Post–COVID-19 Conditions

Key Points

• PASC (post-acute sequelae of COVID-19) is defined by US Department of Health and Human Services in collaboration with CDC and other partners as persistent symptoms of COVID-19 that can vary across systems, occurring at least 4 weeks after acute COVID-19 infection, and which cannot be explained by another etiology^1,10
  • WHO definition of post–COVID-19 condition (long COVID) differs such that new or continuing symptoms of COVID-19 must be present at least 12 weeks after initial SARS-CoV-2 infection and last for at least 2 months with no other explanation to make the diagnosis²
• Common PASC symptoms include fatigue, brain fog, chest pain, shortness of breath, cough, muscle pains, neuropathy, headache, depression, anxiety, PTSD, new rash, sinus congestion, loss of taste and smell, insomnia, diarrhea, acid reflux, palpitations, dizziness, and vision changes
• The type and duration of PASC symptoms can vary for each patient
• Initial workup of PASC should focus on ruling out underlying medical conditions that may have similar clinical presentation
• Treatment of PASC focuses on symptomatic management and supportive care at this time
• Treatment of acute COVID-19 with nirmatrelvir-ritonavir and vaccination for prevention of COVID-19 should be emphasized as a potential strategy for prevention of PASC
• Research into drug therapy for treatment of PASC is currently being pursued
• Close monitoring of symptoms and support of patient, including assistance with access to disability assistance when needed, are important components of patient management for the primary provider

Terminology

• PASC (postacute sequelae of COVID-19)
  • Also known as long COVID, long-haul COVID, or chronic COVID
  • New, persistent, or relapsing symptoms of COVID-19 occurring at least 4 weeks after initial COVID-19 infection; may last for various amounts of time and cannot be explained by another etiology¹
  • Persistent symptoms can vary in severity and can present as either a single symptom or a combination of various symptoms^1,2

Epidemiology

• Prevalence is estimated at around 40% for those with any PASC symptom; prevalence of severe debilitation is estimated at 5%³
  • An estimated 16 million Americans likely suffer from some form of PASC, with around 4 million out of work as a result³
• Greater predominance in female patients⁴
• No clear association with a particular ethnic group

Etiology and Risk Factors

Approach to Diagnosis

• There is no single PASC syndrome: each case is unique and requires individualized evaluation and management
• Diagnosis of PASC is based on the following:
  • WHO defines post–COVID-19 condition (ie, long COVID) as new or continuing symptoms of COVID-19 at least 12 weeks after initial SARS-CoV-2 infection with symptoms persisting for at least 2 months with no other explanation²
    • Definition acknowledges that it may take up to 3 months for symptoms of acute COVID-19 illness to fully resolve in some cases
  • US Department of Health and Human Services in collaboration with CDC and other partners define post–COVID conditions as follows:^1,10
    • Symptoms of COVID-19 persisting at least 4 weeks after a previous SARS-CoV-2 infection and lasting for various amounts of time
    • Symptoms may wax and wane in intensity and cannot be related to an alternative diagnosis
    • Symptoms may include (Figure 1):
      • General
        • Fatigue, including PEM (postexertional malaise): symptoms that get worse after physical or mental effort¹
        • Insomnia
        • Fevers
        • Weight changes
        • Poor appetite
        • Easy bruising or bleeding
        • Changes to menstrual cycle
        • Rashes
        • Urinary frequency¹¹
        • New or worsening sinus congestion
      • Cardiopulmonary
        • Shortness of breath with exertion or at rest
        • Chest pain or tightness
        • Palpitations
        • Peripheral edema
        • Cough
      • Neuropsychiatric
        • Difficulty thinking or concentrating, sometimes referred to as "brain fog"¹
          • Concentration deficits
          • Memory loss
        • Headaches (new onset or worsening from prior)
        • Dizziness
        • Neuropathy
          • Mononeuropathies
          • Small fiber neuropathies
        • Loss or change in taste or smell (isolated or together)
        • Depression, anxiety, and/or PTSD (posttraumatic stress disorder)
        • Sleep problems
      • Audiovestibular
        • Tinnitus
        • Hearing loss¹²
      • GI (gastrointestinal)
        • Diarrhea
        • Vomiting
        • Nausea
        • Abdominal distention
        • Acid reflux
        • Abdominal pain or discomfort
      • Musculoskeletal
        • Joint pains
        • Muscle aches
        • Weakness
    • Requires exclusion of other conditions that may have similar clinical presentation:
      • Confirmatory laboratory or imaging studies that would support an alternative diagnosis
      • Post–COVID-19 vaccine-related sequelae
      • Symptoms that may have preceded COVID-19 infection and have not changed in severity or character since COVID-19 infection
• 4 phenotypic subtypes of PASC have been identified in a study involving over 30,000 COVID-19 positive patients with PASC:¹³
  • Subphenotype 1: Cardio-renal
    • Classified as primarily having cardiac and pulmonary symptomatology, acute renal failure, anemia, and fluid/electrolyte disturbances
  • Subphenotype 2: Respiratory, sleep, and anxiety
    • Classified as primarily having respiratory issues, sleep disorders, anxiety issues, headaches, and chest pain
  • Subphenotype 3: Musculoskeletal and nervous
    • Classified as primarily having musculoskeletal pain, headaches, and sleep disorders
  • Subphenotype 4: Digestive and respiratory
    • Primarily digestive and respiratory conditions

History

• Obtain detailed history of COVID-19 infection, including any need for hospitalization, COVID-19 treatments utilized, and COVID-19 vaccination status in order to properly assess risk of PASC
• Assess for timing and characterization of symptoms to distinguish from acute COVID-19 infection
  • Symptoms of acute COVID-19 infection typically resolve within a few days to a few weeks^2,14,15
  • Symptoms of PASC may be new, worsening, or exhibit a relapsing-remitting pattern
  • Symptoms of PASC may be multisystemic
  • Associated with decreased quality of life
• A positive COVID-19 test result is not required for diagnosis due to limited testing availability early in the pandemic; probable or suspected clinical diagnosis of COVID-19 can be made based on medical history
• If patients note their diagnosis of COVID-19 was made clinically early in the pandemic when testing was limited, ensure their symptoms did not start before December 2019
• Assess for the following symptoms:
  • Fatigue
    • Most common symptom, noted in 34% to 46% of PASC cases¹⁶
    • Symptoms may be similar to those of myalgic encephalitis/chronic fatigue syndrome, which require the following for diagnosis:¹⁷
      • Persistent fatigue impairing ability to work, go to school, or have a social life for at least 6 months
      • PEM, described as "crashing"
      • Nonrestorative sleep
      • Must additionally have 1 of the following:
        • Concentration or memory difficulties
        • Orthostatic intolerance
  • Persistent fevers that come and go with flares of symptoms¹⁸
    • Rashes¹⁹
      • Hives
      • Papulosquamous eruptions
      • COVID toes: chilblains or pernio-like painful, red inflammation of toes associated with COVID-19 infection²⁰
  • Tinnitus²¹
    • New onset or worsened from prior
  • Hearing loss
    • New onset or worsened from prior
    • Primarily sensorineural hearing loss due to hampering of cochlear function¹²
  • Sinus congestion
    • New onset or worsened from prior
  • Vision changes²²
    • Most common complaint is blurry vision not associated with vision loss that persists for at least 28 days following a positive COVID test result
    • Serious manifestations may include retinal vein occlusion with associated macular edema and, rarely, retinal artery occlusion and ocular inflammation
  • Shortness of breath
    • May present as dyspnea on exertion, orthopnea, or shortness of breath at rest; may be associated with cough, chest discomfort, or wheezing
    • Important underlying etiologies known to be associated with COVID-19 infection, such as pulmonary embolism, should be ruled out
      • A recent self-controlled case series in Sweden demonstrated that incidence rate ratios for pulmonary embolism increased up to 110 days after COVID-19 infection, particularly in those with severe infection or comorbidities, though risk is highest in acute phase²³
  • Chest pain
    • Pain or tightness may be intermittent or persistent with worsening flares
    • American College of Cardiology categorizes patients with chest pain following COVID-19 infection as:²⁴
      • PASC-CVD (cardiovascular disease): chest pain symptoms in patients with discernable cardiovascular issues
        • Myocarditis
        • Myocardial involvement
        • Myocardial injury
      • PASC-CVS (cardiovascular syndrome): chest pain symptoms in patients whose cardiovascular testing remains normal
  • Palpitations
    • May be intermittent and flare with uncontrolled anxiety
    • May be associated with POTS (postural orthostatic tachycardia syndrome)²⁵
      • Defined as a 30-beats-per-minute rise in heart rate after standing for 10 minutes with no associated hypotension
      • Incidence of approximately 2% to 14% of COVID-19 survivors, with up to 61% experiencing POTS-like symptoms, including tachycardia and orthostatic intolerance
      • May present as palpitations upon standing
    • Atrial fibrillation is most common arrhythmia that can present after COVID infection²⁶
      • More commonly seen in patients with severe COVID-19 requiring hospitalization
  • Lower extremity (peripheral) edema
    • Consider deep vein thrombosis or myocarditis in differential diagnosis
      • A recent self-controlled case series in Sweden demonstrated significantly increased incidence rate ratios for deep vein thrombosis up to 70 days after COVID-19 infection²³
  • Brain fog
    • Initial cohort study on the long-term impact of COVID-19 on cognition determined an overall incidence of cognitive impairment in survivors 12 months post discharge of 12.45%²⁷
      • Cognitive deficits were more severe as determined by Telephone Interview of Cognitive Status-40 scores for individuals with severe COVID-19 as opposed to nonsevere cases and control (uninfected) individuals (median interquartile range: severe, 22.50 [16.00-28.00]; nonsevere, 30.00 [26.00-33.00]; control, 31.00 [26.00-33.00]) at 1-year follow-up²⁷
      • History of severe infection was also associated with a higher risk of early-onset (odds ratio, 4.87; 95% CI, 3.30-7.20) , late-onset (odds ratio, 7.58; 95% CI, 3.58-16.03), and progressive cognitive decline (odds ratio, 19.00; 95% CI, 9.14-39.51)²⁷
    • Frontal lobe dysfunction may present as executive dysfunction or concentration deficits
  • Headaches
    • New onset or worsened from prior
    • Consist primarily of migraine or tension-type headaches²⁸
    • Associated with activation of trigeminovascular circuits²⁸
  • Dizziness
    • Consider cardiac versus neurologic etiology
    • May be associated with underlying arrhythmia or syndrome (eg, POTS, orthostatic hypotension)
    • Vertigo
    • Balance issues
  • Neuropathy
    • Mononeuropathies or polyneuropathies²⁹
      • May result from infection-associated immune dysregulation
      • Small fiber neuropathy
        • Often first symptom of PASC, beginning within 1 month of COVID-19 infection²⁹
        • Pins-and-needles sensations, tingling, and hyperalgesia throughout the body
        • Additional symptoms may include orthostatic intolerance, urinary difficulties, GI issues, abnormal sweating, dry eyes or mouth, and palpitations
  • Loss of taste and smell³⁰
    • A meta-analysis with parametric cure modelling of recovery curves identified persistent self-reported loss of taste and smell in approximately 5% of patients post–COVID-19³⁰
      • Females were less likely than males to recover their sense of smell and taste; patients with more severe dysfunction or having nasal congestion are less likely to recover³⁰
  • Psychiatric disorders including depression, anxiety, and PTSD
  • GI symptoms include gastroesophageal reflux disease, nausea, vomiting, constipation, diarrhea, abdominal distention and pain³¹
    • Can include hepatic issues, including cholangiopathy as well as pancreatitis
  • Myalgia
    • Vague without localization to specific muscles or specific joints
    • Fibromyalgia can be present in up to 30% of patients³²

Physical Examination

• Perform comprehensive physical examination, noting any pertinent findings that may reveal an underlying medical condition or indicate a possible diagnosis of PASC
  • In patients with chest pain, shortness of breath, or fatigue, obtain:
    • Vital signs, including orthostatic vital signs, to assess for presence of arrhythmia and to rule out orthostatic hypotension or evidence of POTS
    • Pulse oximetry to assess for hypoxia, which could indicate an underlying pulmonary condition such as pulmonary fibrosis or pulmonary embolism
    • Pulmonary examination to evaluate for crackles or wheezing, which could indicate underlying pulmonary or cardiac issue
    • Cardiac examination to include evaluation for lower extremity edema to rule out heart failure or deep vein thrombosis
  • In patients with palpitations, evaluate for:
    • Arrhythmia or murmur suggestive of underlying valve issue
  • Evaluate skin for:
    • Hives present in mast cell activation syndrome
    • Chilblains, which could indicate a vascular or rheumatologic pathology
    • Cellulitic features as possible source of persistent fevers
  • In patients with neuropathy, evaluate:
    • Deep tendon reflexes to rule out other hyporeflexia syndromes
    • Tinel or Phalen test to rule out carpal tunnel syndrome
  • In patients with new-onset or worsening headaches:
    • Cranial nerve examination and evaluate for focal neurologic deficit to ensure no other signs of possible cerebrovascular accident or cranial nerve pathology
  • In patients with dizziness, evaluate:
    • Orthostatic vital signs to rule out possible orthostatic hypotension
    • Nystagmus to evaluate for possible benign paroxysmal positional vertigo
  • In patients with GI symptoms, evaluate for:
    • Abdominal tenderness as possible sign of other primary GI pathology including colitis or gastric ulcer

Laboratory Tests

• Obtain laboratory testing based on presenting symptoms and alternative diagnoses with similar presentation under consideration when making diagnosis of PASC (Table 1)

• Table 1. Recommended laboratory testing to evaluate for PASC.

  ANA, antinuclear antibody; BMP, basic metabolic panel; CMP, complete metabolic panel; EBV, Epstein-Barr virus; GI, gastrointestinal; PASC, postacute sequelae of COVID-19; RPR, rapid plasma reagin; SIBO, small intestinal bacterial overgrowth.

  Symptoms	Laboratory test	Alternative diagnoses in consideration
  Fatigue	CBC	Anemia
  	TSH	Thyroid disease
  	Vitamin B12	Vitamin B12 deficiency as possible source of anemia
  	Vitamin D	Vitamin D deficiency
  	CMP	Electrolyte abnormalities, kidney or liver dysfunction
  	Hemoglobin A1C	New-onset hyperglycemia or diabetes
  	HIV, RPR, hepatitis C	Alternative infectious etiologies of symptomatology
  Persistent fevers	CBC	Leukocytosis associated with underlying infection
  	Blood cultures	Evaluate for bacteremia
  	Urine studies	Urinary tract infection
  	Stool studies	If having diarrhea, could be related to parasitosis or bacterial GI infection
  Brain fog Memory impairment	CBC	Anemia
  	TSH	Thyroid disease
  	CMP	Electrolyte abnormalities
  	HIV, RPR, hepatitis C	Alternative infectious etiologies of symptomatology
  	Vitamin D, B12, B1, B6	Vitamin deficiencies
  Joint aches Muscle pains	ANA	Autoimmune disorder
  	Immunoglobulins	Immunoglobulinopathies
  Small fiber neuropathy	Vitamin B12	Vitamin B12 deficiency
  	BMP	Electrolyte abnormalities
  	ANA	Autoimmune diseases
  	CBC	Anemia, leukopenia
  	TSH	Thyroid disease
  	Hemoglobin A1C	New-onset hyperglycemia or diabetes
  	HIV, Lyme titers, EBV, hepatitis C	Alternative infectious etiologies of symptomatology
  GI symptoms: bloating, dyspepsia	Helicobacter pylori	Helicobacter pylori infection
  	SIBO breath test	SIBO
  GI symptoms: diarrhea	Clostridium difficile	Clostridium difficile infection
  	Bacterial stool culture	Possible bacterial source of diarrhea (eg, salmonella, shigella)
  	COVID-19 viral quantification for stool (consider in immunocompromised individuals)	Persistent viral reserve of COVID-19 in GI tract
  Shortness of breath Chest pain	High sensitivity troponin	Cardiac ischemia

Imaging Studies

• Consider the following imaging tests to rule out alternative diagnoses for long COVID
  • Shortness of breath
    • Obtain chest radiograph to evaluate for infectious process
    • Consider high-resolution chest CT if history of hospitalization for COVID-19
    • Obtain CT angiogram to rule out pulmonary embolus if clinically indicated given increased risk of venous thromboembolism following COVID-19 infection³³
    • Consider transthoracic echocardiogram if concern for cardiac etiology of shortness of breath
  • Chest pain and palpitations
    • American College of Cardiology consensus guidelines recommend ECG, high sensitivity troponin, and transthoracic echocardiogram for all symptomatic patients²⁴
  • Lower extremity edema
    • Consider lower extremity duplex ultrasonography to evaluate for possible venous thromboembolism
    • Consider transthoracic echocardiogram to evaluate for heart failure
  • Tinnitus/vertigo
    • Consider MRI of intra-auricular canals
  • Brain fog
    • Consider MRI of brain with and without contrast

Diagnostic Procedures

• While the following tests are not diagnostic for long COVID, they can help to identify treatable conditions and rule out alternative diagnoses:³⁴
  • Shortness of breath
    • Consider 6-minute walk test to elucidate if hypoxia or tachycardia are noted during ambulation
    • Consider PFT (pulmonary function testing) to evaluate for other primary lung conditions (eg, COPD or asthma)
    • In-clinic spirometry can provide information to help clarify diagnosis of COPD or asthma
  • Palpitations
    • Evaluate for arrhythmias with ECG and consider further evaluation with ambulatory cardiac monitor
  • Neuropathy
    • Consider skin biopsy for definitive diagnosis of small fiber neuropathy
    • Consider autonomic reflex screen to assist in making diagnosis of dysautonomia, which often correlates with small fiber neuropathy
    • Obtain EMG to further evaluate symptoms consistent with peripheral neuropathy
  • Hearing loss
    • Perform audiology screening to evaluate for hearing loss
  • Dysautonomia
    • Consider autonomic reflex screen to assist in making definitive diagnosis of dysautonomia
    • NASA lean test can be performed in clinic to evaluate for POTS
  • GI symptoms
    • Obtain colonoscopy to evaluate for concerning GI symptoms and to rule out conditions such as inflammatory bowel disease or colon cancer
    • Obtain esophagogastroduodenoscopy to evaluate etiology of upper GI symptoms (eg, esophagitis, gastric ulcer)
    • Obtain CT of abdomen/pelvis with contrast to evaluate for lower GI symptoms (eg, masses, colitis)
  • Dizziness
    • Perform Dix-Hallpike maneuver to evaluate for benign paroxysmal positional vertigo
  • Insomnia/fatigue
    • Obtain sleep study to evaluate for sleep apnea or other sleep disorders (eg, narcolepsy, parasomnias, restless leg syndrome)

Other Diagnostic Tools

• Additional screening tools and assessments can be used to assess the degree to which symptoms of PASC are impacting a patient’s quality of life (Table 2)³⁴

• Table 2. Assessment tools to evaluate patients with PASC.

  COMPASS, Composite Autonomic Symptom Score; GAD, general anxiety disorder; HVLT, Hopkins Verbal Learning Test; MMSE, Mini-Mental State Examination; MOCA, Montreal Cognitive Assessment; PASC, postacute sequelae of COVID-19; PHQ-9, Patient Health Questionnaire; PSQI, Pittsburgh Sleep Quality Index; PTSD, posttraumatic stress disorder; STOP-Bang, snoring, tired, observed, pressure, body, age, neck, gender.

  Data from US Department of Veterans Affairs. Whole Health System Approach to Long COVID Patient-Aligned Care Team (PACT) Guide. August 1, 2022. Accessed November 22, 2022. https://www.publichealth.va.gov/n-coronavirus/docs/Whole-Health-System-Approach-to-Long-COVID_080122_FINAL.pdf.

  Symptom	Test	Description
  Fatigue	Fatigue Assessment Scale	Assessment for level of fatigue Can be monitored over time for improvement
  	WHO Disability Assessment Schedule	Assessment for how symptomatology is affecting quality of life Can be monitored over time for improvement
  	PHQ-9	Assessment for depression
  	GAD-7	Assessment for anxiety
  Dysautonomia	COMPASS-31	Can help ascertain if patients have dysautonomia and if additional screening, such as autonomic reflex screening, is indicated for patients with a myriad of symptoms
  Insomnia	STOP-Bang	Evaluation for sleep apnea
  	Epworth Sleepiness Scale	Assessment of disability as a result of insomnia and fatigue
  	PSQI	Assessment etiology of insomnia
  Brain fog	MMSE	Evaluation for dementia
  	MOCA
  	HVLT	Assessment for short-term memory loss
  Neuropsychiatric symptoms	PHQ-9	Assessment for depression
  	GAD-7	Assessment for anxiety
  	PTSD Checklist for DSM-5	Assessment for PTSD

Approach to Treatment

• Treatment for PASC is typically supportive and based on patient’s presenting symptoms

Nondrug and Supportive Care

• Fatigue and PEM⁴¹
  • Multidisciplinary collaborative consensus guidance statement on the assessment and treatment of fatigue in patients with PASC recommends developing a structured, individualized, and titrated return-to-activity program
    • Avoid high-intensity exercise or heavy weightlifting, which may worsen fatigue and precipitate PEM
    • Employ energy conservation strategies
  • Encourage a well-balanced diet with adequate hydration
    • Currently no scientific data supporting one specific diet
  • Consider acupuncture
    • Preliminary low-quality evidence supports use of acupuncture in chronic fatigue syndrome, though there is as of yet no direct evidence to support its use in PASC-related fatigue⁴²
  • Treat underlying medical conditions contributing to fatigue, including insomnia, poor sleep hygiene, and mood disorders
• POTS⁴³
  • Consider POTS-specific graded exercise program, including Levine protocol
    • Focus on recumbent exercises with gradually increased incline
  • Compression garments
  • Adequate salt and fluid intake
  • Physical counter maneuvers and biofeedback therapy
• Mood disorders
  • Recommend cognitive behavioral therapy under consultation with mental health specialists as indicated for patients with depression, anxiety, and PTSD related to COVID-19 infection
  • Provide patients with resources for available patient advocacy and peer support groups
• Cognitive dysfunction (ie, brain fog)
  • Consider referral for cognitive rehabilitation therapy, particularly in ICU survivors⁴⁴
• Loss of taste and smell
  • Limited evidence is available on efficacy of treatments for persistent olfactory dysfunction following COVID-19 infection⁴⁵
  • Consider olfactory retraining in those patients with loss of smell for greater than 2 weeks’ duration⁴⁶

Drug Therapy

• There are no approved drug treatments specific to long COVID at this time
• Symptomatic management is recommended
  • Fatigue
    • Replete vitamin deficiencies
    • Consider use of supplements suggested to alleviate chronic fatigue in other causes of chronic illness, including branched‐chain amino acids, coenzyme Q₁₀, echinacea, ginseng, L-carnitine, magnesium, omega-3 fatty acids, and vitamins B₁₂, C, and D⁴¹
      • Consider the use of fish oil 1000 mg with EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid) daily; avoid in patients who are on blood thinners or who suffer from acid reflux³⁴
      • Use of these supplements should be considered on a case-by-case basis; there is currently no consensus on their dosage or use with limited scientific evidence available at this time⁴¹
    • In a single-center uncontrolled study of 52 participants, improvement in self-reported limitation in activities of daily living, energy levels, and overall recovery from COVID-19 was noted with the use of low-dose naltrexone as follows:⁴⁷
      • Initial dose 1 mg daily for 1 month, increasing by 1 mg each month up to a maximum dose of 3 mg daily (eg, 1-2-3 mg approach)
      • Must be compounded at a compounding pharmacy
      • Close monitoring for GI symptoms is recommended
  • POTS^24,25
    • Midodrine: 2.5 to 10 mg 3 times daily for orthostatic intolerance and venous pooling
    • β-blockers or nondihydropyridine calcium channel blockers for tachycardia
      • Propranolol: 10 to 20 mg 4 times daily
      • Diltiazem or verapamil (titrated dosing for symptoms)
      • Contraindicated in those with bradycardia
    • Fludrocortisone: 0.1 to 0.2 mg at bedtime for hypovolemia, orthostatic intolerance
    • Ivabradine: 2.5 to 7.5 mg twice daily for tachycardia and fatigue; often used when intolerant to atrioventricular nodal blockers
    • IV saline: 2 liters over 2 to 3 hours for acute hypovolemia
  • Depression, anxiety, and PTSD
    • Antidepressants are primary part of medication management as indicated for individual mood disorders
  • Insomnia
    • Consider use of hypnotics on a case-by-case basis as recommended in American Academy of Sleep Medicine clinical practice guidelines for the pharmacologic treatment of chronic insomnia in adults^48,49
      • Melatonin agonists
        • Ramelteon: 8 mg at bedtime for sleep-onset insomnia
      • Heterocyclics
        • Doxepin: 3 to 6 mg at bedtime for sleep-maintenance insomnia
      • Orexin receptor antagonists
        • Suvorexant: 10 to 20 mg at bedtime for sleep-maintenance insomnia
      • Benzodiazepine receptor agonists (reduce dose by half in older patients)
        • Eszopiclone: 0.2 to 0.3 mg at bedtime for sleep-onset or sleep-maintenance insomnia
        • Zaleplon: 0.10 mg at bedtime for sleep-onset insomnia
        • Zolpidem: 10 mg at bedtime for sleep-onset or sleep-maintenance insomnia
      • Benzodiazepines
        • Triazolam: 0.25 mg at bedtime for sleep-onset insomnia
        • Temazepam: 0.15 mg at bedtime for sleep-onset or sleep-maintenance insomnia
    • Note duration of treatment should be as brief as possible (less than 4 weeks)⁴⁸
  • Small fiber neuropathy⁵⁰
    • α-Lipoic acid (at least 300 mg daily) is a powerful antioxidant
    • Acetyl-L-carnitine: 500 to 1000 mg 3 times daily promotes peripheral nerve regeneration
    • Replete vitamin deficiencies as appropriate on a case-by-case basis, in particular vitamins D, B₁, B₆, and B₁₂
    • Duloxetine: 20 to 60 mg daily
    • Gabapentin: 300 to 1200 mg 3 times daily
    • Pregabalin: 25 to 75 mg daily
    • Venlafaxine: 37.5 to 150 mg daily
  • Cough (if determined to be nonpulmonary, nonlaryngeal)⁵¹
    • Amitriptyline: 10 to 25 mg
    • Montelukast: 10 mg daily⁵²
  • Shortness of breath
    • If PFT results are abnormal, treat accordingly for identified respiratory condition (ie, asthma, COPD)
    • If PFT results are normal, consider further evaluation and management of possible PFT-negative COPD or asthma
  • GI symptoms
    • Consider treatment of acid reflux with H₂-blockers or proton pump inhibitors
    • Consider bowel regimen to regulate bowel movements
    • Consider amitriptyline (50 mg daily) or buspirone (10 mg 3 times daily), which have both shown some efficacy in the treatment of functional dyspepsia^53,54
  • Headaches³⁴
    • Riboflavin: 400 mg every morning with food
    • Magnesium oxide: 420 mg every evening
  • Loss of taste and smell⁴⁶
    • Recommend intranasal corticosteroid spray (eg, fluticasone propionate nasal spray 93 mcg/spray) as first line treatment
    • Alternative options include topical intranasal corticosteroid drops or rinses
    • Recommend against vitamin A drops, α-lipoic acid, oral corticosteroids
  • Brain fog
    • A small, combined open-label trial of participants with long COVID brain fog noted improved cognitive abilities in 8 of 12 participants with combined treatment with guanfacine and N-acetylcysteine⁵⁵
      • Guanfacine: 1 mg PO at bedtime for first month, increased to 2mg after 1 month, if well-tolerated, and 600 mg N-acetylcysteine daily⁵⁵
      • Further placebo-controlled trials are necessary to definitively establish efficacy

Treatment Procedures

• No approved treatment procedures specific to PASC
• Consider TMS (transcranial magnetic stimulation) under expert consultation for severe major depression or tinnitus when indicated⁵⁶
  • Involves noninvasive brain stimulation utilizing changing magnetic fields to create an electric current directed to a specific portion of the brain

Persistent or Recurrent Disease

• Symptoms can last for weeks to years and can wax and wane in their intensity
• Symptoms can initially resolve and return after exposure to an identifiable or unidentifiable stressor
  • Increased life stressors
  • Infections, including colds, influenza or influenza-like illnesses, or recurrent COVID infection

Admission Criteria

• Worsening hypoxia
• New thromboembolic complication
  • Pulmonary embolism
  • Cerebrovascular accident
  • Myocardial infarction

Post-Vaccination Symptomatology

• Obtain medical history of symptoms to determine if they are related to prior COVID infection versus COVID vaccination
  • It is unclear if "long post–COVID-vaccination syndrome" shares the same pathophysiology as PASC and research is ongoing^57,58

Recurrent COVID Infections

• A study compared 5 million patients with no prior COVID infection with those having had 1 or more infections (443,588 versus 40,947, respectively) and found that those with history of at least 1 prior COVID infection had:⁵⁹
  • Higher all-cause mortality
  • Higher probability of at least 1 symptom of PASC at 6 months post infection

Monitoring

• Many patients will improve with time, but close follow-up and coordination of care with subspecialists, as needed, is recommended
• Consider frequent follow-up appointments (eg, every 4 to 6 weeks) to provide patients with adequate support throughout chronic illness

Complications

• Long-term sequelae can lead to significant disability requiring healthcare provider assistance in securing accommodations for employment and school to allow for recuperation
• Some patients may meet criteria to pursue long-term disability due to this diagnosis

Prognosis

• Limited data are currently available on long-term prognosis of PASC
• In a nonrepresentative study of 668 patients, the majority of hospitalized and nonhospitalized patients continued to have at least 1 symptom of PASC 2 years after their initial COVID infection⁶⁰
  • Most persistent symptoms noted were fatigue, memory loss, and pain

Referral

• Consider cardiology consultation if clinical findings are concerning for myocarditis, arrhythmia, or other cardiovascular sequelae
• Consider pulmonary consultation for pulmonary rehabilitation if indicated or if clinical findings are consistent with possible pulmonary fibrosis, COPD, or asthma⁶¹
• Consider neuropsychiatric consultation if cognitive symptoms are debilitating or fail to improve or cognitive testing screening is abnormal
• Consider psychiatric consultation for patients with signs and symptoms of severe depression, anxiety, or PTSD
• Consider rheumatologic consultation to rule out underlying autoimmune conditions with persistent associated joint or muscle pain
• Refer patients with ongoing physical limitations related to PASC to appropriate rehabilitation specialists⁶¹
• Refer patients to appropriate social services for assistance with access to disability assistance when indicated

Screening

• Refer for age-appropriate routine preventative health screenings

Prevention

• Nirmatrelvir-ritonavir
  • A US Department of Veterans Affairs study of over 9000 patients suggested the use of nirmatrelvir-ritonavir during treatment of acute COVID-19 may prevent PASC symptomatology⁶²
  • A cohort US Department of Veterans Affairs study of over 280,000 COVID-19-positive patients who had at least 1 risk factor for complication of COVID-19 were prescribed nirmatrelvir-ritonavir and had a reduced risk of subsequent PASC symptoms (relative risk, 0.74; 95% CI, 0.72-0.77; absolute risk reduction, 4.51%; 95% CI, 4.01-4.99)⁶³
• A meta-analysis of 11 COVID vaccination studies showed vaccines reduce risk of developing PASC in at least 6 of the studies, thus providing moderate evidence to suggest vaccination as a potential strategy for PASC prevention⁶⁴