Postacute Coronavirus (COVID-19) Syndrome

Etiology

Long COVID has variable definitions. The United States Centers for Disease Control and Prevention defines long COVID as symptoms lasting longer than 28 days from COVID diagnosis, while the United Kingdom National Institute for Health and Care Excellence and the World Health Organization require symptoms to be present at least 12 weeks after infection diagnosis. Symptoms can last weeks, months, or even years.[4] 

The previous epidemics of SARS-CoV and MERS-CoV left individuals who recovered from these viral illnesses with persistent symptoms of severe fatigue, decreased quality of life, persistent shortness of breath, and behavioral health problems that resulted in a significant burden on local healthcare systems where the epidemics occurred.[10] Similarly, a constellation of various clinical symptoms ranging from physical, psychological, and cognitive natures have been described in a substantial proportion of patients not actively infected with SARS-CoV-2-induced, as indicated by a negative polymerase chain reaction, PCR. 

Following any severe infection or trauma, the human body reacts with an overwhelming immune response called systemic inflammatory response syndrome (SIRS), followed by a prolonged compensatory, counterbalancing anti-inflammatory cascade called compensatory anti-inflammatory response syndrome (CARS).[5][6]

A delicate balance between SIRS and CARS determines the immediate clinical outcome and, eventually, the prognosis associated with the infection. Acutely, SARS-CoV-2 infection may lead to excessive cytokine release called "cytokine storm." Persistent cytokine release results in acute respiratory distress syndrome, hypercoagulable state, maladaptation of the angiotensin-converting enzyme 2 pathway, hypoperfusion to end-organs, septic shock, multiorgan failure, and possibly death.[6][7]

Many theories exist regarding the cause of long COVID, and the cause is likely multifactorial. The leading possibilities include ongoing viral infection, immune system dysregulation, microthrombi, dysbiosis, systemic fibrosis, autoimmunity, persistent central nervous system infection, and autonomic dysfunction.[3][4][8][9][10][11]

Ongoing Viral Infection

SARS-CoV-2 may have virus reservoirs after initial infection, contributing to ongoing inflammation and immune response. Many studies show that viral ribonucleic acid is detectable by PCR 100 to 150 days after initial infection.[4][7] To differentiate viral shedding from an active viral infection, viral culture or load quantification must be performed, which is beyond the scope of many laboratories; however, the long-term persistence of positive PCR suggests ongoing infection.[3][10][12] For example, SARS-CoV-2 has been found in the gastrointestinal (GI) tract of patients with long COVID GI symptoms at 4 to 7 months after initial infection.[3][7][13] Similarly, patients presenting with neuropsychiatric symptoms of long COVID were found to have the S1 component of SARS-CoV-2 in neuronal- and astrocyte-derived exosomes.[4][7] The cardiovascular system, neurologic systems, and lymphatic system have also demonstrated long-term positivity for SARS-CoV-2.[9][11]

Given that reservoirs of the virus may contribute to long COVID, antiretrovirals have been tried anecdotally with the improvement of long COVID symptoms.[4] In addition, 2 ongoing trials are evaluating nirmatrelvir-ritonavir versus placebo to treat post-acute COVID symptoms (NCT05576662 and NCT05595369).

Immune Dysregulation

As explained above, the initial SIRS leading to cytokine storm and activation of the host immune system is then balanced by counterbalancing CARS, leading to long-term immune suppression. Evidence supporting immune suppression is that patients with long COVID are prone to latent virus activation and secondary fungal and bacterial infections.[7] Ebstein-Barr virus (EBV), human herpesvirus 6, and cytomegalovirus have especially been studied.[3][4] EBV deoxyribonucleic acid has been found in increased numbers in patients with long COVID compared to those without.[4][14] Some patients have also been noted to have likely reactivation of SARS-CoV-2, demonstrating a positive SARS-CoV-2 PCR after testing negative.[7][12]

Although immune impression has been proposed as a possible mechanism, the opposite—low-grade inflammation—has also been postulated as a mechanism. Elevation of certain biomarkers, such as interleukin (IL)-6, tumor necrosis factor alpha, and IL-1B, have been reported in multiple studies as correlated with long COVID.[3][4] Further supporting this theory, the RECOVERY collaborative group showed decreased mortality in patients with acute COVID-19 infection and respiratory failure who were given dexamethasone.[4]

On a cellular level, reduced CD4+ and CD8+ T-cells have been found up to 13 months post-COVID-19 infection.[3][4] Decreased naive T- and B-cells have also been found.[3][4][10] Between 15% to 20% of patients with acute COVID-19 are found to have thyroid dysfunction, which is closely linked to T-cell-mediated autoimmunity.[10] Increased autoantibodies to angiotensin-converting enzyme-2 and connective tissue have also been associated with long COVID. There is a possibility that increased autoimmunity correlates with decreased SARS-CoV-2 immunity, which explains both over- and under-active immune reactions.[3][10]

Microthrombi and Hypercoagulability 

Some researchers have reported increased levels of microthrombi markers as well as serum amyloid A in patients with long COVID.[3][4][9] One South African study treated patients with post-acute COVID with dual antiplatelet therapy—clopidogrel 75mg/aspirin 75 mg—with improved symptoms. Other small studies evaluated the use of the direct oral anticoagulants apixaban and rivaroxaban, also with improved clinical symptoms.[4]

Dysbiosis

Much attention has been paid to the importance of the gut microbiome recently, and significant changes in this have been reported with SARS-CoV-2 infection. Patients with prolonged post-acute infection symptoms show increased levels of Ruminococcus and Bacteroides and lower Faecalibacterium levels. Using probiotic agents such as highly fermented foods may improve these shifts.[3][4][10]

Myalgic Encephalitis/Chronic Fatigue Syndrome and Postural Orthostatic Tachycardia 

Myalgic encephalitis/chronic fatigue syndrome (ME/CFS) is a multisystem neuroimmune illness that includes profound fatigue, postexertional malaise, and cognitive impairment. Significant overlap exists between the symptoms of ME/CFS and long COVID. Other similarities include T-cell exhaustion, neuroinflammation, and vascular and endothelial dysfunction.[3][4] Both ME/CFS and long COVID are also linked to volume reduction in the limbic system gray matter.[9] 

Postural orthostatic tachycardia (POTS) is a dysautonomia found in up to 67% of patients with long COVID. Many patients with long COVID exhibit dysautonomia and other symptoms of POTS, suggesting treatments for POTS may alleviate some of the symptoms of long COVID.[3][4]

Epidemiology

More than 65 million people worldwide are estimated to have been living with long COVID since the onset of the pandemic.[3] Acute hospitalization for COVID-19 is a risk factor for long COVID compared to outpatient treatment. Vaccination against COVID-19 decreases the chances of post-acute symptoms.[4] Patients with a history of asthma, obesity, diabetes, hypothyroidism, and depression have a higher risk of long COVID.[5]

Long COVID affects individuals of all age groups. Study results suggest increased long COVID symptoms in different age groups, but no clear age predominance exists.[4][6][7] A significantly increased incidence of long COVID is noted in female patients compared to males.[3][9][10] Several studies from the United States and the United Kingdom show an increased risk of long COVID in Black, Asian, and Hispanic populations compared to White individuals.[3][4][8][9] 

Pathophysiology

The various pathophysiologies of long COVID include:

Pulmonary Manifestations

• Dyspnea, cough, oxygen dependence, fibrotic lung changes, decreased diffusion capacity, and reduced endurance are common pulmonary sequelae in patients with long COVID.[8][10]
• Dyspnea is the predominant pulmonary symptom. At a 6-month follow-up, the average 6-minute walking distance was significantly lower than the standard reference because of shortness of breath. About 6% of patients continue to require supplemental oxygen at 60-day follow-up.[11] 
• Persistent lung structure and functional changes were reported in patients hospitalized with COVID-19. Patients who develop acute respiratory distress syndrome or require mechanical ventilation are especially at risk of pulmonary fibrosis.[2][10]
• The degree of dyspnea and fatigue seem disproportionate to the measurable impairment of gas exchange; therefore, the dyspnea may be multifactorial.[10]

Cardiovascular Manifestations

• Direct virus-mediated cytotoxicity, ACE2 receptor down-regulation, and immune-mediated inflammation affecting the myocardium and pericardium are the most common mechanisms of cardiovascular damage resulting in clinical symptoms such as dyspnea, fatigue, myocarditis, decreased cardiac reserve, dysregulation of the renin-angiotensin-aldosterone system, autonomic dysfunction, and arrhythmias.[10][12]
• Patients with preexisting coronary artery disease are also prone to plaque rupture in the inflammatory cytokine milieu.[10][6]

Gastrointestinal Manifestations

• Gastrointestinal symptoms, such as nausea, vomiting, diarrhea, loss of appetite, and abdominal pain affect up to 10% to 20% of patients with acute COVID-19.[10]
• The GI tract is known to have high concentrations of the angiotensin-converting enzyme 2 (ACE2) receptor, which may explain prolonged shedding from the GI tract associated with long COVID symptoms.
• Alterations in the gut microbiome have been found up to 14 months after acute COVID-19 infection. Fungal translocation from the gut to the plasma has also been seen in long COVID.[3][10]

Hematologic Manifestations

• Acute COVID-19-associated thromboembolism is secondary to the hyperinflammatory and hypercoagulable state.[13] Hypoxia, endothelial injury, platelet activation, and proinflammatory cytokines result in disproportionately high thromboembolism rates in acute COVID-19. The duration and severity of this hyper-inflammatory state contribute to the risk of thrombotic complications in long COVID. 

Neuropsychiatric Manifestations

• Microvascular thrombi, systemic inflammation, and direct viral-mediated neurotoxicity are hypothesized to be the possible mechanisms contributing to neuropathology in patients recovering from COVID-19.
• Dysautonomia, deconditioning, and posttraumatic stress disorder can contribute to post-COVID-19 "brain fog." Prolonged duration of intensive care unit stay and prolonged intubation contribute significantly to long-term cognitive impairment in COVID-19 patients.[10][14]
• Patients often complain of ongoing anosomnia and dysgeusia, suggesting ongoing central nervous system involvement. Of note, the brainstem has higher ACE2 receptor levels than other areas of the brain, suggesting the possibility of long-term brainstem damage.[10][11] 
• Cough lasting for weeks or months after acute COVID-19 infection is thought to be related to hypersensitivity of the vagal nerve related to direct nerve invasion by SARS-CoV-2 or by neuroinflammation that can affect both central and peripheral sensory pathways.[11]
• Many researchers liken the treatment of long COVID-19 to myalgic encephalitis/chronic fatigue syndrome, in which the pathology is presumed to be central nervous system inflammation. Dopamine D2 agonists, such as aripiprazole, have been shown to decrease neuroinflammation, astroglial activation, and apoptosis in humans and mice; as such, aripiprazole has been used to treat myalgic encephalitis/chronic fatigue syndrome.[15] Naltrexone is also thought to decrease microglial activation.[16] Both naltrexone and aripiprazole have been proposed as treatments for long COVID-19, and currently, a randomized double-blinded placebo trial is studying low-dose naltrexone for symptomatic treatment of long COVID-19 (NCT05430152).

Endocrine Manifestations

• Viral injury and inflammatory and immunologic damage contribute to post-acute COVID-19 endocrine manifestations. Isolated case reports of new-onset diabetes and subacute Hashimoto thyroiditis have been reported weeks after resolving acute COVID-19 symptoms.[17][18] Immobilization, steroid use, and vitamin D deficiency during acute and post-acute recovery from COVID-19 might also contribute to bone demineralization.

Multisystem Inflammatory Syndrome in Children 

• Multisystem inflammatory syndrome in children is a new clinical entity characterized by fever, multiorgan dysfunction, and increased inflammatory markers seen in individuals younger than 21 with recent or current SARS-CoV-2 infection.[10]
• The most likely underlying mechanisms are an acquired immune response from complement activation, autoantibodies (viral host mimicry) formation, and excessive cytokine release from T-cell stimulation.[19]

Histopathology

An autopsy study was conducted on patients diagnosed with COVID-19 between a few days to as long as 7 months prior to death. Findings revealed that the most common site to detect SARS-CoV-2 ribonucleic acid (RNA) was the respiratory tract, as expected. However, in more than 50% of cases where the diagnosis of COVID-19 was made more than 31 days prior to death, persistent RNA was detected in the myocardium, lymph nodes, and central nervous system. In addition, the quantitative difference between respiratory and extra-pulmonary tissue greatly narrowed in the group with "late infections." This demonstrates the ongoing presence of SARS-CoV-2 RNA in various organ systems long after acute infection.[4][18]

History and Physical

As noted above, over 200 symptoms have been associated with long COVID. The Centers for Disease Control and Prevention describes the most common symptoms by system on their website as follows:

General symptoms 

• Tiredness or fatigue that interferes with daily life
• Symptoms that get worse after physical or mental effort (also known as post-exertional malaise)
• Fever

Respiratory and heart symptoms

• Difficulty breathing or shortness of breath
• Cough
• Chest pain
• Fast-beating or pounding heart (eg, heart palpitations)

Neurological symptoms

• Difficulty thinking or concentrating (sometimes referred to as “brain fog”)
• Headache
• Sleep problems
• Dizziness when standing up (lightheadedness)
• “Pins-and-needles” feelings
• Change in smell or taste
• Depression or anxiety

Digestive symptoms

• Diarrhea
• Stomach pain

Other symptoms

• Joint or muscle pain
• Rash
• Changes in menstrual cycles

Some symptoms attributed to long COVID are not typically described in other postviral infection syndromes, including hair loss, menstrual irregularities, and dermatologic manifestations like swelling and discoloration of the toes.

Of the many subjective complaints, some are recurrent across different studies. Various meta-analysis study results confirm that the most common symptoms are fatigue/weakness, myalgias/arthralgias, psychiatric stress, “brain fog” (eg, memory loss, difficulty concentrating), cough/dyspnea, and sleep problems.[2][4][7][11]

Physical exams are variable, and many of the symptoms of long-term COVID-19 are subjective without physical exam correlates. Some of the findings may be as follows: hypoxia, especially with exertion; dysautonomia or orthostatic hypotension; tachycardia, increased jugular venous pressure, myocardial rub if myocarditis or pericarditis is present; abnormal pulmonary exam with rales or crackles; hyperactive bowel sounds; decreased muscle strength or numbness in dermatomal distributions; and abnormal rash or skin discoloration.

Evaluation

The following include suggested long COVID evaluation methodologies:

• A detailed clinical history regarding the onset and duration of current symptoms, underlying medical comorbidities, the severity of COVID-19, and medication history must be obtained by clinicians during the follow-up visit.
• Hospitalization records of COVID-19-related admission, if applicable, must be reviewed thoroughly, including the pertinent diagnostic tests performed and the duration of hospitalization.
• Given that long COVID is an evolving clinical entity, there aren’t any guidelines regarding its management. Until further guidance is available, this condition should be considered a diagnosis of exclusion. All other complications associated with COVID-19 and other acute alternative diagnoses must first be ruled out with pertinent laboratory and radiologic assessment.
• Multiple cases have reported reactivation and relapse of SARS-CoV-2 in patients who had fully recovered from the previous infection; therefore, SARS-CoV-2 reinfection needs to be ruled out, along with other postviral secondary bacterial and fungal infections or other viral illnesses.[9] 
• Routine laboratory assessment with complete blood count, a comprehensive metabolic panel that includes testing for renal and liver function, and a coagulation panel must be considered in all patients.
• Other tests, such as C-reactive protein, fibrinogen, D-dimer, troponin, and ferritin, can also be considered if clinically indicated.[10]
• Repeat pulmonary imaging, preferably with a high-resolution computed tomography (CT) scan or CT angiogram, can be considered if clinically indicated in patients presenting with predominantly respiratory symptoms.[11]
• Cardiac function tests such as echocardiography must also be considered to rule out an underlying cardiopulmonary disease process. Changes in the QRS complex have been noted with long COVID.[3]
• Cardiac magnetic resonance imaging (MRI) and transthoracic echocardiography can be used to diagnose acute and chronic coronary pathology such as myopericarditis, ventricular dysfunction, and wall motion abnormalities.[6]
• Neuroimaging (CT/MRI) that includes neurovascular and neuropsychological testing must be performed if clinically indicated in patients presenting with neuropsychiatric manifestations.
• Tilt table testing can be used to evaluate for postural orthostatic tachycardia syndrome. Many of the tests used to evaluate ME/CFS can also be used to evaluate for long COVID, such as saliva tests, erythrocyte deformation, and electrical impedance blood tests.[3]

Treatment / Management

Overwhelming evidence demonstrates a reduced incidence of long COVID in patients who are vaccinated, further highlighting the importance of primary prevention.[4][7] As noted above, data also show a correlation between using the antiviral nirmatrelvir-ritonavir (Paxlovid) during acute infection and a decreased incidence of long COVID.[4]

Immunomodulators

• Given that long COVID may be related to an abnormally regulated immune system, various immunomodulatory strategies have been suggested. These include transforming growth factor-B (a pro-fibrotic cytokine) inhibitors, checkpoint inhibitors, and antivirals such as remdesivir, favipiravir, and nirmatrelvir-ritonavir.[8]
• Some other anti-inflammatories currently being studied are ibudilast, imatininb, infliximab, and cannabinoids.[3][8]
• Many treatments for ME/CFS have also been used for long COVID, including pacing and other immunomodulators such as low-dose naltrexone and aripiprazole.[3][4]
• Therapeutic apheresis has also been used for ME/CFS to reduce presumed autoantibodies and may also have the benefit of reducing microclots in long COVID.[3][8]
• postural orthostatic tachycardia syndrome is treated with B-blockers, fludrocortisone, midodrine, and ivabradine; similar treatments may be effective for long COVID-associated dysautonomia.[3][8]
• Anticoagulants have been used to treat possible microthrombi and for evidence of long-term clotting.[3][8]
• Vitamin D supplementation is recommended for bone health.

General Considerations

• As described earlier, long COVID can be considered a multi-system disorder manifesting commonly with respiratory, cardiovascular, hematologic, and neuropsychiatric symptoms, either alone or in combination. As such, therapy should be individualized and incorporate an interprofessional approach to addressing the clinical and psychological aspects of this disorder.
• Given the increased clinical awareness of this illness, post-COVID care clinics providing multidisciplinary assessment and patient resources are opening at major medical centers across the United States.
• Treatment for coexisting conditions such as diabetes, chronic kidney disease, and hypertension should be optimized.[11][13]
• Patients should be educated about self-monitoring at home with devices such as pulse oximeters, blood pressure, and glucose monitors.
• Patients should be encouraged to consume a healthy, balanced diet, maintain proper sleep hygiene, limit alcohol use, and quit smoking.[11]
• Simple analgesia with acetaminophen as needed should be considered.
• If tolerated, a structured exercise program consisting of aerobic and resistance components should be advised, provided there are no other contraindications.[14]

Pulmonary

• Patients who previously had COVID-19 with persistent/residual pulmonary symptoms after recovery should be seen by a pulmonologist for evaluation and close follow-up. 
• Patients with persistent symptoms may benefit from enrollment into a pulmonary rehabilitation program and vaccination against influenza and Streptococcus pneumoniae.[8]
• If clinically indicated, pulmonary function tests and a 6-minute walking test should be considered.
• The role of steroids in long COVID is unknown, and data evaluating its effectiveness in post-COVID-19 patients is limited. A small study evaluating patients with COVID-19 four weeks after discharge demonstrated rapid and significant improvement with early initiation of steroids.[15] Further clinical trials are required to ascertain its benefit in COVID-19 patients.

Cardiovascular

• Patients who previously had COVID-19 with persistent cardiac symptoms after recovery should be followed closely by a cardiologist.
• Cardiac function tests such as echocardiography must be considered to rule out arrhythmias, heart failure, and ischemic heart disease.
• Additionally, given the increased incidence of myocarditis in patients with COVID-19, an MRI of the heart can be considered to evaluate for myocardial fibrosis or scarring if clinically indicated.
• Although too early to predict long-term sequelae, 40% of patients infected with the genetically similar SARS-CoV-1 showed cardiovascular abnormalities at 12-year follow-ups.[8]

Hematologic

• Although COVID-19 is associated with a prothrombotic state, there is currently no consensus regarding the benefit of venous thromboembolism prophylaxis in the outpatient setting. However, current CHEST guidelines recommend anticoagulation therapy for a minimum duration of 3 months in COVID-19 patients who develop proximal deep vein thrombosis or pulmonary embolism.[16]

Neuropsychiatric

• Patients should be screened for common psychological issues (eg, anxiety, depression, insomnia, post-traumatic stress disorder) and should be referred to behavioral health specialists if indicated.
• Neurological evaluation should be considered early because of the vast neurological symptoms associated with this syndrome.
• In addition to the routine laboratory workup described above, additional laboratory tests such as hemoglobin A1C, thyrotropin, thiamine, folate, vitamin B12, and vitamin B12 must be checked to evaluate for other contributing metabolic conditions.[17]
• Electroencephalography and electromyography should be considered if there are concerns for seizures and paresthesias.

Differential Diagnosis

Knowledge of long COVID is limited at this time, and any organ system can potentially be affected. Hence, long COVID should be considered a diagnosis of exclusion. All other well-described complications associated with COVID-19 and other acute alternative diagnoses must be first ruled out with pertinent laboratory assessment and imaging.

Considering that this novel clinical entity manifests various respiratory, cardiovascular, hematologic, and neuropsychiatry symptoms alone or in combination, the following common conditions can be considered in the differential diagnosis of long COVID.

Respiratory

• Pulmonary embolism
• Lung atelectasis/fibrosis
• Postviral bacterial pneumonia

Cardiovascular

• Ischemic heart disease
• Post viral myocarditis
• Myocardial fibrosis/scarring
• Congestive heart failure
• Arrhythmias

Hematologic

• Deep vein thrombosis

Neuropsychiatric

• Stroke
• Cerebral vein thrombosis
• Seizures
• Anxiety
• Depression
• Insomnia
• Post-traumatic stress disorder 

Infectious

• Bacterial and fungal infections
• Other viral infections that include SARS-CoV-2 reinfection

Prognosis

This new clinical entity's prognosis is unknown and is likely dependent on the severity of clinical symptoms, underlying comorbid conditions, and response to treatment. More clinical studies evaluating post-COVID-19 in patients are required to understand the duration and the long-term effects of this new clinical entity.[12]

Complications

Long COVID itself is an increasingly recognized complication of COVID-19, and secondary complications associated with this syndrome are poorly understood at this time. More clinical data is required to understand this syndrome's long-term sequelae further.[13]