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Review of organ damage from COVID and Long COVID: a disease with a spectrum of pathology

  • Andrew G. Ewing ORCID logo EMAIL logo , Spela Salamon , Etheresia Pretorius , David Joffe , Greta Fox , Stephane Bilodeau ORCID logo and Yaneer Bar-Yam
Published/Copyright: July 2, 2024
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Medical Review
From the journal Medical Review Volume 5 Issue 1

Abstract

Long COVID, as currently defined by the World Health Organization (WHO) and other authorities, is a symptomatic condition that has been shown to affect an estimated 10 %–30 % of non-hospitalized patients after one infection. However, COVID-19 can also cause organ damage in individuals without symptoms, who would not fall under the current definition of Long COVID. This organ damage, whether symptomatic or not, can lead to various health impacts such as heart attacks and strokes. Given these observations, it is necessary to either expand the definition of Long COVID to include organ damage or recognize COVID-19-induced organ damage as a distinct condition affecting many symptomatic and asymptomatic individuals after COVID-19 infections. It is important to consider that many known adverse health outcomes, including heart conditions and cancers, can be asymptomatic until harm thresholds are reached. Many more medical conditions can be identified by testing than those that are recognized through reported symptoms. It is therefore important to similarly recognize that while Long COVID symptoms are associated with organ damage, there are many individuals that have organ damage without displaying recognized symptoms and to include this harm in the characterization of COVID-19 and in the monitoring of individuals after COVID-19 infections.

Keywords: COVID-19; Long COVID syndrome; asymptomatic organ damage; reduced functional capacity

Introduction

It is estimated that 10 %–30 % of people who contract COVID-19 experience symptoms that last beyond the initial illness, depending largely on the definition used [1], [2], [3]. Organ damage might affect over 50 % of post-COVID-19 individuals [4], [5], [6] and perhaps more in adolescents and children [7].

As COVID-19 continues to transmit across the world, the consequences of the pandemic are becoming clearer. It is now known that this virus is not only contagious and potentially deadly but can cause long-term damage as well. Acute COVID-19 is known to cause a wide range of symptoms, ranging from mild to severe and life-threatening complications. Some do not develop symptoms in the acute phase at all. Others experience sudden deaths [8], heart attacks, strokes [9], [10], [11], debilitating systemic infections [12], [13], [14], [15], [16], heart failure, new autoimmune disorders [17], [18], [19], [20], and more are being noticed. Increasing numbers of publications since 2020 describe the pathophysiology mechanisms behind these [1], [21], [22], [23], [24], [25], [26], [27] complications, and large case-control studies [27], [28], [29], [30], [31] indicate a significant increase in them.

Across the spectrum of acute symptoms, many still develop longer-term symptoms known as Long COVID. Most estimates range from 10 %–30 % of people who contract COVID-19 experience symptoms that last beyond the initial illness, depending largely on definition. But what is even more concerning and less widely known is the long-term effect that COVID-19 can have on the organs of those who were infected.

Recent studies have shown that well over 50 % of people, in some reports 70 % or more, who have contracted SARS-COV-2 suffer damage to their organs [4], [5], [6]. For example, COVID-19 has the potential to cause lasting scarring in the lungs of infected patients, resulting in reduced lung function [32], 33]. It has been linked with long-term cardiovascular damage [10], 34], 35], which can cause difficulties when exercising [36], 37] and even increase the risk of a heart attack [9] or stroke. COVID-19 can cause brain damage including loss of brain tissue, small blood vessels, and merged brain cells. In some patients, perhaps many, there is also damage to the immune system.

The spectrum from COVID-induced organ damage to Long COVID

While the term Long COVID refers to a set of symptoms whose exact causes are not yet fully understood, the virus’ underlying effects on the body are an even more common and insidious aspect of many COVID-19 infections. They can lead to a range of consequences including sudden severe events, loss of quality of life or a diminished lifespan [38]. Some of these effects have been recognized in the literature since 2020 and yet have been largely ignored. There are many effects resulting from COVID-19 on bodily systems. Here we discuss evidence for five of these, the heart, brain, endothelial cells and blood vessels, endocrine system, and immune system (see Figure 1).

Figure 1: Overview figure of effects of COVID and Long COVID on organ systems. Created with Biorender.com.
Figure 1:

Overview figure of effects of COVID and Long COVID on organ systems. Created with Biorender.com.

The heart

According to work published recently [39], people infected with SARS-COV-2 between March and November 2020 were shown to be at higher risk for heart attacks, coronary heart disease, heart failure, and deep vein thrombosis. In this work, they followed over 7,500 people, both with and without pre-existing heart conditions. This was pre-vaccine and pre-omicron; however, data published in May 2023 shows that after omicron, the risk is essentially as high as that for alpha/delta and varied with the severity of infection, but still present in those who experience a mild acute infection [40]. The infected group was 40 % more likely to develop cardiovascular disease when compared to those uninfected. This group was also five times more likely to die during the following 18 months when compared to those not reporting prior SARS-COV-2 infection. The risk of adverse outcomes, such as hospitalization or death, is significantly greater in cases of severe infection compared to mild infection. However, it is important to note that even mild infections carry a higher risk of complications and should not be taken lightly.

This was not a surprise as early work using cardiovascular magnetic imaging [41] on a cohort of 100 recovered German patients in 2020, one-third hospitalized and two-thirds recovered at home, showed cardiac involvement in 78 patients (78 %) and ongoing myocardial inflammation in 60 patients (60 %). These were not dependent on preexisting conditions, disease severity and overall course of the acute illness, and time from the original diagnosis.

Reduced blood oxygen or ischemia in the heart can cause acute myocardial infarction (AMI) and stroke. This can result from disruption of underlying chronically inflamed atherosclerotic plaques, and this has been clearly shown to be a clinical complication of COVID-19 [42], 43]. It has recently been established that SARS-CoV-2 infects coronary vessels, and thereby induces inflammation of the plaques [44]. These might trigger acute cardiovascular complications, and the elevated chance of long-term cardiovascular risk. AMI and stroke can also result from other respiratory viral infections, including influenza virus [45]. It is important to note, however, that patients with COVID-19 are seven times more likely to have a stroke than patients after influenza [46] and the risk for either AMI or stroke is still elevated up to 1 year after infection [9].

The brain

There is now compelling evidence that the SARS-CoV-2 virus can invade the brain during infection, causing damage that includes the loss of both gray and white matter, thereby affecting nerve cells as well as support cells. The virus has been shown to disrupt the blood-brain barrier that protects the brain [47]. The impact of COVID-19 on the brain has been extensively studied, and some key findings have been reviewed [48], [49], [50], [51], [52].

SARS-COV-2 might enter via a damaged blood-brain barrier [53], 54] as SARS-COV-2 damages endothelial cells [47], 54] or it might enter from the nose via a nasal nanotube mechanism [55]. Peripheral inflammation has also been shown to lead to post-infection brain deficiency, probably via the release of cytokines [56]. Inflammation of the Vagus nerve has been observed to cause dysautonomia during acute infection leading to disruption of the autonomic nervous system and affecting heartbeat, blood pressure, digestion, breathing, bladder control, dental health, and so on [57]. These all can occur during the entire spectrum of illness of COVID-19 from mild to severe.

Acute infection can lead to direct changes in the brain resulting in losses in learning/memory ability and cognition [58], 59]. Significant neurologic and psychiatric outcomes of COVID-19 have been shown [60] including higher incidence of ischemic stroke, intracranial hemorrhage, dementia, and mood/anxiety disorders. Cerebral blood flow is diminished during acute COVID-19 infection [47]. The neurosymptoms of acute COVID-19 have been found to resolve in many patients, but magnetic resonance imaging has found that alterations can persist after 6 months in the amplitude of low-frequency fluctuation (ALFF) and functional connectivity in the right frontal, temporal, and occipital lobes of the brain [61]. Importantly, ALFF is a stable and reliable parameter to characterize intrinsic or spontaneous brain activity found in various brain diseases, including Parkinson’s disease, posttraumatic stress disorder, major depressive disorder, and bipolar disorder [62]. There is evidence of dopaminergic senescence with SARS-COV-2 infection which bodes poorly for a number of neurodegenerative disorders [63]. Direct invasion of the brain by SARS-COV-2 could lead to ORF3a expression, which has been shown to disrupt the autophagy-lysosomal pathway, impair sphingolipid homeostasis, and to drive neuropathogenesis including the accumulation of α-synuclein [64].

There is a higher risk for psychiatric diseases in those who have had an acute COVID infection [65] and many mental health consequences have been noted in Long COVID. These include fatigue, cognitive dysfunction, short-term memory deficits, general memory loss, compromised attention, language and praxis abilities, encoding and verbal fluency, impairment of executive functions, psychomotor coordination, sleep disturbance, depression, anxiety and post-traumatic stress disorder [66], [67], [68].

These acute and long-term remaining conditions are worrisome, but there are now a number of studies that suggest that SARS-COV-2 is causing longer-term damage via protein changes in the brain. In fact, the demarcation between acute COVID-19 and Long COVID is becoming blurred. The UK Biobank has conducted a magnetic resonance study on people aged between 51 and 81 years old, which revealed some concerning findings. Specifically, the study highlighted a significant reduction in the thickness of gray matter in the brain, as well as tissue contrast in two specific regions – the orbitofrontal cortex and parahippocampal gyrus [69]. They also saw a reduction in global brain size in those having COVID-19 relative to controls. Post COVID-19 patients also reported a greater cognitive decline approximately 6 months after infection. A follow-up study indicates that although some patients seem to recover cognitively, patients with symptoms can have cognitive issues after 2 years, suggesting an average 10-year increase in aging of the brain [70].

The physical changes in the brain caused by SARS-COV-2 may take months or years to become apparent. Evidence suggests that recovery can take years and may not be complete. There is solid evidence that at least in severe infections the same chemical structures found in the brains of neurodegenerative patients (e.g., Parkinson’s disease, Alzheimer’s disease) are involved [71]. A worrisome study has shown that Alzheimer’s disease and COVID-19 patients, adjusted for age and gender, show similar molecular and cellular changes [72]. It has been suggested that COVID-19 might well lead to a higher predisposition of Alzheimer’s disease or dementia [73], and those with already existing dementia are more likely to see a more rapid progression following SARS-COV-2 infection [74]. Similar circumstances have been observed for Parkinson’s disease. A very real possibility exists that we will see a major increase in neurodegenerative diseases in increasingly younger cohorts in the following decades after the pandemic. And, Long COVID incidence has not changed with omicron [75], 76], indicating that the damage continues with new variants and reinfections.

The endothelium and blood vessels

Almost every pathological process during a COVID-19 infection and many in Long COVID can be related to its effects on the endothelial cells in the vasculature. Endothelial cells form the barrier between blood or lymphatic solution and the vessel walls controlling the flow of substances and fluid into and out of a tissue. These cells are critical to all functions involving circulation. SARS-COV-2 infection leads to elevated turnover of endothelial cells [77]. Data suggest that even for those who have had COVID-19 without symptoms, there is damage to the endothelial tissues [78], [79], [80], [81].

The endothelium is a thin layer of cells that lines the inside of blood vessels, and it plays a significant role in maintaining vascular health. In COVID-19 patients, the virus can invade and damage these endothelial cells. This damage can lead to the rarefaction of vascular capillaries to become so minuscule that only a single red blood cell can pass through at a time. Unfortunately, this can also lead to the formation of microthrombi – small blood clots that block or restrict blood flow in the capillaries. In severe COVID-19, these microthrombi can form on a large scale which can lead to stroke or organ failure. In a 2021 review of 151 autopsies of those dying of COVID-19, microthrombi in the lung were found in 73 % (91 patients), 11 % in the heart, 24 % in the kidney, and 16 % in the liver [80]. Hence, the observation of damage to endothelial cells in asymptomatic COVID-19 patients [77] bodes poorly for the long-term impact of organ damage. This damage is likely to go unnoticed at first but may be significant in the aging of organs and is likely to be increased with repeated infections.

The endocrine system

The endocrine system is responsible for regulating hormones that control numerous bodily functions, such as metabolism, immune response, stress response, and more. The endocrine system is complex, comprising hormone-producing cells and organs that serve to maintain homeostasis and to modulate the immune response to infections. Several studies have reported multiple endocrine and metabolic abnormalities following virus infections, such as human immunodeficiency virus type-1 (HIV-1) [82], coxsackieviruses B [83], and now SARS-CoV-2 [84]. Although many viral infections have been known to affect the endocrine system [85], the large number of infections and reinfections with SARS-COV-2 makes understanding the impact of this infection on these effects important. COVID-19 can impact the endocrine system in several ways. For example, SARS-COV-2 infection increases the possibility of incident diabetes and antihyperglycemic use [86]. Endocrine diseases include adrenal insufficiency, type 1 and 2 diabetes, Cushing’s syndrome, and thyroid disease [87]. The long list of effects of COVID-19 on the endocrine system includes the following [84], 88]:

  1. Direct viral effects on endocrine tissues: ACE2 receptors, which the virus uses to enter human cells, are found in various endocrine organs like the pancreas, thyroid, and adrenal glands. Infection of these tissues can potentially disrupt hormone production and regulation. One such outcome is Graves disease [88], an autoimmune disorder where the immune system mistakenly attacks the thyroid gland. Reports suggest that SARS-CoV-2 may cause thyroid inflammation in some individuals [89]. This condition, known as De Quervain’s thyroiditis, can lead to temporary thyroid dysfunction as well as thyroid tissue damage, which may affect individuals with or without preexisting autoimmune thyroid conditions like Graves’ disease or Hashimoto thyroiditis. More generally, COVID-19 has been associated with thyroid dysfunction, including both hyperthyroidism and hypothyroidism [90], [91], [92], which can have important health implications.

  2. Hyperinflammation including cytokine storms: During the acute phase of infection COVID-19 can lead to an excessive immune response and hyperinflammation both short or long-term, which can negatively impact the function of several endocrine organs, such as the pituitary gland [93], leading to long term hormone imbalances.

  3. Long-term metabolic changes: These can include glucose intolerance or a compromised response to insulin in the body, potentially leading to the development of type 2 diabetes in adults, and in some cases insulin resistance leading to type 1 diabetes in children [86]. The virus may also affect the function of the pancreas [94], where insulin is produced.

  4. Reproductive hormone changes: The impact of SARS-CoV-2 on reproductive health is significant with reports indicating that the virus can temporarily disrupt menstrual cycles in women [95] and impact fertility in both women and men [96]. But it can also lead to an increased risk of hypogonadism and erectile dysfunction [97], 98], negatively affecting sperm quality parameters [99], and crossing the placental barrier to infect and damage the placenta and fetus [100], [101], [102]. This can result in stillbirths, preeclampsia, low birth weight, fetal loss, preterm birth, and developmental impairments [103], [104], [105].

It is important to note that our understanding of how COVID-19 affects the endocrine system across the population is continuing to develop. However, the existence of significant impacts is already apparent.

The immune system

The immunology of COVID-19 and Long COVID have recently been reviewed [13], 21]. Immune dysregulation is generally considered to be a manifestation of Long COVID, and it occurs in patients after the full spectrum of illness from mild to severe COVID-19. However, Long COVID is usually defined by symptoms, whereas immune dysregulation does not have distinctive symptoms on its own. However, it becomes apparent through recurrent infections. COVID-19 can dysregulate all the common aspects of the immune system. The duration of this dysregulation is still being investigated. The effects of COVID-19 are seen in T cells [106], B cells [107], dendritic cells [108], monocytes [109], and platelets [110], among others. This results in increased vulnerability to other infections [15], for example a more than fourfold increase in risk for other viral infections [12].

COVID-19 causes increased cellular turnover leading to aging of immune cells. These cells have limitations in their proliferative capacity and have a limited ability to divide and create new cells before cell division stops. SARS-COV-2 has been found to have detrimental effects on the length of cells’ telomeres, which are essential for cell proliferation. With each cell division, these telomeres are effectively shortened, potentially leading to accelerated aging and a higher risk of developing various diseases. T cell production is dependent on telomere length, and these shorten naturally with age. Thus, the elderly have shorter telomeres. After SARS-COV-2 infection, these telomeres are also shorter [111], 112]. This could explain why older adults appear to be more susceptible to reinfection following a SARS-COV-2 infection [113].

Viral persistence can lead to a variety of damaging effects on the immune system. A new preprint provides good evidence that even people who are asymptomatic after SARS-COV-2 infection have signs of immune activation that localize in areas of the body from which one can identify the virus up to two years after infection [114]. These include the brain stem, spinal cord, bone marrow, nasopharyngeal and hilar lymphoid tissue, cardiopulmonary tissues, and gut wall. These data suggest that Long COVID and acute COVID-19 are not different entities, but the same infection at different levels of severity and longevity [115].

Implications of these findings are that several forms of damage lead to a condition similar to accelerated aging, with telomeres, mitochondria, the nervous, vascular, endocrine and immune system all showing decreased capacity and resilience. Increases in heart and neuro-inflammation can be caused by these long-lasting immune effects. In essence, this is accelerated aging of the tissues. Instead of being predominantly found in the elderly, in the near future T-cell controlled illnesses might move to middle age, even more so for immunocompromised individuals, dramatically reducing lifespan.

Other organs and systems

Lungs

COVID-19 often begins with respiratory symptoms, and severe cases can lead to acute respiratory distress syndrome. An impact on pulmonary function continues for one fourth of COVID-19 patients, who have impairment of pulmonary function a year after illness [33]. Fibrosis and scarring of lung tissue can lead to chronic respiratory impairment, including but much more widespread than recognized Long COVID respiratory symptoms.

Kidneys

Kidney damage and acute kidney injury have been observed in Long COVID patients [116]. Prolonged kidney dysfunction can lead to chronic kidney disease, which may require ongoing medical management or dialysis, and can have severe consequences if it cannot be controlled effectively.

Intestines

SARS-CoV-2 can infect cells in the intestines, and some COVID-19 patients experience gastrointestinal symptoms [117]. There is ongoing research into potential long-term gastrointestinal complications and impacts on the gut microbiome [118]. A correlation between dysbiosis and Long COVID has been reported in patients one year after acute infection [119]. This suggests a correlation between Long COVID and changes in the gut microbiome. It has been well recognized that Long Covid is characterised by gut viral persistence [120] with evidence of persistent shedding in faecal sample for up to 7 months [117]. There is considerable and increasing evidence that gastrointestinal complications of Long COVID are common. In a large meta-analysis of 14 studies and including 296,487 patients [121], gastrointestinal symptoms were present in 22 % of Long COVID sufferers.

Blood

The SARS-COV-2 virus has been associated with protein changes and long-standing blood changes including microclots in many patients [122], [123], [124].

COVID-19 and SARS-COV-2 adversely affects nearly every organ in the body including also the skin [125], the eyes [126], the ears [127], and more.

Conclusions

The importance of Long COVID symptoms impacting many millions around the world is gaining recognition [128]. While symptomatic Long COVID affects 10 %–30 % of those infected, and its widespread impact is great enough to affect macroeconomic conditions [129], it is only part of the long-term consequences of SARS-COV-2 infections. Varied levels of organ damage from COVID-19 have been shown to occur in over 50 % of those infected. Organ damage leads to reduced functional capacity and physiological reserve of organs that is consistent with reduced health, reduced life expectancy, and increased vulnerability to future infections and conditions. It also manifests as acute events such as heart attacks, strokes, as well as recurrent infections of other kinds. Organ damage is an important substrate for Long COVID symptoms, and the symptoms of Long COVID may be considered the tip of the iceberg of multisystem and organ damage manifestations. What is important to recognize is that even the known severe consequences of Long COVID are only part of the long-term consequences of COVID-19. It is crucial to acknowledge that SARS-CoV-2 poses significant threats that are further exacerbated by reinfections [130], resulting in a detrimental impact on various aspects of health. As we continue to study these impacts to better address them, we must take preventive measures to avoid repeated infections [131].

Corresponding author: Andrew G. Ewing, Department of Chemistry and Molecular Biology, University of Gothenburg, Medicinareberget 7B, Gothenburg 40530, Sweden; and World Health Network, Cambridge, MA 02139, USA, E-mail:

Acknowledgement

We thank Nicholas Bertram for reading and commenting on the language in this manuscript.

  1. Research ethics: Not applicable.

  2. Informed consent: Not applicable.

  3. Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission. All authors participated in writing and/or editing the manuscript as well as suggesting references and interpretation.

  4. Competing interests: Etheresia Pretorius has filed various patents related to methods for the early detection of inflammatory disease risk. She has also filed a patent for a novel method for the diagnosis of coagulation pathology in Long COVID. All other authors state no conflict of interest.

  5. Research funding: None declared.

  6. Data availability: Not applicable.

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Received: 2024-03-28
Accepted: 2024-06-11
Published Online: 2024-07-02
Published in Print: 2025-02-25

© 2024 the author(s), published by De Gruyter, Berlin/Boston

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

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https://doi.org/10.1515/mr-2024-0030
Keywords for this article
COVID-19; Long COVID syndrome; asymptomatic organ damage; reduced functional capacity
Creative Commons
BY-NC-ND 4.0

Articles in the same Issue

  1. Frontmatter
  2. Reviews
  3. Biophysical stimuli for promoting bone repair and regeneration
  4. A stepwise approach to deriving functional β-cells from human embryonic or induced pluripotent stem cells
  5. Eco-fertility: examining the climate change-total fertility rate nexus in the context of sustainable developmental goals in a systematic review approach
  6. Redefining chronic mountain sickness: insights from high-altitude research and clinical experience
  7. Review of organ damage from COVID and Long COVID: a disease with a spectrum of pathology
  8. Perspective
  9. Combining transcriptomic and metabolomic insights to guide the clinical application of adipose- and bone marrow-derived mesenchymal stem cells
  10. Research Highlight
  11. Precision phototherapy and imaging with aggregation-induced emission-based nanoparticles cloaked in macrophage membrane
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