Long-Term Sequelae of COVID-19
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).
Among non-COVID patients with PICS, cognitive impairments, acute brain dysfunction, hypoxia, hypotension, and glucose dysregulation are among the major risk factors. 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. 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.
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. 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.
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. At least 25% of these patients experience a dramatic loss of independence and require assistance in daily living one year after ICU admission.
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. 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. 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.
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. Notably, signs of hypercytokinemia were detected among fatal COVID-19 cases. A meta-analysis of delirium in intensive care patients reported persistent neurocognitive deficits up to 18 months post-discharge. Thus, given the evidence of hypercytokinemia in hospitalized COVID-19 patients, there is a potential for long-term delirium post-SARS-CoV-2.
Association has been mentioned between SARS-CoV-2 infection with olfaction and taste perception dysfunction. Angiotensin-converting enzyme 2 (ACE2) is expressed by olfactory epithelial cells, however the mechanism that mediates anosmia in COVID-19 remains unclear. 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.
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. 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. 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).
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. This is a significant increase from the 3% pre-infection prevalence of any psychiatric diagnoses. 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. 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.
An increased risk for developing schizophrenia has been associated with in-utero, during childhood development, and in adulthood exposure to viral infections. One study reported increased prevalence of antibodies against four HCoV strains in patients with recent psychotic episodes. This suggests a possible association between CoV infections and psychosis.
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). 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. 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.
Parkinsonism has been described following the influenza pandemic of 1918. Anti-CoV antibodies have been identified in cerebrospinal fluid of people with Parkinson’s disease. 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.
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.
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. Some patients in the study also presented with pleural effusion, lymphadenopathy, and round cystic changes. 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. 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.
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. 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). 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.
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.
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