximately one-fifth of patients in a report of COVID-19 patients in Wuhan, China.[15] Notably, signs of hypercytokinemia were detected among fatal COVID-19 cases.[2] A meta-analysis of delirium in intensive care patients reported persistent neurocognitive deficits up to 18 months post-discharge.[16] Thus, given the evidence of hypercytokinemia in hospitalized COVID-19 patients, there is a potential for long-term delirium post-SARS-CoV-2.[17]

Anosmia and Ageusia

Association has been mentioned between SARS-CoV-2 infection with olfaction and taste perception dysfunction.[2] Angiotensin-converting enzyme 2 (ACE2) is expressed by olfactory epithelial cells, however the mechanism that mediates anosmia in COVID-19 remains unclear.[18] Formal studies are needed to further understand COVID-19-related anosmia. There is however, a growing number of clinical cases and it also has emerged as a screening criterion for COVID-19, but whether acute anosmia during the initial phase of infection will be associated with post-viral olfactory disorders (PVOD) is currently unknown.[2][19]

Depression, anxiety, and trauma-related disorders

Depression, anxiety, and trauma-related disorders are associated with past coronavirus outbreaks, however it is unclear if the risks are attributable to viral infections or due to the host immune response.[2] Studies of healthcare workers during the coronavirus outbreaks (SARS-CoV-1, MERS-CoV, and SARS-CoV-2) have suggest that frequency and severity of psychiatric symptoms are associated with proximity to CoV-infected patients.[20][21][22][23][24] It should be noted that these studies are limited because it does not test serology or immune markers in healthcare workers. History of mood disorder however, has been associated with seropositivity for a human CoV strain (HCoV-NL63).[25]

SARS-CoV-1 survivors were clinically diagnosed with PTSD (54.5%), depression (39%), pain disorder (36.4%), panic disorder (32.5%), and obsessive compulsive disorder (15.6%) at 31 to 50 months post-SARS-CoV-1 infection.[26] This is a significant increase from the 3% pre-infection prevalence of any psychiatric diagnoses.[26] One study found that more than one-third of hospitalized SARS-CoV-1 patients had moderate to severe symptoms of depression and anxiety 1 year later.[22] In addition, fears of illness, death, social isolation and uncertainty for the future can be significant stressors for people and can threaten to worsen public mental health.[27]

Psychotic disorders

An increased risk for developing schizophrenia has been associated with in-utero, during childhood development, and in adulthood exposure to viral infections.[28][29][30] One study reported increased prevalence of antibodies against four HCoV strains in patients with recent psychotic episodes.[31] This suggests a possible association between CoV infections and psychosis.

Demyelinating and neuromuscular complications

Post-SARS-CoV-1 and post-MERS-CoV infections have been observed to have delayed neurologic sequelae that occurred two to three weeks after respiratory symptoms such as peripheral neuropathy, myopathy, Bickerstaff brainstem encephalitis (BBE), and Guillain-Barre syndrome (GBS).[10][12] Noted, these complications were observed only in a small number of cases and causality.

Postmortem analysis of brain tissue from multiple sclerosis (MS) patients indicates that HCoV RNA was present in 48% of all donors and that its association with demyelinating disorders such as MS may be strain-specific.[32] It is unknown yet if the post-SARS-CoV-2 cohort will exhibit an delayed neurologic sequelae or MS symptomatology, however, it is still important to consider these impacts.

Neurodegenerative disorders

Parkinsonism has been described following the influenza pandemic of 1918.[33] Anti-CoV antibodies have been identified in cerebrospinal fluid of people with Parkinson’s disease.[34] Parkinsonism has not been associated with CoV outbreaks and remains to be seen in COVID-19. It is possible however, that this could contribute to delayed neurodegenerative sequelae given that latent CoV can hide in neural and immune cells.[35]

Potential Long-term Liver Damage impacts

A study in Shenzhen, China found that 47% of COVID-19 patients with mild disease and 61% with moderate disease had abnormal liver function tests, which indicates injury to the liver.[36]

Potential Long-Term Pulmonary Sequelae

Another study examined the pattern of CT imaging features from 81 COVID-19 patients found that the predominant pattern of abnormality was bilateral (79% of patients), peripheral (54%), and ground-glass opacification (65%) mainly involving right lower lobes with ill-defined margins, air bronchograms, smooth or irregular interlobular or septal thickening, and thickening of the adjacent pleura.[3] Some patients in the study also presented with pleural effusion, lymphadenopathy, and round cystic changes.[3] These findings suggest possible pulmonary long-term complications.

In addition, pneumonia has been known to progress to acute respiratory distress syndrome (ARDS), which sometimes can lead to scarring of the lungs, which can cause long-term breathing problems. Furthermore, survivors of ARDS have been found to have persistent functional disability one year after their discharge from ICU with some patients experiencing other complications such as muscle wasting and weakness.[37] Clues from pneumonia studies may be able to shed some insight into the lasting disabilities of COVID-19 because like COVID-19, pneumonia is a respiratory infection that also inflames the air sacs of the lungs.

Potential Long-Term Vascular Disease

A study examined the association between hospitalization for pneumonia and subsequent risk for cardiovascular disease found that compared to controls, the risk for heart disease was highest (4-fold) during the first year after discharge and remained high (~1.5-fold) through 10 years.[38] Lungs autopsy from deceased COVID-19 patients was examined and presented with damaged endothelial cells in addition to widespread blood clotting and angiogenesis (may be a result of the body’s response to virus).[4] It is unclear yet if these findings speak of long-term sequelae, however, it is possible for these features to spur the development of secondary complications.

Gaps in knowledge

While data for long term sequelae of COVID-19 is yet to be confirmed and all mentions here are potential long-term complications derived from past studies of similar respiratory viral infection and current studies of COVID-19, it is still important to acknowledge and take seriously the need for a coordinated response to the cohort of post-COVID-19 patients. Thus, more research is needed to ascertain the following mentions.

Author Information

Authors: Thanh Tran, BS, UCSD;
Completed on: June 23, 2020
Last revised on: Not yet revised

Reviewed by: Marsha-Gail MD
Reviewed on: June 28, 2020

This summary was written as part of the CoRESPOND Earth 2.0 COVID-19 Rapid Response at UC San Diego. For more information about the project, please visit http://earth2-covid.ucsd.edu

References

  1. Stam HJ, Stucki G, Bickenbach J. Covid-19 and Post Intensive Care Syndrome: A Call for Action. J Rehabil Med. 2020;52(4):jrm00044.  [PMID:32286675]
  2. Troyer EA, Kohn JN, Hong S. Are we facing a crashing wave of neuropsychiatric sequelae of COVID-19? Neuropsychiatric symptoms and potential immunologic mechanisms. Brain Behav Immun. 2020.  [PMID:32298803]
  3. Shi H, Han X, Jiang N, et al. Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: a descriptive study. Lancet Infect Dis. 2020;20(4):425-434.  [PMID:32105637]
  4. Ackermann M, Verleden SE, Kuehnel M, et al. Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19. N Engl J Med. 2020.  [PMID:32437596]
  5. Rawal G, Yadav S, Kumar R. Post-intensive Care Syndrome: an Overview. J Transl Int Med. 2017;5(2):90-92.  [PMID:28721340]
  6. Harvey, M. and Davidson, J., 2016. Postintensive Care Syndrome. Critical Care Medicine, 44(2), pp.381-385.
  7. Edwards E. ‘Post intensive-care syndrome’: Why some COVID-19 patients may face problems even after recovery People who remain in the ICU for weeks may end up with memory problems and trouble thinking clearly. [Internet]. 2020 Mar [cited 2020 Apr 9]. Available from: https://www.nbcnews.com/health/health-news/post-intensive-caresyndrome-why-some-COVID-19-patients-may-n1166611
  8. Zhou C, Wu L, Ni F, et al. Critical illness polyneuropathy and myopathy: a systematic review. Neural Regen Res. 2014;9(1):101-10.  [PMID:25206749]
  9. Griffiths J, Hatch RA, Bishop J, et al. An exploration of social and economic outcome and associated health-related quality of life after critical illness in general intensive care unit survivors: a 12-month follow-up study. Crit Care. 2013;17(3):R100.  [PMID:23714692]
  10. Kim JE, Heo JH, Kim HO, et al. Neurological Complications during Treatment of Middle East Respiratory Syndrome. J Clin Neurol. 2017;13(3):227-233.  [PMID:28748673]
  11. Manjunatha N, Math SB, Kulkarni GB, et al. The neuropsychiatric aspects of influenza/swine flu: A selective review. Ind Psychiatry J. 2011;20(2):83-90.  [PMID:23271861]
  12. Tsai LK, Hsieh ST, Chao CC, et al. Neuromuscular disorders in severe acute respiratory syndrome. Arch Neurol. 2004;61(11):1669-73.  [PMID:15534177]
  13. Wu H, Zhuang J, Stone WS, et al. Symptoms and occurrences of narcolepsy: a retrospective study of 162 patients during a 10-year period in eastern China. Sleep Med. 2014;15(6):607-13.  [PMID:24767723]
  14. Mao L, Jin H, Wang M, et al. Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease 2019 in Wuhan, China. JAMA Neurol. 2020.  [PMID:32275288]
  15. Chen T, Wu D, Chen H, et al. Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study. BMJ. 2020;368:m1091.  [PMID:32217556]
  16. Salluh JI, Wang H, Schneider EB, et al. Outcome of delirium in critically ill patients: systematic review and meta-analysis. BMJ. 2015;350:h2538.  [PMID:26041151]
  17. Yang, Y., Shen, C., Li, J., Yuan, J., Yang, M., Wang, F., Li, G., Li, Y., Xing, L., Peng, L., Wei, J., Cao, M., Zheng, H., Wu, W., Zou, R., Li, D., Xu, Z., Wang, H., Zhang, M., Zhang, Z., Liu, L. and Liu, Y., 2020. Exuberant Elevation Of IP-10, MCP-3 And IL-1Ra During SARS-Cov-2 Infection Is Associated With Disease Severity And Fatal Outcome.
  18. Brann, D., Tsukahara, T., Weinreb, C., Lipovsek, M., Van den Berge, K., Gong, B., Chance, R., Macaulay, I., Chou, H., Fletcher, R., Das, D., Street, K., de Bezieux, H., Choi, Y., Risso, D., Dudoit, S., Purdom, E., Mill, J., Hachem, R., Matsunami, H., Logan, D., Goldstein, B., Grubb, M., Ngai, J. and Datta, S., 2020. Non-Neuronal Expression Of SARS-Cov-2 Entry Genes In The Olfactory System Suggests Mechanisms Underlying COVID-19-Associated Anosmia.
  19. Vaira LA, Salzano G, Deiana G, et al. In Response to: In Reference to Anosmia and Ageusia: Common Findings in COVID-19 Patients. Laryngoscope. 2020.  [PMID:32603478]
  20. Kang L, Ma S, Chen M, et al. Impact on mental health and perceptions of psychological care among medical and nursing staff in Wuhan during the 2019 novel coronavirus disease outbreak: A cross-sectional study. Brain Behav Immun. 2020.  [PMID:32240764]
  21. Lai J, Ma S, Wang Y, et al. Factors Associated With Mental Health Outcomes Among Health Care Workers Exposed to Coronavirus Disease 2019. JAMA Netw Open. 2020;3(3):e203976.  [PMID:32202646]
  22. Lee AM, Wong JG, McAlonan GM, et al. Stress and psychological distress among SARS survivors 1 year after the outbreak. Can J Psychiatry. 2007;52(4):233-40.  [PMID:17500304]
  23. Lee SM, Kang WS, Cho AR, et al. Psychological impact of the 2015 MERS outbreak on hospital workers and quarantined hemodialysis patients. Compr Psychiatry. 2018;87:123-127.  [PMID:30343247]
  24. Lin CY, Peng YC, Wu YH, et al. The psychological effect of severe acute respiratory syndrome on emergency department staff. Emerg Med J. 2007;24(1):12-7.  [PMID:17183035]
  25. Okusaga O, Yolken RH, Langenberg P, et al. Association of seropositivity for influenza and coronaviruses with history of mood disorders and suicide attempts. J Affect Disord. 2011;130(1-2):220-5.  [PMID:21030090]
  26. Lam MH, Wing YK, Yu MW, et al. Mental morbidities and chronic fatigue in severe acute respiratory syndrome survivors: long-term follow-up. Arch Intern Med. 2009;169(22):2142-7.  [PMID:20008700]
  27. Carvalho PMM, Moreira MM, de Oliveira MNA, et al. The psychiatric impact of the novel coronavirus outbreak. Psychiatry Res. 2020;286:112902.  [PMID:32146248]
  28. Brown AS, Derkits EJ. Prenatal infection and schizophrenia: a review of epidemiologic and translational studies. Am J Psychiatry. 2010;167(3):261-80.  [PMID:20123911]
  29. Khandaker GM, Zimbron J, Dalman C, et al. Childhood infection and adult schizophrenia: a meta-analysis of population-based studies. Schizophr Res. 2012;139(1-3):161-8.  [PMID:22704639]
  30. Menninger K.A. Influenza and schizophrenia. Am. J. Psychiatry. 1926;82:469–529. doi: 10.1176/ajp.82.4.469.
  31. Severance EG, Dickerson FB, Viscidi RP, et al. Coronavirus immunoreactivity in individuals with a recent onset of psychotic symptoms. Schizophr Bull. 2011;37(1):101-7.  [PMID:19491313]
  32. Arbour N, Day R, Newcombe J, et al. Neuroinvasion by human respiratory coronaviruses. J Virol. 2000;74(19):8913-21.  [PMID:10982334]
  33. Cheyette SR, Cummings JL. Encephalitis lethargica: lessons for contemporary neuropsychiatry. J Neuropsychiatry Clin Neurosci. 1995;7(2):125-34.  [PMID:7626955]
  34. Fazzini E, Fleming J, Fahn S. Cerebrospinal fluid antibodies to coronavirus in patients with Parkinson's disease. Mov Disord. 1992;7(2):153-8.  [PMID:1316552]
  35. Desforges M, Le Coupanec A, Dubeau P, et al. Human Coronaviruses and Other Respiratory Viruses: Underestimated Opportunistic Pathogens of the Central Nervous System? Viruses. 2019;12(1).  [PMID:31861926]
  36. Gou W, Fu Y, Yue L, et al. Gut Microbiota May Underlie the Predisposition of Healthy Individuals to COVID-19. Public and Global Health; 2020. doi:10.1101/2020.04.22.20076091
  37. Herridge MS, Cheung AM, Tansey CM, et al. One-year outcomes in survivors of the acute respiratory distress syndrome. N Engl J Med. 2003;348(8):683-93.  [PMID:12594312]
  38. Corrales-Medina VF, Alvarez KN, Weissfeld LA, et al. Association between hospitalization for pneumonia and subsequent risk of cardiovascular disease. JAMA. 2015;313(3):264-74.  [PMID:25602997]
  39. Mongioì LM, Barbagallo F, Condorelli RA, et al. Possible long-term endocrine-metabolic complications in COVID-19: lesson from the SARS model. Endocrine. 2020.  [PMID:32488837]