Ongoing serious symptoms in COVID-19 survivors

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The COVID-19 pandemic has infected more than 40 million people worldwide. Despite the high mortality seen among hospital patients, many survived, although little is known about the medium to long-term effects of COVID-19 disease after discharge. Although this is primarily a respiratory disease, emerging data suggests that multi-organ lesions are common, especially in moderate to severe infections. New study posted on the pre-print server medRxiv* in October 2020 describes the after-effects of the disease in the months following recovery.

Multi-organ damage from COVID-19

COVID-19 is primarily a respiratory or pneumonic disease, but with data coming from all over the world, it appears that several organs are affected by the virus, especially when the infection is severe or moderate. The most sensitive organs appear to be the brain, heart, gastrointestinal system, and kidneys.

This extensive injury mechanism could be a deregulation of the virus-mediated immune response, leading to exuberant inflammation, endothelial injury, coagulation abnormalities, and resulting damage. The results depend on the extent of infection, inflammation, and individual health condition prior to infection.

The link between abnormal inflammation and the chronic sequelae of COVID-19 is emerging. Some researchers have shown that recovering patients have inflammation of the lungs even months after recovery, which may be the case with other organs.

Systemic effects of COVID-19 and relationship to the inflammatory response
Systemic effects of COVID-19 and relationship to the inflammatory response. A, B: Comparison of cardiopulmonary stress test (CPET) parameters (VO2 max and VE / VCO2) between the control corresponding to comorbidity and COVID-19 survivors. C: Relationship between VE / VCO2 and white blood cell count in COVID-19. D, E: Comparison of sensitivity-weighted T2 * signal (left and right thalamus) and MoCA scores between controls and COVID-19 survivors. F: Relationship between volume of periventricular white matter hyperintensity (pWMH) volume and white blood cell count in COVID-19. G, H: Comparison of native myocardial T1 (basal and middle ventricle) between controls and COVID-19 survivors. I: Relationship between native basal T1 and C-reactive protein (CRP). J, K: Comparison of hepatic T1 and hepatic iron corrected for iron between controls and COVID-19 survivors. An internal algorithm was used to calculate the iron corrected T1, so these values ​​cannot be compared to the LiverMultiScan cT1. L: Relationship between iron corrected hepatic T1 and CRP in COVID19. M, N: Comparison of mean cortical kidney T1 and cortico-medullary differentiation in control and COVID-19 survivors. O: Relationship between T1 cortical kidney 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 comparing Gaussianized and ungrounded variables).

Understanding the aftermath of COVID-19

The current study aims to understand how exercise capacity, intellectual function, mental health and quality of life are affected by this disease. They assessed people who had survived a moderate to severe episode of COVID-19, discharged 2-3 months after 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 inflammation and multi-organ damage using magnetic resonance imaging (MRI), the walking test, and other rating scales.

Persistent symptoms and signs of organ damage

They found that persistent shortness of breath was present in two-thirds of the patients, with fatigue in more than half of the patients. Imaging revealed abnormalities in the lungs in 60% of patients, while a quarter to a half showed changes in the heart and kidneys, respectively. Only a tenth had liver damage.

Fitness was significantly 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 impaired in the executive and visuospatial domains. (10%) and kidneys (29%) of patients. The damage observed in several organs during convalescence was correlated with inflammatory markers and with the severity of the acute disease, thus providing the latter prognostic value.

Moderate to severe anxiety and depression have been reported by more than a third of patients, mainly due to their persistent shortness of breath when testing negative for the virus. Overall, they reported a significant decline in the quality of life they enjoyed, compared to controls. A significant percentage of this impairment was due to loss of physical condition, continued shortness of breath and fatigue, which prevented activities of daily living from proceeding normally.

Chronic post-viral inflammation holds the key

The study draws attention to the medium term regarding the sequelae of COVID-19 in surviving patients. In a high proportion, the lungs and other organs show signs of MRI abnormalities, possibly due to ongoing chronic inflammation. The results of lung parenchymal abnormalities in many MRI patients are consistent with previous studies, which show the presence of persistent inflammation in 71% of survivors, even three months after discharge.

The first outbreaks of SARS were similarly followed by permanent lung damage and impaired lung function in many survivors, for months and years later. Decreased lung function in up to 13% of survivors has also been recently reported by other researchers.

There is mounting evidence that SARS-CoV-2 produces a high viral load and that the ACE2 and TMPRSS2 receptors are found at high levels in the lungs, kidneys, heart and brain. These are necessary 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 did not show serious brain damage in most cases. This could be due to microvascular damage as shown by the presence of calcification and the breakdown products of the blood. This could explain the tendency of these images to show an increase in white matter hyperintensities and the increased incidence of strokes in these patients.

Implications and future directions

The increased blood coagulability and chronic inflammation of nervous tissue may 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, mainly reflecting impaired executive function. These findings should trigger future research into the link between cognitive impairment and COVID-19.

Up to a third of COVID-19 patients who require hospitalization have acute myocardial injury, which predicts a higher risk of death. Cardiac MRI is helpful in this situation. Previously, this modality has shown that up to 60% of patients present with significant inflammation of the heart tissue during convalescence, and a third of this subgroup had to be hospitalized.

In the present study, only a quarter of patients showed the presence of cardiac inflammation, correlated 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 damage in COVID-19 survivors could also be due to hyperinflammation, abnormal 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, as ACE2 receptors are present in these cells. More than a tenth of recovering patients have consistently elevated hepatic biomarkers at 2-3 months, and 10% have fibro-inflammatory markers, which correlates to some extent with MRI results.

Kidney damage appears to be due to renal inflammation that is both prolonged and accompanied by loss of cortico-medullary differentiation. This pattern is not unique to COVID-19, being seen with other post-inflammatory glomeruli injuries.

The researchers conclude that the chronic inflammatory reaction is responsible for the evidence of persistent damage to several organs, and this is not due to the occurrence of serious disease but to the immunopathology of the infection.

They conclude, ” Further 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 adverse effects of COVID-19 on vital organs..  »

About a third of patients have stopped physiotherapy due to fatigue and myalgia, indicating the possible occurrence of muscle wasting. This is known to accompany severe illness, which induces a catabolic state. Thus, it could contribute significantly to the deconditioning effect observed in convalescents, as well as to lung damage.

Further studies will be needed to understand how psychological injury relates 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 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 after discharge from hospital. These results highlight the need for further large-scale surveys.  »

*Important Notice

medRxiv publishes preliminary scientific reports which are not peer reviewed and, therefore, should not be considered conclusive, guide clinical practice / health-related behavior, or be treated as established information.

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