The COVID-19 pandemic has infected over 40 million people worldwide. Despite the high mortality seen among hospitalized patients, many have survived, although little is known about the medium-to-long term effects of COVID-19 disease after discharge. Although predominantly a respiratory illness, emerging data suggests that multi-organ injury is common, particularly in moderate to severe infections. A new study published on the preprint server medRxiv* in October 2020 describes the illness's sequelae in the months after recovery.
Multi-Organ Damage from COVID-19
COVID-19 is mostly a respiratory or pneumonic illness, but as data comes in from around the globe, it would seem that multiple organs are affected by the virus, the more so when the infection is severe or moderate. The most susceptible organs appear to be the brain, heart, gastrointestinal system, and kidneys.
This extensive injury mechanism could be virus-mediated dysregulation of the immune response, leading to exuberant inflammation, endothelial injury, coagulation abnormalities, and resulting damage. The outcomes depend on the extent of infection, inflammation, and individual pre-infection health status.
The link between abnormal inflammation and chronic COVID-19 sequelae is emerging. Some researchers have shown that convalescent patients show lung inflammation even months into recovery, which may be the case with other organs.
Systemic effects of COVID-19 and relationship with inflammatory response. A, B: Comparison of cardiopulmonary exercise test (CPET) parameters (VO2 max and VE/VCO2) between comorbidity-matched control and COVID-19 survivors. C: Relationship between VE/VCO2 and white cell count in COVID-19. D, E: Comparison of susceptibility weighted T2* signal (left and right thalamus) and MoCA scores between control and COVID-19 survivors. F: Relationship between periventricular white matter hyperintensity volume (pWMH’s) volume and white cell count in COVID-19. G, H: Comparison of myocardial native T1 (base and mid ventricle) between control and COVID-19 survivors. I: Relationship between basal native T1 and C-reactive protein (CRP). J, K: Comparison of liver T1 and iron-corrected liver T1 between control and COVID-19 survivors. An in-house algorithm was used to calculate iron-corrected T1, so these values cannot be compared to the LiverMultiScan cT1. L: Relationship between iron-corrected liver T1 and CRP in COVID19. M, N: Comparison of average cortical kidney T1 and corticomedullary differentiation in control and COVID-19 survivors. O: Relationship between average cortical kidney T1 and CRP in COVID-19 (p-values for comparisons are from Student’s t-tests for all variables; Spearman’s correlation coefficient and p-values are reported for correlations, # signifies pvalues were derived from comparison of variables that were Gaussianised and deconfounded).
Understanding the Sequelae of COVID-19
The current study aims at understanding how exercise capacity, intellectual function, mental health, and the quality of life are affected by this disease. They assessed individuals who had survived a moderate-to-severe bout of COVID-19, discharged at 2-3 months from disease onset, persistent inflammation in multiple organs, and the effect in terms of actual health outcomes.
The study included 58 discharged COVID-19 patients and 30 controls with the same comorbidity profile. The prospective study looked for multi-organ inflammation and damage using magnetic resonance imaging (MRI), walk test, and other assessment scales.
Persistent Symptoms and Signs of Organ Damage
They found that persistent breathlessness was present in two-thirds of patients, with fatigue in well over half the patients. Imaging revealed abnormalities in the lungs in 60% of patients, while one quarter to a half showed changes in the heart and kidneys, respectively. Only a tenth showed liver injury.
Physical fitness was markedly reduced as demonstrated by a reduced exercise tolerance and the distance walked within 6 minutes.
Other observable changes included abnormalities in various parts of the brain, while cognitive performance was impaired in both executive and visuospatial areas. (10%) and kidneys (29%) of patients. The damage seen in multiple organs during convalescence correlated with inflammatory markers and with the severity of acute illness, thus offering the latter prognostic value.
Moderate to severe anxiety, and depression, were reported by over a third of patients, mostly because of their persistent shortness of breath while testing negative for the virus. Overall, they reported a significant fall in the quality of life they enjoyed, relative to controls. A large percentage of this impairment was due to loss of physical condition, continuing breathlessness, and tiredness, which prevented daily living activities from proceeding as normal.
Chronic Post-Viral Inflammation Holds the Key
The study draws attention to the medium-term concerning sequelae of COVID-19 in surviving patients. In a high proportion, the lungs and other organs show MRI evidence of abnormalities, perhaps due to ongoing chronic inflammation. The findings of abnormalities in the lung parenchyma in many patients on MRI agree with earlier studies, which reveal the presence of persistent inflammation in 71% of survivors even three months after discharge.
The earlier outbreaks of SARS were similarly followed by permanent lung damage and impaired lung function in many survivors, for months and years later. The diminished lung function in up to 13% of survivors has also been reported recently by other investigators.
The evidence is piling up that SARS-CoV-2 produces a high viral load and that ACE2 receptors and TMPRSS2 are found at high levels in the lungs, kidneys, heart, and brain. These are necessary for viral entry into the host cells and viral replication, indicating this virus's tropism for organs other than the lung.
Despite the presence of neurological symptoms in half the patients in this study, MRI failed to show severe injury to the brain in most cases. This could be due to microvascular injury as shown by the presence of calcification and the products of blood degradation. This might account for the tendency for these images to display increased white matter hyperintensities and the increased incidence of stroke among these patients.
Implications and Future Directions
The increased coagulability of blood and chronic inflammation of nervous tissue might well lead to brain damage secondary to vascular damage in these patients. This could be why they also experience cognitive decline in the executive realm, primarily reflecting executive function impairment. These findings should trigger future research on the link between cognitive impairment and COVID-19.
Up to a third of COVID-19 patients who require hospitalization have an acute myocardial injury, which predicts a higher risk of fatality. Cardiac MRI is useful in this situation. Earlier, this modality has demonstrated that up to 60% of patients have significant inflammation of the heart tissues during convalescence, and a third of this subgroup had to be admitted to hospital.
In the current study, only a quarter of patients showed the presence of cardiac inflammation, correlating with inflammatory serum markers. This may require further work on the comparability of different studies that use different reference ranges and methods and have different patient cohorts.
Liver injury in COVID-19 survivors could also be due to hyperinflammation, abnormalities of liver metabolism due to hypoxia, venous thrombosis, and the effects of the drugs used in the treatment of the infection. The cholangiocytes may also be susceptible to direct infection, as ACE2 receptors are present in these cells. Over a tenth of convalescent patients have persistently high liver biomarkers at 2-3 months, and 10% have fibroinflammatory markers, which is correlated with MRI findings to some extent.
Kidney damage seems to be due to renal inflammation that is both prolonged and accompanied by loss of corticomedullary differentiation. This pattern is not unique to COVID-19, being seen with other post-inflammatory injuries to the glomeruli.
The researchers conclude that the chronic inflammatory reaction is responsible for evidence of persistent injury to multiple organs, and this is due not to the occurrence of critical illness but to the immunopathology of the infection.
They conclude, "Further efforts to understand the role of specific immunopathological mechanisms underlying this inflammatory process, and strategies to arrest them, could be important in limiting the long-term detrimental effects of COVID-19 on vital organs."
About a third of patients discontinued their physiotherapy because of fatigue and myalgia, indicating the possible occurrence of muscle wasting. This is known to accompany severe illness, which induces a catabolic state. Thus, this could significantly contribute to the deconditioning effect observed in convalescents, along with the lung damage.
More studies will be necessary to understand how psychological injury is related to the systemic or neurological inflammation following COVID-19. However, it is clear that multidisciplinary care will be needed to help survivors regain a better quality of life and good health following their discharge.
The researchers sum up: "This is the first exploratory study to comprehensively undertake a holistic assessment of multiple vital organs, mental, cognitive, and physical health in patients with COVID-19 post-hospital discharge. These findings underscore the need for further large scale investigations."
medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.