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The COVID-19 pandemic has infected more than 40 million people around the world. Despite the high mortality seen among hospitalized patients, many have survived, although little is known about the medium and long-term effects of COVID-19 disease after discharge. Although predominantly a respiratory disease, emerging data suggest that multi-organ injury is common, particularly in moderate to severe infections. A new study published on the prepress server medRxiv* in October 2020 describes the aftermath of the disease in the months after recovery.
Multi-organ damage from COVID-19
COVID-19 is primarily a respiratory or pneumonic disease, but as data comes in from around the world, it would appear that the virus affects multiple organs, 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 mechanism of injury could be a virus-mediated dysregulation of the immune response, leading to exuberant inflammation, endothelial injury, coagulation abnormalities, and resulting damage. Results depend on the extent of infection, inflammation, and individual health status prior to infection.
The link between abnormal inflammation and the chronic sequelae of COVID-19 is emerging. Some researchers have shown that convalescent patients show lung inflammation even months after recovery, which may be the case in other organs.
Systemic effects of COVID-19 and relationship with the inflammatory response. A, B: Comparison of cardiopulmonary stress test (CPET) parameters (VO2max and VE / VCO2) between comorbidity-matched control and COVID-19 survivors. C: Relationship between VE / VCO2 and white blood 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) and white blood cell count in COVID-19. G, H: Comparison of native myocardial T1 (base and middle ventricle) between control and COVID-19 survivors. I: Ratio 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 internal algorithm was used to calculate iron corrected T1, therefore these values cannot be compared with the LiverMultiScan cT1. L: Relationship between iron-corrected liver T1 and CRP in COVID19. M, N: Comparison of mean cortical renal T1 and corticomedullary differentiation in control and survivors of COVID-19. O: Relationship between mean renal cortical 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, # means that the p-values were derived from the comparison of variables that were gaussianized and misunderstood)
Understanding the aftermath of COVID-19
The present study aims to understand how exercise capacity, intellectual function, mental health and quality of life are affected by this disease. They evaluated people who had survived a moderate to severe COVID-19 episode, discharged within 2-3 months of illness 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 inflammation and multi-organ damage using magnetic resonance imaging (MRI), walking test, and other assessment scales.
Persistent symptoms and signs of organ damage
They found that persistent dyspnea was present in two-thirds of the patients, with fatigue in more than half of the patients. The images revealed abnormalities in the lungs in 60% of the patients, while between a quarter and half showed changes in the heart and kidneys, respectively. Only one-tenth showed liver damage.
Physical fitness was markedly reduced, as evidenced by reduced exercise tolerance and distance covered in 6 minutes.
Other observable changes included abnormalities in various parts of the brain, while cognitive performance was affected in both executive and visuospatial areas. (10%) and kidneys (29%) of the patients. Multiple organ damage observed during convalescence was correlated with inflammatory markers and acute disease severity, offering the latter prognostic value.
More than a third of the patients reported moderate to severe anxiety and depression, primarily due to their persistent shortness of breath while testing negative for the virus. Overall, they reported a significant drop in the quality of life they enjoyed, relative to controls. A large percentage of this deterioration was due to loss of physical condition, continued shortness of breath, and fatigue, which prevented activities of daily living from proceeding normally.
Chronic postviral inflammation is the key
The study draws attention to the worrying medium-term sequelae of COVID-19 in surviving patients. In a high proportion, the lungs and other organs show evidence of abnormalities on MRI, perhaps due to ongoing chronic inflammation. The findings of abnormalities in the lung parenchyma in many patients on MRI are consistent with previous studies, which reveal the presence of persistent inflammation in 71% of survivors even three months after discharge.
The first SARS outbreaks were similarly followed by permanent lung damage and declining lung function in many survivors, for months and years afterward. Other researchers have also recently reported decreased lung function in up to 13% of survivors.
Evidence is accumulating that SARS-CoV-2 produces a high viral load and that ACE2 and TMPRSS2 receptors are found at elevated levels in the lungs, kidneys, heart, and brain. These are required for viral entry into host cells and viral replication, indicating the tropism of this virus for organs other than the lung.
Despite the presence of neurological symptoms in half of the patients in this study, MRI showed no severe brain lesions in most cases. This could be due to microvascular injury as evidenced by the presence of calcification and blood breakdown products. This could explain the tendency of these images to show increased white matter hyperintensities and the higher incidence of stroke among these patients.
Implications and future directions
Increased blood coagulability and chronic inflammation of the nervous tissue could well lead to brain damage secondary to vascular damage in these patients. This could be the reason why they also experience cognitive decline in the executive domain, primarily reflecting a decline in executive function. These findings should trigger future research on the link between cognitive decline and COVID-19.
Up to a third of COVID-19 patients who require hospitalization have an acute myocardial injury, predicting an increased risk of death. Cardiac MRI is helpful in this situation. Previously, this modality has shown that up to 60% of patients have significant inflammation of the cardiac 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, correlated with inflammatory serum markers. This may require more work on the comparability of different studies that use different reference ranges and methods and have different cohorts of patients.
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 drugs used to treat the infection. Cholangiocytes can also be susceptible to direct infection, since ACE2 receptors are present on these cells. More than one-tenth of convalescent patients have persistently high liver biomarkers at 2-3 months, and 10% have fibro-inflammatory markers, which correlate to some extent with MRI findings.
Kidney damage appears to be due to prolonged renal inflammation and accompanied by loss of corticomedullary differentiation. This pattern is not unique to COVID-19, as it is seen with other post-inflammatory lesions of the glomeruli.
The researchers conclude that the chronic inflammatory reaction is responsible for the evidence of a persistent lesion in multiple organs, and this is not due to the appearance of a critical illness but to the immunopathology of the infection.
They conclude, “Additional efforts to understand the role of the specific immunopathological mechanisms underlying this inflammatory process and strategies to stop them could be important in limiting the long-term damaging effects of COVID-19 on vital organs.. “
Approximately a third of the patients discontinued their physical therapy due to fatigue and myalgia, indicating the possible occurrence of muscle atrophy. This is known to accompany severe illness, inducing a catabolic state. Therefore, this could contribute significantly to the deconditioning effect seen in convalescents, along with lung damage.
More studies will be needed to understand how psychological injury is related to 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 after discharge.
The researchers summarize: “This is the first exploratory study to conduct a comprehensive assessment of multiple vital organs, mental, cognitive and physical health in COVID-19 patients after discharge from hospital. These findings underscore the need for more large-scale research.. “
*Important news
medRxiv publishes preliminary scientific reports that are not peer-reviewed and therefore should not be considered conclusive, guide clinical practice / health-related behavior, or be treated as established information.
