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In the year since the global COVID-19 pandemic was declared in March 2020 by the World Health Organization,1 short-term treatments such as prone positioning of patients2 or the use of neutralizing antibody cocktails3 have been optimized, and strategies for patients who remain symptomatic for months or experience long-term sequelae4,5 are being developed. Although several effective vaccines6-9 have been developed and the end of the pandemic is now within sight, the long and laborious healing process for patients with long COVID and society as a whole is only just beginning.
“Politicians, key opinion leaders, and other stakeholders must realize that long-COVID-19 will have a big impact on society. If millions of people feel that they are unable to get back to work, it will mean a lot for society,” said Dr Daniel Kondziella, clinical research associate professor in the Department of Neurology at Rigshospitalet, Copenhagen University Hospital. “The after-effects [of the pandemic] will go on for many years to come.”
A detailed follow-up of 150 patients who were treated at the University of Tours Hospital in France showed that 2 months after symptom onset, more than half (68%) of patients presented with 1 or more lingering symptom of COVID-19. The most common symptoms included diarrhea (33.3%), anosmia/ageusia (22.7%), flu-like symptoms (21.5%), a greater than 5% weight loss (17.2%), arthralgia (16.3%), chest pain (13.1%), cutaneous signs (11.5%), palpitations (10.9%), and dyspnea (7.7%).8
A longer-term, larger study of 1733 Chinese patients who were followed up at 6 months after hospital discharge revealed that most (63%) of the patients experienced fatigue and muscle weakness, and many reported difficulty sleeping (23%), below-average 6-minute walking distances (24%), anxiety or depression (23%), and diffusion impairments (22%).9
The Respiratory System
SARS-CoV-2 infection primarily affects the respiratory tract, causing pneumonia in severe cases with a proinflammatory response.10,11 “We categorize pneumonia as typical or atypical, involving different parts of the lungs. COVID-19 is an atypical pneumonia,” explained Dr Ali Gholamrezanezhad, a radiologist and assistant professor of clinical radiology with Keck Medicine of the University of Southern California, in Los Angeles.
Because COVID-19 may manifest as an atypical pneumonia, patients with severe disease can present with peripheral or posterior distribution of bilateral, multilobar ground-glass opacification, septal and/or pleural thickening, bronchiectasis, and subpleural involvement.11
In the long term, patients who present with complex lung manifestations seen on computed tomographic imaging are at increased risk for tissue scarring. “For patients who needed to be admitted into the hospital for COVID-19, the number [of patients with scarring] can be up to 30% to 40%. In patients who are not admitted, this number is much less, possibly less than 10%. It depends on the severity of the disease,” Dr Gholamrezanezhad added. For example, 6 weeks after discharge from University Hospital RWTH Aachen in Germany, 33 patients who did not require ventilation still presented with symptoms of fatigue (45%), cough (33%), and dyspnea (33%), but there was no evidence of widespread scarring.12
The Cardiovascular System
Although primarily a disease of the respiratory tract, extrapulmonary symptoms have been highly penetrant across tissue systems,10 and many of the lingering symptoms appear to involve other organs.8,9
Dr Valentina Püntmann, consultant physician, cardiologist, clinical pharmacologist, and assistant professor in the Department of Cardiology at the University Hospital Frankfurt, and colleagues recruited 100 patients who had recently recovered from COVID-19. Most patients had acute illness, with only 33% requiring hospitalization. Using cardiovascular magnetic resonance imaging a median of 71 days after their COVID-19 diagnosis, most patients presented with persistent cardiac involvement.13
“We actually thought we were not going to find anything because we were only permitted to scan patients later in their recovery,” said Dr Püntmann. “We also didn’t think at the time about COVID-19 as a cardiac condition. And yet, we were surprised to see myocardial inflammation, scarring, and also pericarditis persisting a few months after the original infection,” she continued.
In total, 78% of the patients had abnormal cardiovascular magnetic resonance scans, most commonly elevated myocardial native T1 (73%) and T2 (60%), myocardial late gadolinium (32%), and pericardial (22%) enhancement.13 These results are particularly intriguing, as they were sourced primarily from individuals who recovered at home, indicating that patients who experience even mild symptoms can have persistent myocardial inflammation and scarring for months.
“We are following up with these patients regularly, and for many patients, things do get better. They may not get better very quickly, which is perhaps something that is long-COVID specific,” stated Dr Püntmann. “But there is also a number of patients who don’t get better. I think we definitely need to get much better at understanding why some patients don’t improve, as well as work on developing effective treatments that we can administer early.”
The Nervous System
Throughout the pandemic, hospitalized patients have presented with a wide range of neurologic manifestations, thrombotic events, delirium, seizure-like events, encephalopathy, periodic discharges, ischemic lesions, and white matter lesions, among others.14,15 There has been little to no evidence collected during hospitalization to suggest there is widespread infiltration by the SARS-CoV-2 virus across the blood-brain barrier.14,16-17 With little direct evidence, it has been speculated these presentations occur as a result of neuroinflammation.15,18
During a 3-month follow-up of 61 patients admitted to Rigshospitalet, Copenhagen University Hospital in Denmark, nearly half (45.9%) of the patients had persistent central and peripheral nervous system complications.14
“Many patients actually still have affected cognitive ability. The average MOCA [Montreal Cognitive Assessment] score was 22 out of 30. Particularly, patients [who] were discharged from the intensive care unit had 19.5 out of 30, so they’re affected cognitively,” described Dr Michael E. Benros, professor of immuno-psychiatry in the Department of Immunology and Microbiology at the University of Copenhagen.
Dr Kondziella added, “There are 3 main ways by which COVID-19 might affect the nervous system. First, the virus itself has some sort of neurotropism. That means the virus crosses the blood-brain barrier and enters the brain, where it damages the tissue directly. The other option is that there is an autoimmune response by which cross-reaction toward the virus particles induces a neuroinflammatory pathway in the brain. We did find that in our study to a relatively lesser extent, compared to the third category, which is peripheral nervous system damage not directly caused by the virus or by autoimmune responses, but more because of treatment-related disorders.”
Because many of these nervous system manifestations were attributed to treatment-related complications (n=34 vs unresolved [n=4] vs para/postinfectious [n=3]),14 many of the younger, fitter patients likely will improve over time with rehabilitation after several months, predicted Dr Benros. However, patients who experience stroke or other thrombotic events may experience life-long COVID-19 complications.
The neurologic presentations observed among patients with COVID-19 may have psychiatric consequences. “Symptoms from long-term COVID-19 are commonly fatigue, headache, insomnia, and brain fog,” stated Dr Samoon Ahmad, professor in the Department of Psychiatry at New York University Grossman School of Medicine and Unit Chief of Inpatient Psychiatry at Bellevue Hospital Center. “However, we don’t know whether these symptoms are neurologic or caused by depression.”
Dr Ahmad explained that approximately 30% of patients who recovered from COVID-19 went on to develop post-traumatic stress disorder (PTSD).19,20 Symptoms of PTSD also have been reported in multiple studies of highly exposed individuals working in the healthcare sector.21
The observation of PTSD among healthcare workers is important because it brings to the forefront the fact that by no means do you need to be infected with the virus to be experiencing psychiatric consequences from SARS-CoV-2.
Dr Ahmad expounded, “Using data from 2019, on average we see that around 8% of people have anxiety disorders, and 6% [have] depressive disorders. If you look at the most recent data in a similar population, it is mind-boggling because rates of anxiety and depression have fluctuated between 34% and 42%. It’s just remarkable that during the pandemic, about 4 in 10 adults have reported symptoms of anxiety or depressive disorders.”
Dr Ahmad commented that the extent of the psychiatric consequences from the pandemic are likely far from being realized. Future research is needed to focus on the long-term psychiatric effects among patients who have recovered from severe illness, healthcare workers who were exposed to traumatic situations, the general public who experienced increased loneliness or the loss of loved ones, and children who were isolated because of the suspension of schools.
The need for ongoing collection of highly robust data and for the streamlining of definitions, data collection strategies, and patient stratification such that more consistent data become available is apparent. A more collaborative approach to conducting SARS-CoV-2 research would not only improve understanding but allow for more precise communication with the general public, which is imperative for successful vaccination campaigns and COVID-19 rule compliance.
In the meantime, Dr Püntmann implores fellow clinicians not to ignore the exercise intolerance that persists for weeks or months after infection among some COVID-19 patients. They may offer advice to patients to slow down for 3 to 6 months and not try to push themselves back to their former fitness too early. “By [not] doing that, they can make the symptoms a lot worse and slow down their recovery. This may feel very counterintuitive, especially to the young and fit patients because they are used to getting fit as soon as possible after a flu or a cold. Recovery after COVID-19 is a different, much more protracted process.”
The other largely protracted process will be to overcome the long-term stress associated with the pandemic. “In the short term it is easy to put mental health concerns on the back burner. This sort of constant stress will eventually have an impact on mental health in general,” cautioned Dr Ahmad. “At a certain point, people just reach their breaking point.” He stated that there is a great need for large-scale improved access to basic mental health support, such that everyone can be armed with basic tools to reduce stress and develop healthy routines.
1. World Health Organization. Report of the WHO-China joint mission on coronavirus disease 2019 (COVID-19). Published February 16-24, 2020. Accessed June 1, 2021. http://who.int/docs/default-source/coronaviruse/who-china-joint-mission-on-covid-19-final-report.pdf
2. Guérin C, Albert RK, Beitler J, et al. Prone position in ARDS patients: why, when, how and for whom. Intensive Care Med. 2020;46(12):2385-2396. doi:10.1007/s00134-020-06306-w
3. Weinreich DM, Sivapalasingam S, Norton T, et al. REGN-COV2, a neutralizing antibody cocktail, in outpatients with Covid-19. N Engl J Med. 2021;384(3):238-251. doi:10.1056/NEJMoa2035002
4. Ella R, Vadrevu KM, Jogdand H, et al. Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine, BBV152: a double-blind, randomised, phase 1 trial. Lancet Infect Dis. 2021;21(5):637-646. doi:10.1016/S1473-3099(20)30942-7
5. Voysey M, Clemens SAC, Madhi SA, et al. Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK. Lancet. 2021;397(10269):99-111. doi:10.1016/S0140-6736(20)32661-1
6. Baden LR, El Sahly HM, Essink B, et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N Engl J Med. 2021;384(5):403-416. doi:10.1056/NEJMoa2035389
7. Sadoff J, Le Gars M, Shukarev G, et al. Interim results of a phase 1–2a trial of Ad26.COV2.S Covid-19 vaccine. 2021;NEJMoa2034201. N Engl J Med. doi:10.1056/NEJMoa2034201
8. Carvalho-Schneider C, Laurent E, Lemaignen A, et al. Follow-up of adults with noncritical COVID-19 two months after symptom onset. Clin Microbiol Infect. 2021;27(2):258-263. doi:10.1016/j.cmi.2020.09.052
9. Huang C, Huang L, Wang Y, et al. 6-month consequences of COVID-19 in patients discharged from hospital: a cohort study. Lancet. 2021;397(10270):220-232. doi:10.1016/S0140-6736(20)32656-8
10. Behzad S, Aghaghazvini L, Radmard AR, Gholamrezanezhad A. Extrapulmonary manifestations of COVID-19: radiologic and clinical overview. Clin Imaging. 2020;66:35-41. doi:10.1016/j.clinimag.2020.05.013
11. Salehi S, Abedi A, Balakrishnan S, Gholamrezanezhad A. Coronavirus disease 2019 (COVID-19): a systematic review of imaging findings in 919 Patients. AJR Am J Roentgenol. 2020;215(1):87-93. doi:10.2214/AJR.20.23034
12. Daher A, Balfanz P, Cornelissen C, et al. Follow up of patients with severe coronavirus disease 2019 (COVID-19): pulmonary and extrapulmonary disease sequelae. Respir Med. 2020;174:106197. doi:10.1016/j.rmed.2020.106197
13. Puüntmann VO, Carerj ML, Wieters I, et al. Outcomes of cardiovascular magnetic resonance imaging in patients recently recovered from coronavirus disease 2019 (COVID-19). JAMA Cardiol. 2020;5(11):1265-1273. doi:10.1001/jamacardio.2020.3557
14. Nersesjan V, Amiri M, Lebech A-M, et al. Central and peripheral nervous system complications of COVID-19: a prospective tertiary center cohort with 3-month follow-up. J Neurol. Published online January 13, 202. doi:10.1007/s00415-020-10380-x
15. Lambrecq V, Hanin A, Munoz-Musat E, et al. Association of clinical, biological, and brain magnetic resonance imaging findings with electroencephalographic findings for patients with COVID-19. JAMA Netw Open. 2021;4(3):e211489. doi:10.1001/jamanetworkopen.2021.1489
16. Moriguchi T, Harii N, Goto J, et al. A first case of meningitis/encephalitis associated with SARS-Coronavirus-2. Int J Infect Dis 2020;94:55-58. doi:10.1016/j.ijid.2020.03.062
17. Domingues RB, Mendes-Correa MC, de Moura Leite FBV, et al. First case of SARS-COV-2 sequencing in cerebrospinal fluid of a patient with suspected demyelinating disease. J Neurol. 2020;267(11):3154-3156. doi:10.1007/s00415-020-09996-w
18. Boldrini M, Canoll PD, Klein RS. How COVID-19 affects the brain. JAMA Psychiatry. Published online March 26, 2021. doi:10.1001/jamapsychiatry.2021.0500
19. Forte G, Favieri F, Tambelli R, Casagrande M. COVID-19 pandemic in the Italian population: validation of a post-traumatic stress disorder questionnaire and prevalence of PTSD symptomatology. Int J Environ Res Public Health. 2020;17(11):4151. doi:10.3390/ijerph17114151
20. Janiri D, Carfì A, Kotzalidis GD, et al. Posttraumatic stress disorder in patients after severe COVID-19 infection. JAMA Psychiatry. 2021;78(5):567-569. doi:10.1001/jamapsychiatry.2021.0109
21. Tucker P, Czapla CS. Post-COVID stress disorder: another emerging consequence of the global pandemic. Psychiatric Times. 2021;38(1).