Long-Term COVID-19 and Cardiovascular Compromise: Implications for Post-COVID Care

Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes acute respiratory illness, numerous patients who recovered from COVID-19 subsequently experience a constellation of late heterogeneous symptoms and events lasting more than 3 months after the onset of illness. the acute illness. infection.

After an initial movement on social networks triggered by patients, the medical-scientific community recognized, in the spectrum of symptoms and late manifestations, a possible link with COVID-19. The condition was named LONG-COVID or POST-COVID. These terms were introduced to provide a common nosology suitable for coding all symptoms and clinical evidence of organ/system involvement.

The World Health Organization (WHO) recognized that "some people who have had COVID-19, regardless of whether they have been hospitalized, continue to experience symptoms, such as fatigue, cardiovascular, respiratory and neurological symptoms." The WHO specified the use of the term POST-COVID as follows: ’the need for disambiguation between acute illness, late effects or prolonged course led to the neutral formulation of Post-COVID’. The latest WHO update now includes a new ICD code for post-COVID-19 condition (specific condition UO9+).

Epidemiology

Early studies included only patients who had been hospitalized with acute COVID-19. The percentages of long COVID in survivors ranged from 30% to 80%; patients reported at least one symptom that lasted several months after resolution of the acute phase of the disease. However, most COVID-19 patients did not need hospitalization.

Therefore, a global estimate can only depend on systematic monitoring of patients who have tested positive for the virus or have demonstrated positive serology. The expected prevalence of post-COVID symptoms is around one-third of the entire population’s COVID-19 cases. The burden is such that it has led to the activation of Long-COVID outpatient clinics in all countries affected by the pandemic.

Symptoms

Heterogeneous clinical manifestations include both constitutional symptoms such as fatigue, difficulty or loss of attention and memory disturbances, as well as symptoms and events related to organs/systems involving immunological, respiratory, cardiovascular, central and peripheral neurological, muscular, hematological, gastrointestinal, renal/urinary, endocrine and cardiometabolic systems.

Generally, the diagnosis of long COVID or post-COVID syndrome is made in the presence of one or more symptoms commonly described by patients as an unprecedented deterioration of the individual psychophysical state. In this context, cardiovascular involvement requires the identification of measurable biomarkers with diagnostic specificity. 

Long-lasting symptoms

Long COVID is diagnosed at least 12 weeks after the onset of COVID-19.

Symptoms may represent a continuum with those of the acute phase, suggesting persistence of symptoms; It has not yet been established whether “chronic” long COVID exists. Long COVID has a beginning but no precise end. The most recent studies now report prevalence data one year after the onset of infection: "at month 12, only 22.9% of patients are completely free of symptoms."

Maintaining follow-up is essential to define the time limits and, in particular, the end of symptoms. Individual symptoms may last for varying intervals of time, with some regressing and others persisting for longer.

For example, long COVID neurocognitive symptoms may persist for at least 1 year after the onset of COVID-19 symptoms. The long duration of recovery appears to be related to high severity, but hospitalization and admission to intensive care units have also been reported independently of the severity of the acute phase. 

Who develops long COVID?

Long COVID appears to be more common in women than men, but this could reflect greater severity of COVID-19 in men, who demonstrated higher rates of hospitalization and risk of mortality. Therefore, the estimates relating to Long COVID do not reflect the epidemiology of COVID-19, but only that relating to COVID-19 survivors and exclude the high number of deceased patients, mainly male, elderly.

The age distribution in Long COVID should be read from the perspective of survivors of the acute phase: this condition is indeed prevalent in middle-aged people. On the one hand, COVID-19 is less common in younger people, on the other, many older people have died. 

Two main groups can be distinguished: (i) patients with pre-existing comorbidities , cardiovascular, respiratory, neurological, gastrointestinal, nephrological, endocrine, etc. (ii) patients without known comorbidities before COVID 19.

Analysis of the relationship between the acute phase, the need for hospitalization in the intensive care unit (ICU), non-ICU wards versus no hospitalization, demonstrates that long COVID can occur regardless of frailty or pre-existing morbidities .

Cardiovascular involvement: symptoms 

Palpitations

Patients potentially affected by Long COVID often complain of palpitations; They may correspond to simple sinus tachycardias or supraventricular or ventricular arrhythmias. These manifestations do not have diagnostic specificity, but must be carefully considered since they are a frequent cause of requests for medical assistance. However, de novo electrocardiographic changes, absent before COVID-19, and even absent at the time of recovery, are rarely described. In fact, these changes should be considered de novo only when a baseline pre-COVID electrocardiogram (ECG) is available. 

Prechoridal pain

Chest pain is another symptom that long COVID patients commonly complain about. These pains often do not correspond to instrumental findings useful for correct interpretation. 

Postural tachycardia syndrome

When excessive orthostatic tachycardia and orthostatic intolerance symptoms for at least 3 months are part of long COVID syndrome, it can lead to a diagnosis of post-COVID-19 postural tachycardia syndrome (POTS). The diagnosis is made in the presence of an increase of > 30 bpm in adults (> 40 bpm in patients aged 12 to 19 years) within 10 min of assuming the upright position in the absence of orthostatic hypotension with associated symptoms of orthostatic intolerance. Several case reports have recently described patients who developed POTS after SARS-CoV-2 infection. 

Cardiovascular involvement: findings and events

Heart failure

Although many review articles include heart failure (HF) among the possible clinical manifestations of Long COVID syndrome, studies that have documented the occurrence of de novo HF in recovered COVID-19 patients are rare. In most studies, data on patients with pre-existing HF possibly worsening after COVID-19 are reported along with the few cases of de novo HF. This limits the ability to identify those cases in which HF is in fact a clinical manifestation of long COVID. 

Venous thrombotic manifestations

Thromboembolic events recorded in Long COVID within the first year after recovering from acute COVID-19 include deep vein thrombosis (2.4%) and pulmonary thromboembolism (1.7%). A follow-up strategy has been proposed to assess the burden of residual risk, small vessel injury, and potential hemodynamic sequelae by observing lung perfusion status.

arterial thrombosis

Arterial thrombosis in subjects without known vascular pathology is often described as occasional in case reports or small clinical series. In addition to the coronary arteries, with manifestations of acute coronary syndromes in low-risk subjects and without significant coronary artery disease on angiography, unexplained thrombotic/thromboembolic episodes continue to be described at the peripheral/cerebral/splanchnic level. The severity of the acute infection, the need for ICU or non-ICU hospitalization, as well as the management of infections in the non-hospitalized setting, do not correlate with these de novo thromboses.

De novo arrhythmias

Although it is difficult to establish the time of onset of arrhythmic episodes, supraventricular and ventricular arrhythmias along with conduction disturbances have been reported among the possible manifestations of long COVID. 

Myocarditis, pericarditis, myopericarditis

Myocarditis is a debated topic in both COVID-19 and long COVID primarily due to incomplete diagnosis and therefore lack of certainty, particularly pathological evidence. In several studies, the diagnosis of myocarditis is based on the levels of isolated hypertroponinemia or the combination of hypertroponinemia and signs of myocardial edema on CMR. It would be correct to describe persistent hypertroponinemia and/or edema, without forcing its interpretation into myocarditis.

Cardiometabolic conditions

Diabetes, both type 1 and type 2, is associated with severe COVID-19 and long COVID. Interventions to target multiple risk factors, combined with the use of novel hypoglycemic agents that improve metabolic function and key processes affected by COVID-19, should be the preferred therapeutic options for the treatment of people with COVID. dragged on.

Markers and measurable findings

The diagnosis of long COVID requires a paradigm shift in the clinician’s aptitude to accept only descriptive reports for diagnosis; Clinical epidemiology data based largely on symptom narrative show such high percentages that the condition is perceived as a real "pathology", to which the WHO has assigned formal recognition in the ICD10 code UO9. However, this code is rarely used in clinical practice, limiting its potential role in epidemiological studies. Additionally, many countries are still adopting the ICD-9 system. Two important diagnostic contributions should be highlighted: biomarkers and instrumental and imaging evidence, especially useful if it is possible to demonstrate their absence in the pre-COVID phase.

The most frequently tested biomarkers are those related to (i) systemic inflammation such as C-reactive protein, neutrophil, lymphocyte and platelet counts; (ii) immune activation such as cytokine dosage [typically interleukin (IL) 6]; (iii) markers of hypercoagulability , such as levels of fibrinogen, D-dimer or functional tests of platelet hyperactivity; (iv) damage to myocytes , such as plasma levels of high-sensitivity troponin I; (v) myocardial stress/load such as natriuretic peptides. Less frequent is the dosage of alarmins (HMGB1; HSP; IL-1α; IL-33; LL-37; S100; defensins), investigated both in the acute phase and in Long COVID. twenty

Instrumental evidence of persistent and non-pre-existing damage is difficult to demonstrate because it must be based on the absence of the finding in the pre-COVID phase. However, imaging studies, including cardiac MRI , are on the rise and provide information that is insufficient to assign the findings to Long COVID with certainty. Between seropositive and seronegative groups, there may be no differences in cardiac structure (left ventricular volumes, mass, atrial area), function (ejection fraction, global longitudinal shortening, aortic distensibility), tissue characterization (T1, T2, extracellular volume fraction, late gadolinium enhancement).

Pathogenetic hypotheses

The pathogenesis of Long COVID is unknown. The wide heterogeneity of symptoms suggests that it is a multisystem disorder. The hypothesis of a direct role of the virus and its possible persistence must be carefully considered, also because there is no direct evidence of viral persistence with replication properties. On the contrary, there is the possibility that fragments of the viral genome or viral antigens, without infectious capacity, persist over time.

A very recent study reports the possibility that the viral genome is retro-transcribed and integrated into DNA, thus becoming a driver and source of the synthesis of RNA and antigens of viral origin. On the one hand, the authors plausibly suggest that this phenomenon underlies persistent positive tests in recovered COVID-19 patients 22; On the other hand, these molecules can keep the immuno-inflammatory-procoagulant cascade active, potentially explaining, for example, late thrombotic events.

The immunological/immune-mediated hypothesis could also be related to this possibility. This hypothesis is supported both by the pathogenic mechanisms of COVID-19, with the cytokine storm induced by the inflammatory-immune reaction to infection, and by the first studies that reported an increase in autoantibodies, for example, elevations of ANA titers. , 9which however do not have diagnostic specificity.

A common research front followed by several teams explores the persistence of both the viral genome/peptides and inflammation, evaluating the possibility that, among immunomodulatory factors/cytokines, substances with neuromodulatory effects may be at the basis of common neurological symptoms in these patients. However, the heterogeneity of symptoms, in particular mental health difficulties, anxiety, panic attacks, and cognitive and memory impairments, should leave open the possibility of pursuing research objectives other than the most plausible ones.

Treatment

Treatment of patients whose diagnosis is based solely on symptoms reflects the lack of measurable markers of the disease, making treatment empirical and oriented toward the sole purpose of controlling subjective symptoms.

Although biochemical testing or non-invasive instrumental evaluations are performed regularly, there may be no diagnostic contribution from biomarkers or instrumental data demonstrating organ or tissue damage. Vice versa, when symptoms are associated with evidence of organ damage [increased biomarker levels (e.g., myocyte damage) or ECG changes, imaging findings, or acute events], treatments are guided by the phenotypes. clinical.

Impact

The global impact of Long COVID cannot be ignored: it refers to individual psychophysical performance, the social, productive and economic spheres in the medical, financial and work context. The loss of efficiency at work, the need for medical support, the demand for diagnosis make this condition worthy of a new vision of investments in the health sector, also aimed at containing the social consequences of the outbreak and managing occupational health. . 

Indeed, the SARS-CoV-2 pandemic diverted attention from returning to work after health issues to resuming work during an outbreak, dealing with lockdown, and taking special account of workers with vulnerabilities.