Long COVID-19: Persistent Symptoms and Clinical Implications

At the beginning of the coronavirus disease 2019 (COVID-19) pandemic, announced in March 2020 by the WHO, almost no one would have thought that the disease could be chronic. The causative agent of COVID-19 is the new severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2).

As the "A" in that acronym indicates, the respiratory disease is acute. However, cases of long COVID-19 began to gain attention among social support groups. At first, doctors considered certain symptoms to be health-related, such as anxiety or stress. However, it soon changed. The term long COVID (post-COVID syndrome or long COVID-19) began to gain recognition in the scientific and medical communities.

Different symptoms of long COVID have already been described. The most common description is that the symptoms continue 3 months after they started. A definition that emerged from a review says that the most common symptoms of long COVID are fatigue and dyspnea .

Other less typical symptoms are: cognitive and mental disorders, headache, myalgia, chest pain and arthralgia, anosmia and agony, cough, hair loss, insomnia, wheezing, rhinorrhea, sputum and cardiac and gastrointestinal problems. These symptoms may persist for up to 6 months after discharge from the hospital or the onset of symptoms. Less common symptoms are: chills, flushing, otalgia and visual deficiencies.

This illustrates the multifaceted nature of long COVID, involving multiple organ systems. Evidently, studies have also reported persistent symptoms of varying durations and frequencies among COVID survivors. This may be due to different characteristics of the sample and the data collection method that each study used. or to the fact that COVID is a very heterogeneous disease. Therefore, the precise symptomatic manifestations of long COVID remain elusive and may involve multiple subtypes or phenotypes.

A puzzling feature of long COVID is that it affects COVID-19 survivors, regardless of the severity of the illness.

Some studies have found that long COVID even mildly to moderately affects younger adults who did not require respiratory or hospital support or intensive care. Patients who did not test positive for SARS-CoV-2 and were discharged from the hospital, as well as outpatients, may also develop long COVID.

More worryingly, long COVID also affects children , including those who had asymptomatic COVID-19, resulting in symptoms such as dyspnea, fatigue, myalgia, cognitive impairments, headaches, palpitations and chest pain, lasting for at least 6 months.

A known aspect of long COVID is that it simulates a post-viral condition , as observed in the previous human coronavirus syndrome. For example, fatigue, myalgia, and psychiatric conditions were observed in survivors of Middle East respiratory syndrome and severe acute respiratory syndrome (SARS) for up to 4 years. Even at 7- and 15-year follow-ups of SARS survivors (most under 40 years of age), lung disease and bone radiological complications were still evident. This is disturbing, as it implies that long COVID can extend beyond a few months, up to years.

Currently, there are limited research works that have discussed the possible pathophysiology, risk factors and treatments for long COVID. In this literature review, the author seeks to fill these gaps.

> Long-term tissue damage

In a 3-month follow-up study of COVID-19 survivors, radiological abnormalities and pulmonary functional deficiencies were detected in 71% and 25% of participants, respectively, despite only -<40% having suffered pneumonia serious.

Another study also showed reduced lung diffusing capacity which, at 3 months, in 42% of COVID-19 survivors, was correlated with radiological abnormalities, regardless of severity. Even at 6 months after symptom onset, lung radiological abnormalities associated with persistent symptoms were still present, in approximately half of COVID-19 survivors.

Many other reports have also found radiological evidence of long-lasting pulmonary fibrosis, up to 6 months after hospital discharge, which also correlated with the severity of the initial disease. Using a more advanced xenon gas radiological technique to study lung function, defects in lung gas exchange function were discovered in discharged patients who had had moderate COVID-19, compared to healthy controls.

Furthermore, in this study, these lung problems were not detected by standard chest CT scan, suggesting that routine radiological examinations might have missed such lung complications. Notably, one study found reduced maximal aerobic capacity at approximately 45 days of follow-up in young recruits with symptomatic COVID-19, compared to non-COVID-19 recruits.

Together, these studies indicate that lung scarring may be a common sequelae of COVID-19, which would be responsible for persistent dyspnea and cough.

Another study found that symptoms of long COVID-19 occur even in those with improvement in radiological and functional lung examinations. Therefore, long COVID may involve other pathophysiologies in addition to lung lesions, such as long-term neurological complications.

For example, 3 months after discharge in COVID-19 survivors, structural and metabolic brain abnormalities were found, which were correlated with persistent neurological symptoms such as memory loss, anosmia, and fatigue . This finding is concerning since most participants had COVID-19 at the start of the study, suggesting that even COVID-19 could have lingering effects on the brain. This result and those of other studies suggest that there are serious brain diseases (encephalopathy, delirium, hemorrhage and stroke) that are associated with COVID-19 from the beginning.

Severity plays a small role in predicting these brain diseases. More severe cases of COVID-19, presenting with delirium , (20-30% of hospitalized patients) are more likely to have long-term neurological symptoms. Delirium is also a strong predictor of long-term cognitive impairment, especially among older adults.

In neuropsychiatric studies of survivors of SARS and COVID-19, delirium has been found to be a common complication in the acute phase of the disease and can lead to various neuropsychiatric sequelae, such as depression, anxiety, post-traumatic stress disorders, loss memory and fatigue. In fact, COVID-19-related fatigue has been suggested to be a result of autonomic nervous system dysfunction .

In a registry of 236,379 COVID-19 survivors, nearly one-third had a neuropsychiatric diagnosis (e.g., stroke, dementia, insomnia, anxiety, and mood disorders) within 6 months of the onset of the first symptom, which was 44% more common than in influenza survivors.

On the other hand, in this study, survivors who were admitted to intensive care units (ICU) were 56% more likely to develop a neuropsychiatric disorder than survivors who were not admitted to the ICU.

As SARS-CoV-2 is a respiratory virus, the development of lung injury is to be expected. However, it was only much later that it was confirmed that SARS-CoV-2 could cause neurotropic and respiratory disorders, as the virus was cultured in neuronal cells, brain organoids, and brain autopsies of mice and humans. In particular, damage to the cardiorespiratory center of the brainstem has been proposed to worsen COVID-19 symptoms.

Since neurons rarely regenerate, the resulting brainstem dysfunction can be long-lasting, leaving neurological and cardiorespiratory sequelae that could underlie long COVID. The brainstem expresses higher levels of angiotensin-converting enzyme 2 (ACE2), the SARS-CoV-2 receptor, than other brain regions.

Autopsy reports also show evidence of SARS-CoV-2 genes and proteins, as well as pathological immunological and vascular activations, in the brainstem of those who died from COVID-19. Therefore, ongoing neuroinflammatory processes may lead to neurological symptoms and damage in long COVID-19.

There is also evidence of cardiac injury . A radiological study of 100 discharged COVID-19 patients found cardiac abnormalities and myocardial inflammation in 78% and 60% of participants, respectively, with no association with baseline COVID-19 severity.

In another study of 26 asymptomatic university athletes with SARS-CoV-2 infection, 46% presented myocardial inflammation. Even 3 months after hospital discharge. Radiological abnormalities of ventricular remodeling were still evident in 29% of 79 COVID-19 survivors. However, the long-term clinical significance of these radiological findings is still unclear. However, cardiac symptoms such as chest pain, heart palpitations, and tachycardia often persist for up to 6 months, suggesting significant cardiac sequelae.

Lastly, long-term damage to other organs may also be involved in long COVID. It has been reported that young adults, mostly without risk factors for severe COVID-19, often develop long COVID with multiple organ impairment at 4-month follow-up. Specifically, at least one radiological abnormality of the lungs, heart, liver, pancreas, kidneys, or spleen were present in 66% of survivors.

Separately, a study of more than 40,000 patients discharged with COVID-19 found increased risk of new respiratory, cardiovascular disease, and diabetes events occurring within the next 140 days, compared to controls. Therefore, the author states, future research is required to consider the possibility of multiple organ involvement, which may be less obvious.

> Pathological inflammation

There have been cases of COVID-19 patients remaining positive for SARS-CoV-2 by real-time reverse transcription-polymerase chain reaction (RT-PCR) testing for up to 3 months.

Other studies have documented cases of prolonged shedding of SARS-CoV-2 in the respiratory tract, using quantitative RT-PCR, up to 4 months. Prolonged shedding of SARS-CoV-2 in feces has also been detected, regardless of overt gastrointestinal symptoms, up to 2 months.

SARS-CoV-2 nucleic acids and proteins have also been discovered in the small intestine, in 50% of asymptomatic COVID-19 cases, 4 months after the onset of the disease. Therefore, these studies showed that persistence of SARS-CoV-2 in the body is possible, which may induce some level of immune activation, contributing to the prolongation of COVID-19.

One review has proposed that T cell dysfunction may promote long-COVID pathophysiology, similar to autoimmune diseases.

Surprisingly, thyroid dysfunction has been detected in 15-20% of COVID-19 patients. As the thyroid gland is closely related to T cell-mediated autoimmunity, its dysfunction may play a role in the pathophysiology of long COVID autoimmunity. B cells may also be involved in long COVID autoimmunity.

On the other hand, antiphospholipid autoantibodies  associated with neutrophil hyperactivity and a more severe clinical picture were found in 52% of serum samples . Other autoantibodies against interferons, neutrophils, connective tissue, cyclic citrullinated peptides, and cell nuclei have also been identified in 10–50% of patients with COVID-19.

While it has not been established that these antibodies persist in COVID patients, research review has closely linked these antibodies to chronic autoimmune diseases, such as Sjögren’s syndrome, lupus erythematosus, and rheumatoid arthritis. In particular, reviews on lupus and rheumatoid arthritis also have symptomatic similarities with long COVID: fatigue, arthralgias, concentration difficulties, and headache.

Furthermore, there is evidence that severe COVID-19 causes lymphopenia (i.e., deficiency of B and T cell lymphocytes), causing hyperinflammation. This is how it has been observed that lymphopenia is accompanied by neutrophilia, considered independent risk factors for severity and mortality from COVID-19. Therefore, as B and T cell lymphocytes are renewed, unresolved elevated inflammation may lead to hyperinflammation and contribute to the development of long COVID.

Furthermore, decreased T cells and B cell numbers correlate with persistent SARS-CoV-2 dissemination, which may later further perpetuate chronic immune activation. Likewise, it has been observed that between 2 and 6 weeks after SARS-CoV-2, numerous cases of multisystem inflammation syndrome occur .

Infections have been documented in children and adults. These patients do not necessarily have a positive result for SARSCoV-CoV-2 or severe respiratory disease, and furthermore, they showed elevated levels of pro-inflammatory systemic markers (e.g. CRP, interleukin-6, ferritin and Ddimer) and severe shock and symptoms. cardiac, gastrointestinal or neurological.

The delayed manifestation of multisystem inflammation syndrome (MIS) post SARS-CoV-2 infection suggests the involvement of deregulation of the adaptive immune system; autoantibodies. Therefore, it would be possible that residual inflammation and post-SARS-CoV-2 SIM symptoms cause long COVID in children and adults. Indeed, elevated levels of pro-inflammatory markers (e.g., CRP, IL-6, and D-dimer) and lymphopenia have been associated with long COVID.

A radiological study of COVID-19 survivors with persistent symptoms for at least 30 days after discharge revealed increased uptake of fluorodeoxyglucose (FDG), meaning persistent inflammation, in the bone marrow and blood vessels. Elevated levels of pro-inflammatory biomarkers related to vascular and lung damage have also been observed 3 months after discharge. However, other large studies did not obtain the same results.

Analysis of available reports shows that lack of resolution of inflammation may only partially explain the pathophysiology of long COVID, particularly inflammation-related symptoms (myalgia, arthralgias, and fatigue).

In particular, chronic fatigue is a complex syndrome that may have causes other than inflammation, such as channelopathies, inadequate brain perfusion, and autonomic nervous system dysfunction, which may also be involved in COVID.

Another possible source of unresolved inflammation in COVID patients could be in the gut . SARS-CoV-2 is known to replicate efficiently in cells of the stomach and intestine, due to the high expression of ACE2 receptors they have, leading to increased fecal excretion of SARSCoV-2. Although the prevalence of gastrointestinal symptoms may vary between studies due to their different designs, meta-analyses have estimated that gastrointestinal manifestations (e.g., loss of appetite, nausea, vomiting, diarrhea, and abdominal discomfort) affect 10-20%. of patients with COVID-19.

Importantly, gastrointestinal symptoms have also been reported in up to a third of people with long COVID. Therefore, the persistence of SARS-CoV-2 in the gastrointestinal tract may underlie the gastrointestinal manifestations of long COVID.

In patients with persistent COVID-19 for at least 10 to 30 days after disease resolution, disruption of the gut microbiome (gut dysbiosis) has been observed. This dysbiosis was correlated with greater severity of COVID-19 and inflammatory biomarkers. And prolonged fecal shedding of SARS-CoV-2. However, it is unclear whether this dysbiosis extends beyond 30 days.

Despite this uncertainty, as the gut is closely intertwined with the immune system, a review has implicated the gut microbiome in numerous diseases related to chronic inflammation. It has also been reviewed that the intestinal microbiome modulates neurotransmitter circuits in the intestine and brain, through the microbiota-gut-brain axis. Therefore, persistent intestinal dysbiosis may also contribute to the gastrointestinal diseases and neurological symptoms of long COVID.

> Biomarkers

At 3 months after hospital discharge, COVID-19 survivors showed elevated blood urea nitrogen (BUN) and D-dimer levels and risk factors for lung dysfunction. Other studies have reported lung injuries from COVID-19 at 2 months after admission, which were associated with increased biomarkers of systemic inflammation. These biomarkers (e.g., CRP, procalcitonin, and neutrophil number) were also correlated with radiological abnormalities of the heart, liver, and kidney, in a 2- to 3-month follow-up of patients discharged from COVID-19.

Another study found that lymphopenia was correlated with chest tightness and heart palpitations, while increased troponin-1 was correlated with fatigue, in patients with long COVID. Therefore, changes in D-dimer, CRP, and lymphocyte levels appeared consistent in some studies, and may serve as potential biomarkers of long COVID. However, it has not been confirmed in other studies.

Discrepancies may be due to different study methods or the heterogeneity and relapsing-remitting nature of long COVID, with multifaceted symptomatic presentations. This hints at the possible involvement of multiple pathophysiologies, and each type has a unique set of biomarkers, which may also be fluctuating. Indeed, it is known that in autoimmune diseases and other chronic inflammatory diseases, inflammatory biomarkers fluctuate, depending on disease activity and patient characteristics.

A study has revealed that COVID-19 survivors with persistent fatigue at 10 weeks after discharge were mostly women and people with a history of anxiety or depression or use of antidepressants. Another study of COVID-19 survivors with persistent symptoms, associated risk factors were female sex and a previous psychiatric disorder. This female predominance was also confirmed in 4 of 5 children with long COVID.

However, some studies found similar rates in both sexes. Another study tracked more than 4,000 COVID-19 survivors and identified factors that predicted long COVID: age >70 years, more than 5 symptoms during the first week of illness, presence of comorbidities, and female sex. The manifestation of at least 10 symptoms during acute COVID-19 was also found to be a risk factor for long COVID.

Most studies found no association between long COVID and severity at the onset of the disease, during the acute phase. However, some have reported that patients who suffered severe COVID-19 requiring invasive mechanical ventilation, intensive ICU care, and prolonged hospitalization were more likely to suffer long-term tissue damage associated with persistent symptoms. High rates of severe functional disabilities and impaired quality of life were also found in COVID-19 survivors 3 months after discharge from the ICU.

In fact, survivors of critical illness typically suffer from post-intensive care syndrome , which involves prolonged cognitive, mental, and physical sequelae, due to extensive tissue damage. Therefore, some of the most prominent risk factors for long COVID are female sex, more than 5 initial symptoms, and severity of acute COVID-19. But the ambiguity of the risk factors cannot be denied, derived from the heterogeneity of the studies.

> Rehabilitation

It is recommended to perform mild aerobic exercise, at the pace of individual capacity. The level of difficulty of the exercise is gradually increased, depending on the tolerance allowed by fatigue and dyspnea, typically over 4-6 weeks.

Rehabilitation also includes breathing exercises, which aim to control slow, deep breathing to strengthen the efficiency of the respiratory muscles, especially the diaphragm. You should inhale through the nose, expanding the abdominal region, and exhale through the mouth. These light aerobic and breathing exercises should be done daily, in sessions of 5-10 minutes.

Complementary behavior modification and psychological support can also help improve survivors’ well-being and mental health. It is recommended that rehabilitation programs be personalized, since the characteristics of the disease may vary in each case.

It should be considered that the lung function of most participants has not completely healed, and neurological symptoms may persist.

So far, only one randomized controlled trial of 72 elderly COVID-19 survivors has shown that a 6-week rehabilitation program (breathing, stretching and home exercises) improves lung function, exercise capacity, quality of life and anxiety, but not depression.

The risks of physical rehabilitation should also be considered, as it may not be suitable for critical COVID-19 survivors with severe lung or heart damage. Therefore, exclusion criteria have been proposed for post-COVID-19 rehabilitation: resting tachycardia (>100 beats/min), arterial hypertension or hypotension (<90/60 or >140/90 mmHg), O2 saturation in low blood (<95%) or other conditions in which exercise is a contraindication.

An international survey found that 85.9% of participants with long COVID experienced symptom relapse after mental or physical activities. Even people with long COVID-like conditions may not respond favorably to rehabilitation, which includes patients with problems such as postural orthostatic tachycardia syndrome (STOP) or myalgic encephalomyelitis (EnM) or chronic fatigue syndrome (CFS), with fatigue or post-exertion discomfort.

More research is required to determine what rehabilitation program would best work for long COVID patients who share symptoms with STOP, EnM, and CFS. In specific cases, cognitive behavioral therapy and gradual exercise therapy can be applied.

> Pharmacological treatment

So far, no drug has been found to improve or attenuate the symptoms (or radiological and blood biomarker abnormalities) of long COVID.

However, paracetamol and non-steroidal anti-inflammatory drugs can be used to control specific symptoms such as fever. However, drugs used to treat similar conditions may have the potential to be repurposed in long COVID, warranting further investigation.

There is increasing evidence that long COVID resembles EnM/CFS and STOP. There are many reports of STOP diagnosis after [SARS-CoV-2] infection. Reviews have suggested that long COVID cases would eventually lead to EnM/CFS, due to the close symptomatic similarity.

Therefore, COVID could share pathophysiology with STOP or EnM/CFS, which could provide a basis for further research and possible drug repurposing. The author notes that a small study of 24 COVID-19 survivors with palpitations or tachycardia found that ivabradine decreased heart rate.

Reviews have proposed that mast cell activation syndrome may also underlie the pathophysiology of long COVID. Mast cells activate fibroblasts, which could lead to lung fibrosis as seen in long COVID patients. The activation of mast cells would also be involved in the pathophysiology of STOP.

Dyspnea, a common symptom of long COVID, is rarely seen in the other syndromes and does not meet the diagnostic criteria for EnM/CFS and STOP. Therefore, attempts to repurpose drugs must consider the symptomatic and pathophysiological differences between these similar conditions. Another treatment problem lies in the heterogeneous nature of long COVID, which likely involves multiple subtypes and complicates diagnosis.

This review presents the current understanding of long COVID, a relatively new and puzzling condition that can affect COVID-19 survivors regardless of initial illness severity or age.

Much remains to be researched and learned about the ambiguity of long COVID, particularly the risk factors. This may be due to its multiple symptomatic presentations and pathophysiologies, ranging from long-term multisystem damage to incomplete resolution of inflammation.

Currently, only rehabilitation has been found to be possibly effective in improving long COVID symptoms, while the pharmacological potential of known medications for EnM/CFS, STO and mast cell activation syndrome still requires further investigation.

In the author’s words: “Evidently, the pandemic has brought us the wave of a new and disabling chronic condition called long COVID , which deserves serious attention among scientists and medical communities, to achieve a resolution. Assuming that at least 10% of COVID-19 survivors develop long COVID (probably underestimated) it is estimated that 5 million people face long COVID worldwide.”