Long COVID

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mitra Chitsazan, M.D.[2] Edzel Lorraine Co, DMD, MD[3]

Synonyms and keywords: Long COVID Syndrome, long COVID, long-haul COVID, post-COVID-19 condition, post-COVID-19 syndrome, post-acute sequelae of COVID-19 (PASC), chronic COVID syndrome (CCS), Long-hauler COVID-19, Long-tail COVID, Long-haulers, Post-acute COVID-19 syndrome, Acute post-COVID symptoms, Long post-COVID symptoms, Persistent post-COVID symptoms, Post-acute COVID-19, On-going symptomatic COVID-19, Chronic COVID-19

Overview

Shortly after the COVID-19 pandemic onset, emerging studies showed that a considerable proportion of patients with COVID-19 might exhibit sustained postinfection sequelae. This condition has been defined by a variety of names, including long COVID or long-haul COVID, and post-COVID-19 condition. The absence of a universally standardized terminology has made characterization of the epidemiology, risk factors, clinical characteristics, and potential treatments options difficult. Symptoms may occur as an unpredictable combination of respiratory, cardiovascular, urological, neurological, and/or gastrointestinal manifestations. However, the most common symptoms include fatigue, dyspnea, and cognitive dysfunction (known as brain fog by the patients). Symptoms may begin following initial recovery from an acute COVID-19 episode or may persist from the initial acute episode. Symptoms might also fluctuate or relapse over time.

Historical Perspective

• The term ‘Long COVID’ was first used as a Twitter hashtag by a patient who was not recovering from COVID-19. This patient-made term soon became a widely accepted concept by both the public and medical professionals.
• Currently, this condition is known by a variety of names, including long COVID, long-haul COVID, post-COVID-19 condition, post-COVID-19 syndrome, post-acute sequelae of COVID-19 (PASC), or chronic COVID syndrome (CCS).
• This condition is listed in the ICD-10 classification as post-COVID-19 condition since September 2020.

Definition

• On October 6, 2021, World Health Organization (WHO) released a clinical case definition of the post-COVID-19 condition through a robust, protocol-based methodology (Delphi consensus), which engaged a diverse group of representative patients, patient-researchers, external experts, WHO staff, and other stakeholders from multiple geographies. It was acknowledged that this definition may change with emerging new evidence and continuously evolving our understanding of the consequences of COVID-19.
• According to WHO clinical case definition, the post-COVID-19 condition is defined as:
  • Post COVID-19 condition occurs in individuals with a history of probable or confirmed SARS-CoV-2 infection, usually 3 months from the onset of COVID-19 with symptoms that last for at least 2 months and cannot be explained by an alternative diagnosis.
  • Common symptoms include fatigue, shortness of breath, cognitive dysfunction and generally have an impact on everyday functioning.
    • Symptoms may be new-onset following initial recovery from an acute COVID-19 episode or persist from the initial illness.
    • Symptoms may also fluctuate or relapse over time.
    • A separate definition may be applicable for children.
    • Notes: There is no minimum number of symptoms required for the diagnosis; though symptoms involving different organs systems and clusters have been described.

• A summary of some published/available definitions of the post-COVID-19 condition include:

Source	Terms	Definition
WHO	Post-COVID-19 condition	Post COVID-19 condition occurs in individuals with a history of probable or confirmed SARS-CoV-2 infection, usually 3 months from the onset of COVID-19 with symptoms that last for at least 2 months and cannot be explained by an alternative diagnosis. Common symptoms include fatigue, shortness of breath, cognitive dysfunction and generally have an impact on everyday functioning. Symptoms may be new-onset following initial recovery from an acute COVID-19 episode or persist from the initial illness. Symptoms may also fluctuate or relapse over time.
CDC	Long COVID	While most persons with COVID-19 recover and return to normal health, some patients can have symptoms that can last for weeks or even months after recovery from acute illness. Even people who are not hospitalized and who have a mild illness can experience persistent or late symptoms."
Nature	Post-acute COVID-19	Persistent symptoms and/or delayed or long-term complications of SARS-CoV-2 infection beyond 4 weeks from the onset of symptoms.
Lancet	Long COVID	Multiorgan symptoms after COVID-19 are being reported by increasing numbers of patients. They range from cough and shortness of breath to fatigue, headache, palpitations, chest pain, joint pain, physical limitations, depression, and insomnia, and affect people of varying ages. At the Lancet–Chinese Academy of Medical Sciences conference on 23 November 2020, Bin Cao presented data (in press at the Lancet) on the long-term consequences of COVID-19 for patients in Wuhan and warned that dysfunctions and complications could persist in some discharged patients for at least 6 months. So-called long COVID is a burgeoning health concern and action is needed now to address it.
Nice	Long COVID	Signs and symptoms that develop during or after an infection consistent with COVID-19, continue for more than 12 weeks and are not explained by an alternative diagnosis.
Scientific American	Long Haul COVID	Individuals whose symptoms persist or develop outside the initial viral infection, but the duration and pathogenesis are unknown.
Royal Society	Long COVID	The onset of persistent or recurrent episodes of one or more of the following symptoms, within x* weeks of infection with SARS-CoV-2 and continuing for y* weeks or more: severe fatigue, reduced exercise capacity, chest pain or heaviness, fever, palpitations, cognitive impairment, anosmia or ageusia, vertigo and tinnitus, headache, peripheral neuropathy, metallic or bitter taste, skin rash, joint pain or swelling. Maximum period between acquisition of the infection (if known) and the onset of symptoms, and the minimum duration of symptoms, should be specified in the definition.
Haute Autorité de santé, France	Long COVID	Three criteria: Having presented with symptomatic form of COVID-19 Presenting with one or more initial symptoms 4 weeks after the start of the disease None of these symptoms can be explained by another diagnosis

Classification

There is no established system for the classification of long COVID.

Pathophysiology

The exact pathogenesis of long COVID is not fully understood. A controlled study found no unique abnormalities However, a number of putative pathophysiologic mechanisms have been suggested.

• 1) Long-term tissue damage:
  • Long-term tissue damage can result in the persistence of symptoms in different organs. For example:
    • Respiratory symptoms
      • Lung fibrosis may be the cause of respiratory symptoms, such as dyspnea and cough.
    • Neurologic symptoms
      • Structural and metabolic abnormalities in the brain and brainstem may be the cause of neurologic symptoms such as headache, delirium, memory loss, anosmia, and fatigue.
    • Fatigue
      • Chronic fatigue occurs as a complex syndrome and a few mechanisms have been suggested. These include:
        • Autonomic nervous system dysfunction
        • Inflammation
        • Channelopathies
        • Inadequate cerebral perfusion
    • Cardiovascular symptoms
      • Autonomic symptoms and findings are common in an uncontrolled study
      • Cardiac injury occurs in a substantial proportion of patients during acute COVID-19 episodes. Resulting cardiac abnormalities (such as impaired contractile function and cardiac remodeling) and myocardial inflammation may account for symptoms such as chest pain, palpitations, and tachycardia.
      • Cardiovascular and respiratory symptoms might also be due to damages of the intrathoracic chemo and mecano-receptors, which are involved in the control and regulation of respiration and heart rate. The SARS-CoV-2 neurotropism (i.e., cell invasion and damage), microcirculation or autoimmune disorders have been suggested as the possible mechanisms for such damages. This hypothesis seems to explain many dysautonomic symptoms which occur due to a dysregulated rate in respiration or heart rate. These symptoms include breathlessness, exercise intolerance, palpitations, or orthostatic malaise.

• 2) Ongoing inflammation
  • Several studies have suggested the presence of an unresolved inflammation in patients recovering from COVID-19. This ongoing inflammation may result from a variety of reasons.
    • 1) Viral persistence in the gastrointestinal tract: Studies have shown the persistence of the virus in the gastrointestinal tract (in the gastric and intestinal cells) after recovering from acute COVID-19 episodes due to the high expression of ACE2 receptors in these cells. Increased fecal shedding of the SARS-CoV-2 virus has been shown in some studies. This may trigger a state of immune activation and ongoing inflammation in the body and also may explain the relatively high prevalence (up to 30%) of gastrointestinal manifestations (e.g. appetite loss, nausea, vomiting, diarrhea, and abdominal discomfort) in patients with long COVID.
    • 2) Lymphopenia: Increased levels of pro-inflammatory markers (e.g. CRP, IL-6, and D-dimer) and lymphopenia occur during acute COVID-19 episodes and have been shown to be associated with long COVID symptoms, particularly myalgia, fatigue, and joint pain.
    • 3) Autoimmunity: Recently, T-cells and B-cells dysfunction have been suggested to promote long COVID pathophysiology similar to autoimmune diseases.
    • 4) Other mechanisms
      • In a recent study using Invasive Cardiopulmonary Exercise Testing (iCPET), the pathophysiologic mechanism of exercise intolerance in post-COVID-19 long-haul syndrome has been investigated. The results of the study showed that patients without cardiopulmonary disease who have recovered from COVID-19 had a marked decrease in peak oxygen consumption and an exaggerated hyperventilation response during exercise. This means that patients who have recovered from COVID-19 had:
        • Reduced peak exercise aerobic capacity
        • Impaired systemic oxygen extraction
        • Abnormal ventilatory efficiency slope.

Cytokines and Biomarkers

• Increased levels of interleukin-17 and interleukin-12, decreased levels of interleukin-4, interleukin-6 and interleukin-10 were observed in the recent study by Queiroz et al.
• Neurological manifestations of long COVID were observed to be associated with the presence of ACE2, SLC6A19, TMPRSS4, TMRSS2, interleukin-17, interferon gamma, and zonulin.
• IL-17D, IL-17A, TNF-a, PIGF, VCAM-1, KL6, and ICAM-1 were linked with an increased susceptibility risk for pulmonary fibrosis in long COVID.

Epidemiology and Demographics

• The reported incidence/prevalence of long COVID varies in different studies mainly due to the absence of single terminology and definition.
• A meta-analysis, including 47,910 patients (age 17-87 years), estimated that 80% of the patients with SARS-CoV-2 infections developed one or more long-term (ranging from 14 to 110 days) symptoms.
• Women seem to be more commonly affected by long COVID than men.

A cohort study found the COVID alpha variant found:

• "Persistent symptoms in COVID-19-positive participants at 90-150 days after COVID-19 compared with before COVID-19 and compared with matched controls included chest pain, difficulties with breathing, pain when breathing, painful muscles, ageusia or anosmia, tingling extremities, lump in throat, feeling hot and cold alternately, heavy arms or legs, and general tiredness."
• "In 12·7% of patients, these symptoms could be attributed to COVID-19, as 381 (21·4%) of 1782 COVID-19-positive participants versus 361 (8·7%) of 4130 COVID-19-negative controls had at least one of these core symptoms substantially increased to at least moderate severity at 90-150 days after COVID-19 diagnosis or matched timepoint."

Risk Factors

• There are no established risk factors for long COVID.
• However, according to several studies, the most common risk factors for the development of long COVID may include:
  • Older age
  • Female gender
  • Pre-existing comorbidities, such as obesity, asthma
  • More severity of the acute COVID-19 episode, including a prolonged hospitalization or ICU stay
    • However, emerging data suggest that even patients with a less severe initial episode of COVID-19, who had not required hospitalization, may also experience persistent symptoms of post-COVID-19 condition
  • Medical complications during acute COVID-19 episode, such as secondary bacterial pneumonia, venous thromboembolism
  • Presence of a higher number of symptoms in the acute COVID-19 episode (i.e. an extended spectrum of symptoms) (more than five initial symptoms)
  • Increased levels of C-reactive protein and D-dimer
  • Decreased lymphocyte count

Screening

There is insufficient evidence to recommend routine screening for long COVID.

Natural History, Complications, and Prognosis

• The natural history, clinical course, long-term complications, and prognosis of long COVID-19 are still not completely understood.
• Manifestations of the post-COVID-19 condition vary considerably in terms of organ involvement and severity of symptoms; however, they generally impact the everyday functioning of affected patients.
• Symptoms might newly develop following initial recovery from an acute COVID-19 illness or occur as a persist from the initial episode.
• Symptoms might also fluctuate or relapse over time.

Diagnosis

Diagnostic Study of Choice

• According to a clinical case definition by WHO, the post-COVID-19 condition is defined as follow:
  • The post-COVID-19 condition occurs in individuals with a history of probable or confirmed SARS-CoV-2 infection, usually 3 months from the onset, with symptoms that last for at least 2 months and cannot be explained by an alternative diagnosis.

History and Symptoms

Long COVID can involve almost every organ. The most common symptoms of long COVID include:

• Physical symptoms:
  • Fatigue
  • Dyspnea
  • Cough
  • Chest discomfort
  • Anosmia

• Neurocognitive symptoms:
  • Memory impairment and Cognitive dysfunction: described by patients as “brain fog”
  • Headache

• Psychologic symptoms:
  • Anxiety
  • Depression
  • Post-traumatic stress disorder (PTSD)

• Other less common symptoms include:
  • Sweating
  • Myalgias
  • Diarrhea
  • Hair Loss (Alopecia)
  • Joint Pain
  • Sicca Syndrome
  • Rhinitis
  • Dysgeusia
  • Poor Appetite
  • Dizziness
  • Vertigo
  • Insomnia

Physical Examination

• In patients with cardiopulmonary symptoms, a throughout chest examination may provide a clue to the underlying condition:
  • On pulmonary examination:
    • Coarse crackles: a sign of fibrosis
    • Dullness on percussion: a sign of pleural effusion or consolidation
    • Egophony: A sign of consolidation
    • Fine basilar crackles: A sign of pulmonary edema
  • On cardiac examination, the following findings may provide a clue to the underlying cardiac complication:
    • Jugular venous distension
    • Peripheral edema
  • Orthostasis
    • Murmurs
    • Pericardial rub
    • Third or fourth heart sounds

Laboratory Findings

There are no diagnostic laboratory findings associated with long COVID. Symptoms do not correlate with the serology of SARS-CoV-2.

Electrocardiography

In patients with cardiopulmonary symptoms, an ECG may be needed.

X-ray

A chest x-ray may be helpful in the diagnosis of pulmonary complications of COVID-19 such as lung damage (ie, ground glass opacities, consolidation, interlobular septal thickening) and pleural effusion.

Echocardiography or Ultrasound

In selected patients with cardiopulmonary symptoms, echocardiography may be necessary.

CT scan

In patients with cardiopulmonary symptoms, a chest CT scan may be needed.

MRI

There are no MRI findings associated with long COVID. However, a cardiac MRI may be helpful in the diagnosis of myocarditis in COVID-19 patients.

Other Imaging Findings

There are no other imaging findings associated with long COVID.

Other Diagnostic Studies

In selected patients with cardiopulmonary symptoms, Holter monitoring, cardiopulmonary exercise testing (CPET), and pulmonary function tests may be necessary.

Treatment

Due to the diversity of symptoms and their severity, the mainstay of long COVID treatment is multidisciplinary and supportive. The management should focus on supporting self-management and individualized rehabilitation.

Medical Therapy

• Dyspnea
  • Dyspnea in long COVID patients should be treated similar to non-COVID-19 patients. General measures in the management of dyspnea in long COVID patients may include:
    • Oxygen therapy
    • Breathing exercises:
      • Pursed lip breathing exercises
      • Deep breathing exercises
    • Pulmonary rehabilitation
  • In the presence of any identified underlying cardiac or pulmonary disease, referral to a cardiologist or pulmonologist and appropriate pharmacotherapy may be required.

• Cough
  • Cough should be managed in a similar to cough in patients with post-viral cough syndrome.
  • Attention should be paid to diagnose and treat other exacerbating or contributing factors such as gastrointestinal reflux disease and asthma.
  • Over-the-counter cough suppressants, including benzonatate, guaifenesin, and dextromethorphan are the mainstay of treatment.

• Cardiac injury
  • Long COVID patients with evidence of cardiac injury should be referred to cardiology services.
  • Patients recovering from cardiac injury with impaired functional status (eg, New York Heart Association class II or higher) should undergo cardiac rehabilitation if no contraindications are present.

• Orthostasis
  • Orthostasis and dysautonomia, such as unexplained sinus tachycardia, dizziness on standing, is initially managed conservatively with compression stockings, abdominal binder, increased intake of fluid and salts, physical therapy/rehabilitation, and behavioral modifications.
  • In patients with postural orthostatic tachycardia syndrome (PoTS) and inadequate response to non-pharmacological therapy, beta-blockers, ivabradine, or fludrocortisone (with blood pressure and response monitoring) might be considered.

• Olfactory/gustatory symptoms
  • In most patients with a loss or decrease in sense of smell or taste, symptoms improve slowly over several weeks and do not require medical intervention. Patients may need education on food and home safety.
  • In patients with persistent symptoms, olfactory training may be appropriate. If conservative management fails, referral to an otolaryngologist and specialized taste and smell clinic may also be considered.

• Fatigue
  • A Consensus Guidance Statement provides practical guidance to clinicians in the treatment of fatigue in postacute sequelae of SARS‐CoV‐2 infection (PASC) patients.
    • Conservative management
      • 1) Initiation of an individualized and structured, titrated return to activity program (individualized rehabilitation)
        • The goal of such a rehabilitation program should be restoring patients to their previous levels of activity and improve quality of life
        • The titration approach ensures that patients are engaged in activities at a submaximal level to avoid exacerbation of fatigue.
        • Level of activity should be adjusted according to change in fatigue-related symptoms that develop during or after activity.
      • 2) Educating patients on energy conservation strategies
      • 3) Encouraging a healthy diet and adequate hydration
      • 4) Treatment of any underlying medical conditions such as pain, insomnia/sleep disorders (including poor sleep hygiene), and mood problems that may be contributing and/or aggravating fatigue.
    • Pharmacologic therapy and supplements
      • A number of herbal remedies/supplements and pharmacologic agents have been used in the treatment of chronic fatigue in other causes of chronic illness (eg, multiple sclerosis, fibromyalgia, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), cancer, brain injury, and Parkinson's disease).
      • These include:
        • Branched‐chain amino acids
        • Omega 3 fatty acids
        • Vitamin B12
        • Vitamin C
        • Vitamin D
        • Magnesium
        • L‐carnitine
        • Coenzyme Q10
        • Ginseng
        • Echinacea
        • Amantadine
        • Modafinil
        • Methylphenidate
        • Antivirals/antibiotics/antiparasitics
        • Antidepressants
        • Cytokine inhibitors
        • Galantamine
        • Glucocorticoids
        • Immunoglobulins
        • Rituximab
      • However, it should be noted that due to limited scientific evidence, currently there is no general consensus on routine administration of these supplements/medications. Thus, they may be considered on a case‐by‐case basis.
      • Other therapeutic interventions such as acupuncture have been suggested in the treatment of fatigue.

• Weight loss
  • In patients with long COVID, weight loss is multifactorial and may occur due to a combination of malnutrition, loss of appetite, catabolic state, swallowing difficulty, and alterations in taste and smell.
  • Patients should be encouraged to eat small, frequent meals with protein and calorie supplementation. Nutrition consultation and referral to a dietician may be required in selected patients with severe weight loss.

• Psychological and emotional issues
  • In patients experiencing emotional distress, mood disturbances, anxiety, or symptoms of post-traumatic stress disorder, mental health assessment and possible referral to a psychiatrist may be required.
  • Cognitive behavioral therapy may benefit patients with anxiety, depression and stress.
  • Neurocognitive concerns may benefit from hyperbaric oxygen

• Alopecia
  • There is no specific therapy for alopecia in COVID-19 patients, and it should be managed similarly to non-COVID-19 patients.
  • In patients with concomitant malnutrition, nutritional deficiencies should be corrected.

• Insomnia
  • All patients with insomnia should be educated on sleep hygiene guidelines, stimulus control instructions, and relaxation techniques. Short-term pharmacologic treatment with benzodiazepines or non-benzodiazepine hypnotics may be needed in selected patients.

Primary Prevention

The most effective measure to prevent the post-COVID-19 condition is to prevent COVID-19. These primary prevention strategies include:

• Vaccination
• Masking
• Social distancing
• Hand hygiene

Secondary Prevention

There are no established measures for the secondary prevention of long COVID.