Long COVID and Post-COVID Conditions

Overview of the Medium- and Long-Term Complications Associated with COVID-19

Last updated on March 12, 2024

This Document is Extensive, but NOT Comprehensive Our understanding of the association between COVID-19 infection and long-term health complications is continually evolving, and this document will be updated as new information becomes available. While the intent of this document is to provide an extensive overview, it should not be considered a comprehensive list of the potential consequences of COVID-19 infections.

This document reviews literature published up until February 25, 2024.

Introduction

For many people, being exposed to SARS-CoV-2 (the virus that causes COVID-19) results in illness characterized by mild symptoms, resolving in a matter of days or weeks. In fact, research has found that 30-60% of COVID-19 cases may be entirely asymptomatic (Shang et al., 2022; Wang et al., 2023). However, that is not the only potential outcome, and each infection is a new opportunity for long-term symptoms to develop (Bowe et al., 2022).

In fact, some people experience severe, debilitating symptoms that may last for several years and may not improve over time (Fernandez-de-las-Peñas et al., 2023). Other people recover from COVID-19, but as a result of the infection, they are now vulnerable to many types of health conditions, known as “post-COVID conditions,” or “PCCs” (Fernandez-de-las-Peñas et al., 2023; Xie et al., 2023).

These conditions affect nearly every organ in the body and range from benign to life-threatening (Bowe et al., 2022; D’Isabel et al., 2023; Zhao et al., 2023; Novak et al., 2022; Fernandez-de-las-Peñas et al., 2023; Xie et al., 2023; Peter et al., 2022; Abbasi, 2022; Ormiston et al., 2022; Ma et al., 2023). However, there is no way to know who will be susceptible to a particular condition until it manifests.

There appears to be a reciprocal relationship between COVID-19 and PCCs:

Underlying health factors place people at higher risk of severe illness from COVID-19.
People who experience severe illness from COVID-19 have a greater risk of developing one or more PCCs (Xie et al., 2023; Perez Giraldo et al., 2023).

However, the damage done by COVID-19 is cumulative (Bowe et al., 2022). Even someone who recovers from an asymptomatic (Ma et al., 2023) or mild case (Novak et al., 2022) of COVID-19 is at risk of developing one or more PCCs.

In fact, a recent review by Boufidou et al. (2023) noted that those who were reinfected were more prone to developing long-term symptoms—in comparison to those who were only infected once—and more prone to “various complications, including potential cardiac, pulmonary, or neurological problems” (p. 7). Even asymptomatic SARS-CoV-2 infections can result in long-term symptoms such as fatigue, loss of taste or smell, or chronic cough (Ma et al., 2023).

Critically, the increased risk of developing PCCs after reinfection may represent a more recent change in the pathology of SARS-CoV-2; in contrast to earlier variants of COVID-19, which had lower rates of reinfection and a higher risk of developing chronic symptoms after the first infection relative to reinfection. The emergence of Omicron BA variants appears to represent a shift in this pattern (Hadley et al., 2023).

Long COVID vs. Post-COVID Conditions

Many post-infection complications may manifest as symptoms associated with long COVID, or “LC,” which refers to the ongoing symptoms many people may experience even after recovering from their acute infection (Zhao et al., 2023). However, everyone is at higher risk of adverse health effects after SARS-CoV-2 infection. For example, even mild to moderate cases of COVID-19 are leaving firefighters with long-term deficits in their cardiorespiratory fitness (D’Isabel et al., 2023).

In a study of 1.5 million medical records, from the National COVID Cohort Collaborative (N3C) as part of the NIH Researching COVID to Enhance Recovery (RECOVER) Initiative, Hadley et al. (2023) noted that the “largest proportion of LC diagnoses occur among individuals with a first reinfection in the Omicron BA epoch,” and that in this new era, LC diagnoses occurred much more closely to the date of infection compared to earlier waves of the pandemic.

PCCs can encompass health conditions that are not commonly associated with COVID-19 infection, as well as new-onset health conditions that arise after acute COVID-19; this term is frequently found in research examining the long-term effects of COVID-19. In contrast, LC is often used to refer to a constellation of chronic symptoms an individual may experience as a result of COVID-19; commonly used among patients and patient communities. The terms “LC” and “PCC” are often used interchangeably.

Conditions Affecting the Nervous System

Loss of sense of taste (ageusia) or smell (anosmia) are defining characteristics of the symptomatology of COVID-19 (Abdullah et al., 2023; Alqahtani et al., 2022; Blomberg et al., 2021; Cazzolla et al., 2020; Davis et al., 2020; Gottlieb et al., 2023; Ma et al., 2023; Mao et al., 2020; Peter et al., 2022; Silva Andrade et al., 2021; Speth et al., 2020; Thaweethai et al., 2023; Abdelmissih, 2022; Radke et al., 2024; Roczkowsky et al., 2023; Wang et al., 2023; Wostyn, 2021; Zayeri et al., 2024).

These symptoms are so common and specific in COVID-19 that they have been used as criteria for participant inclusion in some studies of people with LC, “due to the high diagnostic speciﬁcity of these symptoms” (e.g. Kedor et al., 2022, p. 10). Some studies have even found that loss of smell during acute COVID-19 infection directly predicts long-term sleep quality and level of fatigue in people who have recovered from their initial infection (Alqahtani et al., 2022; Azcue et al., 2022; Speth et al., 2020).

Unfortunately, research over the last several years has consistently found that the loss of smell resulting from COVID-19 is related to the SARS-CoV-2 virus entering the nervous system via the olfactory nerve (Brann et al., 2020; Cazzolla et al., 2020; Lima et al., 2020; Jha et al., 2021; Abdelmissih, 2022; Molaverdi et al., 2023).

Neuropathic Pain

Early in the pandemic, Attal et al. (2021) published a literature review that highlighted the potential for an increasing prevalence of neuropathic pain as a PCC, noting that chronic pain has long been reported to emerge as a result of viral infections. Critically, they noted “a special characteristic of COVID-19 is that it often causes peripheral or central neurological complications, either through direct invasion of the nervous system or through postviral immune reactions [emphasis added]” (Attal et al., 2021, p. 1).

Highlighting the risk of chronic neuropathic pain from COVID-19, the authors wrote (p. 3) that “neuropathic pain has been reported in up to 2.3% of hospitalized patients . . . (Mao et al., 2020), but its prevalence is probably underestimated because it is well established that chronic neuropathic pain may also develop within months after injury to the nervous system (Colloca et al., 2017).”

These predictions have since been supported by empirical research (O’Neill et al., 2023; Comruk et al., 2023; Büyükşireci et al., 2023; Williams & Zis, 2023; Fernández-de-Las-Peñas et al., 2022; Grieco et al., 2022; Shanthanna et al., 2022; Zis et al., 2022; Topal et al., 2022; Fernández-de-Las-Peñas et al., 2022; Jena et al., 2022; Joshi et al., 2022; Juárez-Belaúnde & Serrano Afonso, 2022; Fernández-de-Las-Peñas et al., 2022).

A New Era of Chronic Pain

A recent systematic review of the literature by Williams and Zis (2023) found that the prevalence of chronic neuropathic pain in individuals with LC was 34.3%.

Because LC may affect one in three people (O’Dowd, 2021; Fernandez-de-las-Peñas et al., 2023), they warned that “one in nine of those infected with COVID-19 will develop neuropathic pain” (Williams & Zis, 2023, p. 8). Accordingly, they urgently call for more research, “considering that several patients have been left unable to function due to neuropathic pain following COVID-19” (p. 9).

Further supporting this urgency, a large cohort study has found that pain is reported by roughly 8% of the general population two years after SARS-CoV-2 infection (Fernandez-de-las-Peñas et al., 2023).

Choi (2022, p. 238) noted that “even if the global epidemic of COVID-19 is converted to an endemic disease . . . chronic neuropathic pain related to COVID-19 infection may not easily disappear. Although little is still known about the mechanisms, characteristics, and natural history of COVID-19-related pain, many . . . studies show that the importance of awareness of neuropathic pain should be emphasized for early diagnosis and treatment of COVID-19 patients [emphasis added].”

Debilitating Fatigue

Severe, prolonged fatigue is one of the most common and disabling features of LC (Williams et al., 2020; Salisbury, 2020; Komaroff & Bateman, 2020; Wostyn, 2021; Poenaru et al., 2021; Sandler et al., 2021; Sukocheva et al., 2022; Chasco et al., 2022; Azcue et al., 2022; Twomey et al., 2022; Delgado-Alonso et al., 2022; Hartung et al., 2022; Joli et al., 2022; Abbott et al., 2023; Poole-Wright et al., 2023; Mclaughlin et al., 2023; Qin et al., 2023; Beyer et al., 2023; Vernon et al., 2023; Tate et al., 2023).

Manifestation of Pathophysiological Abnormalities After Infection

While the exact mechanisms of this condition are not yet understood, it is clear that this manifestation of fatigue has a physiological origin within the nervous system.

For example, a recent review by Joseph et al. (2023) found that, although many early studies suggested that extertional intolerance as a post-COVID symptom may be a result of deconditioning, further cardiopulmonary research has revealed “perturbations related to systemic blood flow and ventilatory control associated with acute exercise intolerance” in LC. The authors noted that LC shares pathophysiological commonalities with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), another systemic fatigue condition that has been shown to correspond with neuroimmunological abnormalities and other pathophysiological markers (Bateman et al., 2021; Tokumasu et al., 2022; Grach et al., 2023).

In particular, one common feature of LC is post-exertional malaise (PEM). PEM is the “hallmark criteria of ME/CFS,” and is defined as “the worsening of symptoms and function following a previously tolerated physical, cognitive, orthostatic, emotional, or sensory stressor” (Mooney, 2023, p. 1175). Often termed a “crash,” those who have experienced PEM describe it as “feeling poisoned, drowning in cement, having the flu over and over, and being hit by a bus” (Mooney, 2023).

Because of the severity of symptoms like PEM, 75% of those with this condition are unable to work, and over a quarter are entirely unable to leave their homes—with many people being fully confined to their beds (Bateman et al., 2021).

These symptoms cause a “substantial reduction or impairment in the ability to engage in pre-illness levels of occupational, educational, social, or personal activities” (Committee on the Diagnostic Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome et al., 2015), and it is common to experience “overwhelming fatigue that is not alleviated with rest, [as well as] cognitive impairment, orthostatic intolerance, muscle/joint pain, neurological abnormalities, extreme sensitivity to sensory input, and more debilitating symptoms” (Mooney, 2023).

Physical or Emotional Exertion Can Cause Further Deterioration

PEM plays a critical role in recovery from LC. In a letter published in January 2024, van Rhijn-Brouwer et al. (2024) responded to a recent review of cardiovascular autonomic dysfunction (CVAD, see Fedorowski et al., 2024), noting that an error was made in recommending graded exercise therapy for the treatment of individuals experiencing PEM.

Critically, van Rhijn-Brouwer et al. (2024) note that “exercise in people living with long COVID is significantly associated with abnormal immune and metabolic responses to exercise in skeletal muscle compared with healthy control participants (Appelman et al., 2024). Therefore, graded exercise therapy should not be recommended for people living with long COVID and post-exertional malaise [emphasis added].”

In fact, a reanalysis of a major study on treating PEM with exercise-based therapy has found that the “rates of recovery were consistently low and not significantly different across treatment groups” (Wilshire et al., 2018).

Further highlighting this point, van Rhijn-Brouwer et al. (2024) elaborated:

Some people living with long COVID and CVAD do not have post-exertional malaise, so the exercise recommendations in the Review can safely be followed for these individuals (Blitshteyn et al., 2022). However, people living with long COVID and post-exertional malaise must be supported in keeping daily activities within their available fund of energy or ‘energy envelope’ (Sanal-Hayes et al., 2023). We advise a ‘do no harm’ approach. All people living with long COVID and CVAD should be assessed for post-exertional malaise. People living with long COVID without post-exertional malaise can be guided towards exercise approaches that might improve autonomic responses, while continuing to monitor them for a potential emergence of post-exertional malaise.

van Rhijn-Brouwer, Hellemons, et al. (2024). Graded exercise therapy should not be recommended for patients with post-exertional malaise. Nature Reviews Cardiology.

Exercise can be actively harmful to those experiencing PEM. One study of people living with LC found that, for 75% of participants, following the recommendation from a healthcare provider to exercise had resulted in worsening symptoms and deterioration of their physical condition (Wright et al., 2022). The limited studies that describe positive responses to cognitive behavioral therapy and graded exercise therapy from people with LC have either excluded individuals with PEM or simply did not account for it (Biere-Rafi et al., 2023).

In response to the letter discussed above, the authors of the original review agreed with the clarification (Fedorowski et al., 2024). They stated that, although they discussed the benefits of aerobic reconditioning in patients with certain forms of cardiac dysfunction, they intended to convey that “a more cautious approach is required” for patients showing signs of PEM:

Our understanding is that, in some cases, a standard approach to physical exercise might potentially harm patients with a still poorly defined susceptibility to post-exercise energy depletion (Komaroff, 2019). We apologize for our lack of clarity. Our intention was to raise awareness of this special subgroup of patients among those who have post-COVID-19 cardiovascular dysautonomia . . . We, the authors of the Review, see many patients with POTS in our clinical practices, and each of us has seen patients who had initial worsening at the onset of an individual training programme, but who improved during follow-up under careful supervision by professional staff. Importantly, this approach is supported by [modern diagnostic criteria].

Fedorowski, Fanciulli, et al. (2024). Reply to ‘Graded exercise therapy should not be recommended for patients with post-exertional malaise’. Nat Rev Cardiol.

These modern diagnostic criteria (National Institute for Health and Care Excellence, 2021) are available through the National Library of Medicine.

Note for Healthcare Providers Healthcare providers should be aware of these modern diagnostic criteria for PEM, as exercise-based therapies in the presence of PEM can cause dangerous adverse outcomes (Kielland et al., 2023).

In particular, it is critical to understand the necessary considerations that must be made for caring for individuals with severe or very severe symptoms and to understand the impact that those symptoms have on the individual.

Yet Another Mechanism for Post-Infection Fatigue

In a review conducted early in the pandemic, Komaroff and Bateman (2020) noted that it’s “not surprising” that some individuals would “develop a debilitating chronic fatigue,” as “[p]ost-infectious fatigue syndromes follow in the wake of acute infections with several different types of infectious agents.”

Among the infections that have been shown to cause post-infection fatigue syndromes are: the first SARS coronavirus (Moldofsky & Patcai, 2011); the Epstein-Barr virus (EBV), the virus that causes mono (Jones, 1985; Hickie et al., 2006; White et al., 1998); enteroviruses, a common family of viruses which infect the gastrointestinal system (Chia & Chia, 2007); human herpesvirus-6, which is ubiquitous in the human population (Komaroff, 2006); human parvovirus, which is an often-asymptomatic childhood infection that causes rash (Kerr et al., 2010); Lyme disease (Sigal, 1990); the Ebola virus (Epstein et al., 2015); the West Nile virus (Sejvar et al., 2008); the Dengue virus (Seet et al., 2007); bacterial infections (Nicolson et al., 2003); and parasitic infections (Litleskare et al., 2018).

Komaroff and Bateman (2020) observe that “post-infectious fatigue syndromes following these well-documented acute infections share a group of symptoms in common with people who have ME/CFS,” and that a large proportion of individuals “with ME/CFS note that it began suddenly, with an apparently infectious illness characterized by respiratory symptoms, fever, adenopathy, myalgias, and other symptoms.”

Functional and Neuroinflammatory Biomarkers

In a pre-pandemic study investigating the hypothesis that ME/CFS is caused by a “state of chronic, low-level neuroinflammation,” Mueller et al. (2020) used neuroimaging techniques to measure several metabolites in the brain related to neuroinflammation. They observed metabolic differences across several regions, finding that “[m]etabolites related to neuroinflammation (CHO [choline], MI [myo-inositol], and LAC [lactate]) were higher in ME/CFS patients,” with the high ratio of choline in the left anterior cingulate cortex (ACC) being the most significant.

The excess levels of choline are “interpreted as indicating abnormal phospholipid metabolism and accelerated cell membrane turnover” (p. 9). The excess levels of lactate, in contrast, are “a byproduct of anaerobic cell metabolism (glycolysis) that . . . is produced by various immune cells under inflammatory conditions,” and is indicative of an underlying process which results in “energy deficits at the cellular level” (Mueller et al., 2020, p. 10).

These findings complement the observed associations of fatigue in LC. For instance, Legler et al. (2023) observed elevated levels of antinuclear antibodies (ANA) in 25% of patients, “which is above the prevalence in the general population and which correlated positively with symptom severity up to 20 months post COVID-19” (p. 15). Overall, they concluded that the study “supports the presumption of ongoing inflammation” in LC.

Legler et al. (2023, p. 14) also found that, within the subgroup of LC patients who also met the diagnostic criteria for ME/CFS, those who exhibited “initially reduced [hand grip strength] were more likely to experience high disease burden up to 20 months after infection. Speciﬁcally, higher hand grip force correlated with less fatigue . . . .” In contrast, for individuals who fell short of the criteria for ME/CFS, “links of [hand grip strength] to these symptom measures were not found or were much less pronounced.”

Neural Abnormalities

A recent neuroimaging study examined the brains of individuals with either ME/CFS or LC, using ultra-high field strength MRI to measure the physical volume of multiple regions in the brain stem. The study found multiple regions of abnormal brainstem volume in both groups relative to healthy controls, demonstrating a correlation of “abnormal brainstem volume in both ME/CFS and long COVID consistent with the overlapping symptoms” of these conditions (Thapaliya et al., 2023).

Mood Disorders (Anxiety and Depression)

Cohort studies have consistently found that the incidence of adverse neurological and psychiatric outcomes after SARS-CoV-2 infections is quite high. In one such study, Taquet et al. (2021) found an incidence rate of up to 33% of people receiving a neurological or psychiatric diagnosis within six months of recovering from COVID-19. The incidence of someone receiving their first such neurological or psychiatric diagnosis within six months is about 12%.

More recently, Rahman et al. (2023) showed that COVID-19 is associated with new diagnoses of Schizophrenia Spectrum and Psychotic Disorder (SSPD), with younger individuals being particularly affected.

Many studies have now provided evidence that the frequent occurrence of adverse psychiatric outcomes in people with LC may result from the underlying inflammation and dysregulation of the nervous system (Al-Hakeim et al., 2023; Al-Hakeim et al., 2023; Al-Jassas et al., 2022; Avittan & Kustovs, 2023; Benedetti et al., 2021; Binsaleh et al., 2023; Bouças et al., 2022; Brown, 2022; da Silva Lopes et al., 2021; de Mello et al., 2022; Demiryürek et al., 2022; Deng et al., 2021; Diniz et al., 2023; Ge et al., 2023; Gonçalves de Andrade et al., 2021; Grignoli et al., 2023; Gudivada et al., 2023; Loftis et al., 2023; Lorkiewicz & Waszkiewicz, 2021; Lyra E Silva et al., 2022; Mazza et al., 2021; Mingoti et al., 2022; Mohammadkhanizadeh & Nikbakht, 2021; Naphade et al., 2023; Oh et al., 2022; Ortelli et al., 2021; Pacho-Hernández et al., 2022; Perlis et al., 2021; Poletti et al., 2022; Ramezani et al., 2020; Ritchie & Chan, 2021; Roever et al., 2023; Samprathi & Jayashree, 2021; Seyedmirzaei et al., 2023; Shetty et al., 2023; Speth et al., 2020; Sultana & Ananthapur, 2020; Uzunova et al., 2021; Villarreal-Zegarra et al., 2022; Zhang et al., 2022).

For example, in a recent prospective cohort study examining the predictors of long-term symptom severity in post-COVID syndrome (PCS, another term for LC, Legler et al. (2023) noted:

The majority of patients reported newly emerged affective symptoms and poor emotional well-being after COVID-19 diagnosis, which were thus directly related to their post-COVID-19 condition. These symptoms improved only in patients with PCS along with their overall clinical condition and therefore must rather be considered a consequence of the burdening disease impacting PCS-ME/CFS patients’ quality of life than any primary condition. Consequently, psychological support should be integrated into PCS management.

Legler, Meyer-Arndt, et al. (2023). Long-term symptom severity and clinical biomarkers in post-COVID-19/chronic fatigue syndrome: results from a prospective observational cohort. EClinicalMedicine, 63, 102146.

Likewise, in a study examining dysregulation of the autonomic nervous system in people with LC, Ryabkova et al. (2024) found similar patterns in the association between LC and psychological symptoms:

The correlation analysis revealed some important differences between the patients and HCs [healthy controls]. First of all, depression and anxiety were associated with fatigue only in the [healthy controls], but not in the ME/CFS or PCC patients. The association of fatigue with depression is well known, and a differential diagnosis of ME/CFS or PCC with depression is often difficult due to the overlapping psychological and somatic symptoms in both disorders, including fatigue, reduced concentration, and sleep disturbances. Our study showed that fatigue was not related to depression/anxiety in ME/CFS and PCC, which is highly interesting in view of the renewed attempts of a psychologization of ME/CFS and PCC and represents a strong argument against this concept.

Ryabkova, Rubinskiy, et al. (2024). Similar Patterns of Dysautonomia in Myalgic Encephalomyelitis/Chronic Fatigue and Post-COVID-19 Syndromes. Pathophysiology, 31(1), 1-17.

It’s also worth pointing out that in the study of metabolic abnormalities in ME/CFS (discussed in the Functional and Neuroinflammatory Biomarkers section above), Mueller et al. (2020) found that abnormalities in the anterior cingulate cortex (ACC) “can have a variety of behavioral effects” (p. 9), including the presentation of anxiety. That is, anxiety is a symptom of these underlying physiological abnormalities, not a primary condition.

Dysautonomia

Dysautonomia is a condition that manifests as a malfunction of the autonomic nervous system (Chadda et al., 2022). It was reported early in the pandemic that postural orthostatic tachycardia syndrome (POTS) is one of the most prevalent forms of cardiovascular dysautonomia reported following COVID-19 (Johansson et al., 2021). Individuals with POTS can experience a wide range of cardiac and non-cardiac symptoms as a result, including heart palpitations, chest pain, exercise intolerance, cognitive impairment, fatigue, muscle weakness, and chronic pain, which can all reduce a person’s functional capacity in their daily life (Ormiston et al., 2022).

Different possibilities have been hypothesized for the underlying mechanism of dysautonomia that leads to POTS including: hypovolemia, which is a decrease in blood volume; direct damage to the central nervous system as a result of the neural propagation of the virus; inflammation, which has been previously associated with other markers of dysautonomia; and autoimmunity, through the development of autoantibodies which then attack the brain cells of the autonomic nervous system (Chadda et al., 2022).

A Representative Case Report

Bosco and Titano (2022) present a case report reflective of what many others have experienced following COVID-19: after an initial infection with mild symptoms lasting about two weeks, a previously-healthy 27-year old runner presented with lingering symptoms six months after the initial illness.
Beginning with general weakness affecting her ability to move, it prevented her from returning to work for about a month. Once she was able to return to work, she began to experience fatigue and flu-like symptoms within only a few days, leading to a hospital visit with unremarkable test results.
These symptoms became more significant over time, with worsening post-exertional fatigue, increased forgetfulness, difficult concentrating, headaches, generalized body aches, and weakness. Within a matter of months, she was fully reliant on her husband to perform or assist with most daily activities as a result of these symptoms.
Attempting a new exercise program sent her to the hospital once again, this time with uncontrollable shaking, extreme exhaustion, and diarrhea. Once again, the test results were unremarkable.
Two weeks later, the symptoms had progressed to such an extent that the runner was now in a wheelchair. After a cardiac workup, the results indicated POTS.
About two months following initial contact with this patient, she began a post-COVID rehabilitation program, where, over a period of six months, “she graduated from recumbent to seated and then standing/walking exercises.” The report concludes that about a year after her initial infection, “she is once again independent in her activities of daily living, although she is still not able to return to work.”

Bosco, & Titano. (2022). Severe Post-COVID-19 dysautonomia: a case report. BMC Infect Dis, 22(1), 214.

Conditions Affecting the Brain

People who recover from COVID-19 can “[exhibit] significant cognitive deficits,” which include “‘brain fog’… low energy, problems concentrating, disorientation, and difficulty finding the right words” (Hampshire et al., 2021). Although the causes are not yet fully understood, in addition to damaged brain tissue from viral invasion, some studies suggest that that the cause of conditions affecting the brain may be attributable to neuroinflammation and hypercoagulability (Zilberman-Itskovich et al., 2022).

Neuronal Fusion

Fusogens are a specialized molecule on the surface of cells that many viruses use to enter their host cells. Research has shown that a SARS-CoV-2 infection can induce neurons and glia in the brain to fuse together with neighboring neurons and glial cells, as a result of the viral spike protein mimicking the relevant fusogens (Martínez-Mármol et al., 2023). These fused cells may result in large molecules and organelles being shared between cells, implying “a possible mechanism for the spread of toxic aggregates as observed in several neurodegenerative diseases and could also represent a mechanism of viral spreading that eludes the immune system” (Martínez-Mármol et al., 2023).

The fused neurons remain alive, but with altered functionality. It is not yet know if this condition can be treated, and more research is needed.

Spike Protein Persistence

The spike protein of the SARS-CoV-2 virus can accumulate in the brain, meninges, and skull marrow (Rong et al., 2023). On its own, the spike protein causes cell death in brain tissue, and it has been observed in the skulls of deceased individuals for a significant period of time after their COVID-19 infection; this may be a contributor to many of the PCCs described here (Rong et al., 2023).

It is not yet know what causes this spike protein persistence, and more research is needed.

Impacts are Widespread

The degree of impact COVID-19 has on cognitive performance can vary with the severity of a person’s illness. For example, one study found that individuals who were hospitalized and required medical assistance for respiratory symptoms of COVID-19 exhibited greater cognitive deficits than those who recovered at home (Perez Giraldo et al., 2023). Those who had to be put on a ventilator experienced the greatest cognitive deficits, but individuals with mild illness were not spared.

The impact of COVID-19 on cognitive performance has a significant effect population-wide. One study found that fatigue and neurocognitive impairment are the PCCs that have the greatest impact on general health and the working capacity of individuals for six to twelve months after recovering from acute COVID-19 (Peter et al., 2022). It is not yet known if these effects can be reversed, and more research is needed.

Structural Changes

Even in individuals who have fully recovered from COVID-19, long-term structural changes to the brain have been found (Douaud et al., 2022), including: “reduction in grey matter thickness,” reduction in “tissue contrast in the orbitofrontal cortex and parahippocampal gyrus,” tissue damage localized in “regions that are functionally connected to the primary olfactory cortex,” and an overall reduction in brain size.

It appears that the neurodegeneration caused by SARS-CoV-2 is associated with the loss of smell that is common with COVID-19 (Douaud et al., 2022). It is not yet known if these effects can be reversed, and more research is needed.

Insomnia

One study found that 26% of individuals who were hospitalized for COVID-19 had sleep difficulties six months after their symptoms initially began (Bhat & Chokroverty, 2022). Another has found that insomnia and sleep disturbances were commonly experienced by individuals recovering from COVID-19 (El Sayed et al., 2021). However, more research is needed to fully understand the impacts of COVID-19 on sleep.

Headache Disorders

COVID has been found to cause the sudden worsening of a previous headache disorder, and potentially causes the headache disorder to become a chronic condition; this is especially common in patients with migraine disorders (Caronna et al., 2021). Notably, this can even occur for individuals who did not experience headaches during acute COVID-19 illness, as well as those who have no history of migraine disorders (Caronna et al., 2021, p. 1279).

Like many other PCCs, headache and migraine following recovery from COVID-19 are often associated with other COVID-19 symptoms, such as insomnia, memory loss, dizziness, and fatigue. However, these relationships are not well-understood, and more research is needed to determine if this condition is reversible.

Aphasia

Aphasia is a neurological disorder in which a person is unable to comprehend or express speech, due to damage to areas of the brain responsible for language. It is a common post-stroke condition (Code & Petheram, 2011) that is now frequently manifesting as a PCC.

There is growing evidence of “neurological and dysexecutive syndromes subsequent to interference of brain functions” that result from acute COVID-19 (Kong, 2021), including aphasia-like symptoms in many individuals.

Some of these are likely caused by large-vessel strokes, which have been frequently encountered after SARS-CoV-2 infections, including in young people (Oxley et al., 2020). However, some cases of acute aphasia present in unusual ways that appear to mimick stroke, but lack corresponding structural abnormalities on brain imaging diagnostic tests (Pensato et al., 2020).

In one such example from early in the pandemic, Pensato et al. (2020) reported a case in which a middle-aged man initially presented with expressive aphasia, slowed movement, and hypoxemia. CT, EEG, and MRI assessments of the patient’s brain failed to reveal any abnormalities, but the patient’s neurological status continued to deteriotate. Within two weeks, however, his neurological status had resolved completely. This suggests a functional, rather than structural, impairment of neuronal networks, but the etiology of the condition is not yet fully understood.

Conditions Affecting the Cardiovascular System

The impact of COVID-19 on the cardiovascular system is widespread and significantly detrimental. These effects were noticed from the very beginning, with multiple systematic literature reviews—all of which examined research published in the first half of 2020—noting the high prevelance of cardiac injury following SARS-CoV-2 infection (Hessami et al., 2021; Kunutsor & Laukkanen, 2020; Lee et al., 2021; Mirmoeeni et al., 2021; Momtazmanesh et al., 2020; Roshdy et al., 2020), including in children (Rodriguez-Gonzalez et al., 2020; Sanna et al., 2020).

Further research has since found that no demographic is spared, including children and adolescents (Saed Aldien et al., 2022; Paglialonga et al., 2023); young adults (Rezler et al., 2023); and pregnant women and their fetuses (Yaghoobpoor et al., 2022). Results consistent with these have also been found among groups of people that are typically expected to have a higher level of cardiovascular fitness than the general population, such as athletes (van Hattum et al., 2021; Goergen et al., 2021; Hajduczok et al., 2022; for elite athletes, see Faghy et al., 2023), soldiers (Clark et al., 2021), and firefighters (D’Isabel et al., 2023).

Other research has found that cardiovascular complications have been reported across all major variants of SARS-CoV-2 (Vishwakarma et al., 2023).

Increased Risk of Heart Injury

In general, people who recover from acute COVID-19 illness have a heightened risk of “abnormal heart rhythms, heart muscle inflammation, blood clots, strokes, myocardial infarction, and heart failure,” including individuals who didn’t require hospitalization for their acute infection (Abbasi, 2022).

A large cohort study by Xie et al. (2022)—which looked at the health records of 162,690 U.S. veterans who tested positive for COVID-19 between March 1, 2020 and January 15, 2021—found that “the risk and 1-year burden of cardiovascular disease in survivors of acute COVID-19 are substantial” (p. 583). In particular, the study found that in the 12 months after initial infection, relative to individuals who had no sign of COVID-19 infection in the same time period, there was a 52% higher risk of stroke, 69% higher risk of dysrhythmia, 102% higher risk of inflammatory diseases of the heart, 66% higher risk of ischemic heart disease, 72% higher risk of heart failure, and a 145% higher risk of cardiac arrest (Xie et al., 2022).

The risk from a given infection is related to the severity of illness, but individuals with mild illness are not spared from the increased risks of all these conditions. Notably, the authors found that increased risks of negative cardiovascular outcomes were “evident regardless of age, race, sex and other cardiovascular risk factors,” and that these increased risks “were also evident in people without any cardiovascular disease before exposure to COVID-19, providing evidence that these risks might manifest even in people at low risk of cardiovascular disease” (Xie et al., 2022, p. 587).

Myocardial Inflammation

Background

Myocarditis is an “uncommon, potentially life-threatening disease that presents with a wide range of symptoms in children and adults” (Blauwet & Cooper, 2010). The most commonly affected demographic is young adults, with the mean age of patients with various forms of myocarditis ranging from 20-51 years old. Furthermore, Blauwet and Cooper (2010) note that the “consequences are sometimes devastating in this population, as acute myocarditis has been shown to be the cause of sudden death” in up to 12% of autopsies of young adults (Doolan et al., 2004; Passarino et al., 1997; Shen et al., 1995), military recruits (Eckart et al., 2004), and young athletes (Maron et al., 2009).

Children can also be significantly affected by myocarditis, which “is also an important cause of sudden death in children as well as childhood cardiomyopathy” (Blauwet & Cooper, 2010).

In adults, the severity of the condition “is highly variable, ranging from subclinical disease to fulminant heart failure,” while symptoms can include “chest pain, dyspnea, palpitations, fatigue, decreased exercise tolerance, or syncope”; in children, the severity can also vary with age with infants experiencing “nonspecific symptoms including anxiousness, malaise, fever, poor appetite, tachypnea, tachycardia, and cyanosis,” and older children also experiencing “chest pain, abdominal pain, myalgias, fatigue, cough, and edema” (Blauwet & Cooper, 2010).

COVID-19 and Myocarditis

From early in the pandemic, there has been a strong relationship between COVID-19 and myocarditis. Puntmann et al. (2020) conducted an observational cohort study between April and June 2020, in which 100 unselected patients were examined with cardiovascular magnetic resonance (CMR) imaging about two to three months after COVID-19 diagnosis; notably, the study criteria excluded patients who were “referred for a clinical CMR due to active cardiac symptoms” (p. 1266).

Out of the 100 patients studied, 18 were asymptomatic, 49 had mild to moderate symptoms, and 33 had severe COVID-19 requiring hospitalization. Out of the 100 patients studied, cardiovascular involvement was found in 78 patients “irrespective of preexisting conditions, the severity and overall course of the COVID-19 presentation, the time from the original diagnosis, or the presence of cardiac symptoms” (p. 1271), and myocardial inflammation was detected in 60 patients (Puntmann et al., 2020).

These findings have been supported by large analyses conducted more recently. For instance, Shrestha et al. (2023) conducted a meta-analysis of seven published studies comprising 8,126,462 individuals—1,321,305 cases of COVID-19 and 6,805,157 controls—and found that the odds of developing myocarditis after COVID-19 increased roughly five-fold. Similarly, Sleem et al. (2023) noted that although there have been no large cohort studies of myocarditis in children with COVID-19, a study in the Morbidity and Mortality Weekly Report from the Centers for Disease Control found that children with COVID-19 had nearly 40 times the risk of developing myocarditis as children without COVID-19.

Extensive Risk

As summarized by Kole et al. (2023), the ACE2 receptor that SARS-CoV-2 uses to enter host cells “is also found in many extrapulmonary tissues including cardiomyocytes and pericytes, leading to cardiovascular complications.” The virus can additionally cause myocardial damage indirectly through “increased inflammation, cytokine storm release, and endothelial dysfunction.”

Another example of the reciprocal relationship between COVID-19 and chronic health conditions, endothelial dysfunction is a characteristic of many other risk-factors for negative outcomes in COVID-19, but the presence of a virus in endothelial cells attracts immune cells—leading to further endothelial dysfunction (Kole et al., 2023).

Atrial Fibrillation

A study examining the records of the first 30,999 hospitalized patients in the American Heart Association COVID-19 Cardiovascular Disease Registry found that one in 20 developed new-onset atrial fibrillation, and that this was more common among patients who are white, male, older, or have pre-existing cardiovascular conditions (Rosenblatt et al., 2022).

This study also found that nearly half of those who developed new-onset atrial fibrillation died during their hospitalization, noting that this suggests the condition “may primarily be a marker of other adverse clinical factors,” rather than the direct driver of mortality itself.

Hypercoagulability and Thrombosis

Beyond disease of the heart itself, Xie et al. (2022) also found drastically increased risks of thromboembolic disorders in the year after recovering from COVID-19. Compared to the contemporary control group, the post-COVID recovery group had a 193% higher risk of pulmonary embolism, 109% higher risk of deep vein thrombosis, and 95% higher risk of superficial vein thrombosis—that is, the risk of developing one of these thromboembolic disorders is two to three times higher after SARS-CoV-2 infection.

A large cohort study from Sweden, which included the records of over 1 million individuals and spanned a similar time period (February 1, 2020, to May 25, 2021), found similar increases in the risk of thromboembolic disorders (Katsoularis et al., 2022). Of particular concern is that the risk of pulmonary embolism is 33 times higher in the 30 days after COVID-19, with elevated risk persisting for three months or more.

Katsoularis et al. (2022) also found that COVID-19 was associated with an increased risk of bleeding events, with triple the risk of bleeding events occurring in the first week after infection and an elevated risk persisting for at least two months afterward.

Reduced Vascular Function

A review by Martínez-Salazar et al. (2022) noted that studies have consistently demonstrated “signiﬁcantly lower systemic vascular function and higher arterial stiffness in participants testing positive for SARSCoV-2 compared with controls” (p. 14), including in asymptomatic individuals.

Another recent study examined measures of arterial stiffness and other hemodynamic parameters, comparing the measurements of a small cohort of individuals from before and after each had a COVID-19 infection with mild symptoms. Rather than finding that inflammation caused by COVID-19 decreased over time as hypothesized, the study found that as time elapsed from the COVID-19 infection, vascular impairment became worse. This was a surprising result, as the authors “expected inﬂammation burden associated with COVID-19 to decrease with time” (Podrug et al., 2023, p. 10).

Critically, Podrug et al. (2023) note that the “ﬁndings of this study demonstrated that there is a widespread and long-lasting pathological process in the vasculature following the mild COVID-19 infection which keeps deteriorating during 2–3 months post-infection,” even in their cohort of predominantly young and healthy individuals (p. 12).

Erectile Dysfunction

COVID-19 has been strongly associated with new-onset erectile dysfunction (Chu et al., 2022; DePace & Colombo, 2022; Franczuk et al., 2022; Kaynar et al., 2022; Yousif & Premraj, 2022).

The cause for this relationship is not yet fully understood, and more research is needed. Proposed causes include the location of ACE2 receptors in the testes, endothelial damage to erectile tissue, or other damage resulting from SARS-CoV-2 infection.

Conditions Affecting the Lungs

Individuals who recover from severe COVID-19 often experience persistent symptoms of lung damage—namely, pulmonary fibrosis, a condition characterized by scarred lung tissue, decreased lung function, cough, and frailty. However, respiratory symptoms can persist long-term even in individuals who had mild or asymptomatic COVID-19.

After Moderate to Severe COVID-19

McGroder et al. (2021) found—in a study of adults hospitalized between March 1, 2020 and May 15, 2020, and requiring supplemental oxygen—found “fibrotic-like radiographic abnormalities” in 20% of non-ventilated patients four months after hospitalization. For patients who received ventilator support during hospitalization, 72% showed those same abnormalities after four months.

The damage to lung tissue caused by COVID-19 may be permanent, but more research is needed to determine if it may be treated or reversed.

After Asymptomatic or Mild COVID-19

A study published in February 2020 showed that even asymptomatic patients had chest CT imaging abnormalities (Shi et al., 2020).

Furthermore, a systematic review of research published prior to May 22, 2021 conducted by Sanchez-Ramirez et al. (2021) found a variety of chronic symptoms remained for a significant number of people—three months or more after they recovered from acute COVID-19—including: abnormal lung funtion in both hospitalized and non-hospitalized patients, correlated with severity of COVID-19; fatigue and respiratory symptoms such as fatigue reported by 38% of people, dyspnea reported by 32%, chest pain or tightness by 16%, cough by 13%, sore throat by 4%, and several studies have found no significant association between the severity of acute COVID-19 and the prevelance of fatigue or respiratory symptoms.

Conditions Affecting the Metabolic System

The potential risk to the metabolic system is significant after a SARS-CoV-2 infection. Two major adverse outcomes that are strongly associated with COVID-19 include both new onset diabetes and the worsening of existing diabetes.

A meta-analysis conducted by Shrestha et al. (2021) examined seven studies that were published before November 2020 and found that around 20% of COVID-19 cases were associated with new-onset diabetes.

That analysis also demonstrated the reciprocal relationship between COVID-19 and COVID-related conditions: while the pooled data showed an occurrence rate of adverse events among non-diabetic patients to be about 15%, that rate was about 21% for patients with pre-existing diabetes, and about 46% among the patients with new-onset diabetes (Shrestha et al., 2021, p. 281).

Similarly, a large cohort study of US veterans found that people with COVID-19 had a 40% higher risk of developing diabetes within a year than they otherwise would have (Xie & Al-Aly, 2022). The authors of that study—which included patients who had a positive COVID-19 test between March 1, 2020 and September 30, 2021—noted that the increased risk of diabetes “might translate into substantial overall population level burdens and could further strain already overwhelmed health systems” (Xie & Al-Aly, 2022, p. 318).

More recently, Ssentongo et al. (2022) conducted a systematic review and meta-analysis of eight studies—including the records of over 4 million COVID-19 patients in the pooled data—which found that there was a 66% higher risk of developing diabetes after recovering from acute COVID-19. The authors concluded that “active monitoring of glucose dysregulation after recovery” from SARS-CoV-2 infection “is warranted.”

Conditions Affecting the Senses

Eye Damage and Vision Loss

Sen et al. (2022) conducted a systematic review of research published prior to November 27, 2020, and reported an array of potential conditions that could affect the eye after SARS-CoV-2 infection. Some conditions that don’t typically affect visual acutity included retinal hemorrhages and cotton wool spots; other, more serious conditions—which can result in vision loss—were also found, such as retinal vein occlusion with macular edema, retinal arterial occlusions, and occular inflammation.

The authors noted that while it may be “mostly causing milder disease, COVID-19 may however lead to severe life-threatening thromboembolic complications . . . [B]oth sick and apparently healthy patients may suffer from various retinal complications [emphasis added] which may lead to loss of vision as well” (p. 323).

Another study has found loss of small nerve fibers in the cornea, which may not manifest until months after recovery from acute COVID-19 (Bitirgen et al., 2022); the extent of the damage was generally correlated with severity of COVID-19, but those with mild symptoms were not spared.

It is not yet know if these conditions can be treated or reversed, and more research is needed.

Hearing Damage and Loss

Sudden onset sensorineural hearing loss (SSNHL) is a condition “characterized by rapid onset of hearing loss or a progressive loss over 12 hours” (p. 2865), and studies have shown that viral infections are one of the causes of this condition (Chen et al., 2019).

By July 2020, cases of SSNHL had been reported in patients immediately following a SARS-CoV-2 infection in the UK (Koumpa et al., 2020), in Germany (Degen et al., 2020), in Egypt (Abdel Rhman & Abdel Wahid, 2020), and in Thailand (Sriwijitalai & Wiwanitkit, 2020), among other countries.

Significantly, Mustafa (2020) found that even individuals with asymptomatic COVID-19 showed evidence of hearing damage, concluding that COVID-19 “could have deleterious effects on cochlear hair cell functions despite being asymptomatic [emphasis added]” (p. 3).

More recently, Eldeeb and colleagues (2023) conducted a small survey of post-COVID hearing issues, finding new-onset hearing issues (such as hearing loss and tinnitus) in over 10% of the sample and vertigo in over 20%. Notably, they found no correlation between the reported audiovestibular symptoms and other investigations, such as chest CT results.

Conditions Affecting the Endocrine System

SARS-CoV-2 gains access to host cells through the ACE2 receptor, in a process requiring a protein called TMPRSS2. Both of these prerequisties are abdundant in the human endocrine system—including the pancreas, thyroid, ovaries, and testes—exposing these organs to damage or alterations from COVID-19 (Clarke et al., 2022).

In a review of the potential causes of Graves’ disease developing or worsening after COVID-19 infection, Vamshidhar et al. (2023) noted three potential causes of this COVID-related endocrine dysfunction: cytokine storm, molecular mimicry, and the large number of ACE2 receptors in the thyroid. Likewise, in a review of the role of COVID-19 in adrenal insufficiency, Durcan et al. (2023) noted that similar pathophysiologies underlie impairment of the hypothalmic-pituitary-adrenal axis.

Other effects on the endocrine system following COVID-19 can include hypogonadism, changes to menstrual cycles, hyperglycemia, and ketoacidosis (Clarke et al., 2022). Some of these symptoms may resolve on their own, but more research is needed to understand the long-term impacts that COVID-19 has on the endocrine system.

Conditions Affecting the Gastrointestinal System

As with other major organ systems that have seen direct damage from COVID-19, both the ACE2 receptor and TMPRSS2 protein are expressed in the gastrointestinal tract (Zhang et al., 2020), and evidence for gastrointestinal infection was quickly identified early in the pandemic (Xiao et al., 2020). By 2020, it was already known that around 10% of COVID-19 cases included gastrointestinal symptoms (Sultan et al., 2020), and SARS-CoV-2 RNA was found in the fecal samples of more than 40% of COVID-19 patients (Cheung et al., 2020).

Like many other organ dysfunctions resulting from COVID-19, some of the damage to the gastrointestinal system may result from larger systemic issues. An early study found that, within a cohort of patients hospitalized with COVID-19 and requiring endoscopy, “almost half showed acute mucosal injuries and more than one-third of lower GI endoscopies had features of ischaemic colitis” (Vanella et al., 2021).

An early review of the relationship between COVID-19 and gastrointestinal disease concluded that the “SARS-CoV-2 virus may lead to significant systemic disease and involve the GI tract, liver, biliary tract and pancreas by mechanisms involving cell entry by the ACE2 receptor and TMPRSS2, which are dysregulated” (Hunt et al., 2021, p. 133).

Conditions Affecting the Musculoskeletal System

Significant, widespread impacts from COVID-19 on the musculoskeletal system were noted early in the pandemic, including damage to muscle, joints, nerves, soft tissue, and bone. An early review by Ramani et al. (2021) noted that many patients report experiencing myalgia, a condition with muscle aches and pain, and myositis, a type of muscle inflammation associated with viral infections. Myositis can lead to further complications, including rhabdomyolysis, a condition which involves death of the muscle tissue and high levels of myoglobin in the blood—leading to further complications like acute kidney failure and compartment syndrome.

The review also noted that many individuals experience other long-term symptoms of muscle damage, which includes muscle loss (sarcopenia) and muscle wasting (cachexia). Beyond muscle tissue, Ramani and colleagues (2021) also noted that peripheral neuropathy—nerve damage which manifests as pain, weakness, numbness, or tingling sensations—commonly occurs following SARS-CoV-2 infection, as do other conditions impacting muscles.

Guillain-Barre Syndrome

Notably, many cases of Guillain-Barre syndrome (GBS) following COVID-19—a condition which manifests as muscle weakness and paralysis—were reported early in the pandemic, with a typical onset 3-4 weeks after the beginning of COVID-19 symptoms (Koralnik & Tyler, 2020; Caress et al., 2020; Paliwal et al., 2020; Keyhanian et al., 2020).

GBS is a post-viral “syndrome as defined by an onset that is delayed from the acute symptoms of infection and by a mechanism that is distinct from the infection” (p. 488), and is also associated with viruses like influenza and Epstein-Barr virus (Caress et al., 2020). A more recent study found that, with the exception of a higher prevalence of facial diplegia (weakness or paralysis on both sides of the face), individuals with GBS after COVID-19 had similar presentations as other non-COVID GBS patients (Toydemir et al., 2023); in particular, the most common form of GBS following COVID-19 is acute inflammatory demyelinating polyneuropathy.

More research is needed to understand the relationship between GBS and COVID-19 (Şirin, 2023).

Rheumatological Diseases

Also noted in the review by Ramani et al. (2021) was the significant impact of COVID-19 on the joints and the development of rheumatological diseases. New-onset rheumatological diseases reported after SARS-CoV-2 infection include Graves’ disease, rheumatoid arthritis, psoriatic spondyloarthritis, dermatomyositis—a rare muscle inflammation condition which presents with muscle weakness, skin rash, esophageal dysfunction, and interstitial lung disease (Qudsiya & Waseem, 2024), and systemic lupus erythematosus.

Interestingly, despite several cases of acute clinical arthritis developing following COVID-19, “some of which demonstrate features suggestive of reactive arthritis or crystalline arthritis rather than viral arthritis” (Ramani et al., 2021, p. 1770). More recently, a case series by Yadav et al. (2023) concluded that COVID-19 is a “potential cause of inflammatory arthritis, with both rheumatoid arthritis and reactive arthritis demonstrated” in individuals following SARS-CoV-2 infection.

Bone Loss

Ramani et al. (2021) noted that “critical illness, corticosteroid treatment, and virus-induced coagulopathy may contribute to the development of osteoporosis and osteonecrosis” (p. 1772).

In an experimental study examining mouse models of COVID-19 pathology, they found that—as with COVID-19 in humans—the size of the viral exposure resulted in a corresponding level of disease severity, “where some patients develop severe disease resulting in death, while others have moderate to severe disease but recover, and others are asymptomatic” for their entire infection (Awosanya et al., 2022). Critically, this study found dramatic bone loss in infected subjects, seemingly as a result of a significant increase in the number of osteoclasts present on the bones.

Awosanya et al. (2022) note that severe COVID-19 can cause major up-regulated expression of cytokines leading to a “cytokine storm,” and that many of these cytokines are involved with the regulation of osteoclastogenesis and bone resorption; thus, they hypothesize that the bone loss seen as a post-COVID condition may lead directly from the inflammatory condition caused by COVID-19 more directly.

It’s also worth noting that Awosanya et al. (2022) observed bone loss even in mice infected with the lowest dosage and which showed no clinical signs of illness throughout the study. Further emphasizing the long-term nature of conditions resulting from COVID-19 infection, the study also observed that severely ill mice that survived to the end of the study had “an even more dramatic change” in their bone parameters, suggesting that this condition takes time to manifest.

More research is needed to understand how SAR-CoV-2 affects bone loss in humans and whether these effects can be reversed.

Conditions Affecting the Kidneys

COVID-19 is associated with increased risk of developing chronic kidney disease and acute kidney injury.

Acute Kidney Injury

On its own, a SARS-CoV-2 infection may cause acute kidney injury (AKI) through endothelial damage and local inflammation; more broadly, “indirect mechanisms that injure the kidney, such as sepsis, use of nephrotoxic medications, systemic inflammation, hypercoagulability and thromboembolic disease” may be a major contributor to damage associated with COVID-19 (Yende & Parikh, 2021, p. 792).

When Silver et al. (2021) conducted a systematic review and meta-analysis of studies published up to October 14, 2020, they found the prevalence of AKI to be 28% among patients hospitalized with COVID-19, and 46% among the subset of patients admitted to the ICU.

Decreased Kidney Function Long-Term

A large cohort study of over 89,000 US veterans found that, among those who had survived at least 30 days after the beginning of their COVID-19 symptoms—within the period from March 1, 2020 to March 15, 2021—all groups of patients exhibited decreased kidney function over time, relative to non-infected controls (Bowe et al., 2021); that study found a decrease in kidney function even for cases of COVID-19 that did not result in hospitalization.

Conditions Affecting the Liver

Like kidney injury, the damage to the liver as a result of SARS-CoV-2 infection has multiple potential mechanisms. Russo et al. (2022, p. 277) note that, while the liver does express the ACE2 receptor that SARS-CoV-2 uses to bind to cells, the “current data suggest that liver injury in COVID-19 is mostly secondary to” immune dysregulation (including cytokine storm), endotheliopathy with hypoxic or ischemic injury, or even drug-induced liver injury from the treatment of acute COVID-19.

Long-Term Liver Injury

Another early study by Sonzogni et al. (2020) collected liver biopses from patients who had died of severe respiratory failure from COVID-19 and found vascular thrombosis in at least 50% of the livers.

A more recent review by McConnell et al. (2022) noted that endotheliopathy is a major contributor to thrombosis (pathological blood clot formation), and endotheliopathy “has been reported to be sustained following COVID-19, suggesting endothelial-mediated inflammation as a possible mechanism” (p. 265) for long-term liver injury.

Risks from Existing Liver Disease

Marjot et al. (2021) conducted a cohort study between March 25, 2020, and July 8, 2020, and found that “patients with cirrhosis are at increased risk of death from COVID-19,” and that both “baseline liver disease stage and alcohol-related liver disease are independent risk factors for death from COVID-19.”

Conditions Affecting the Skin

COVID-19 has been associated with the development of one or more skin conditions.

An early review of the literature by Genovese et al. (2021) found several skin conditions associated with varying levels of COVID-19 severity. Found even among asymptomatic patients were Chilblain-like acral patterns, which are painful, itchy, or burning patches of skin on the feet and hands (p. 6). Also appearing in individuals with mild symptoms, urticarial rash is one of the most common skin manifestations associated with COVID-19 (p. 2); in fact, the combination of fever and urticarial rash has been suggested as an early sign of COVID-19 infection, even in the absence of repiratory symptoms (Hassan, 2020; Quintana-Castanedo et al., 2020; van Damme et al., 2020).

Further conditions found in the literature by Genovese and colleagues (2021, p. 8) include: confluent erythematous, maculopapular, or morbilliform rash, manifesting as “[g]eneralized, symmetrical lesions starting from the trunk with centrifugal progression”; papulovesicular exanthem, a condition defined by a widespread pattern of “small papules, vesicles and pustules of different sizes,” or a localized pattern “consisting of papulovesicular lesions, usually involving the mid chest/upper abdominal region or the back”; or purpuric lesions, which can manifest in a number of patterns and “may evolve into hemorrhagic blisters, possibly leading to necrotic-ulcerative lesion.”

While some of these conditions can be treated with topical or systemic corticosteroids, other conditions—such as livedo racemosa-like lesions, which are “large, irregular and asymmetrical violaceous annular lesions frequently described in patients with severe coagulopathy”—the only therapeutic option available is to “[w]ait and see” (Genovese et al., 2021, p. 8).

Conclusion

The complications of COVID-19 can be severe and wide-ranging, even after a minor or seemingly asymptomatic acute infection. COVID-19 remains, even in 2024, a significant threat to public health—and the health of every single individual—and can have severe consequences for the brain, nervous system, heart, veins, lungs, and many other organ systems.

Further research is needed to understand the full extent of the effects of COVID-19 on the many organs and bodily systems implicated in these long-term complications. While vaccination has been shown to help prevent more severe illness, the only known way to avoid these complications is to avoid being infected in the first place.

Only by taking basic precautions to avoid exposure to the virus—such as wearing a high-quality filtering respirator in shared air (N95 respirators or better are preferable), keeping indoor air clean with air purification and ventilation, and avoiding situations where there is a high risk of being exposed—can you keep yourself, your family, and your community protected from the long-term complications of COVID-19.

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Written by Nick Anderegg
Last updated on March 12, 2024

Recommended citation:

Anderegg, N. (2024, February 25). Long COVID and Post-COVID Conditions: Overview of the Medium- and Long-Term Complications Associated with COVID-19. Pandemic Patients. https://pandemicpatients.org/home/covid-19-resources/lc-pcc