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    Post–COVID-19 Conditions

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    Sep.20.2023

    Post–COVID-19 Conditions

    Summary

    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 etiology1,10
      • 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

    Basic Information

    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 symptoms1,2

    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

    Etiology

    • No clear etiology has been identified
    • 5 proposed etiologies:
      • Persistent viral reserve in tissue causing immune perturbation5
      • Autoimmune-type reaction causing persistent inflammatory response6
      • Circulating "micro-clots" blocking microcapillaries and inhibiting oxygenation7
      • Immune dysregulation, with or without reactivation of latent virus8
      • Dysfunctional neurologic signaling8

    Risk Factors

    • Patients with severe illness or hospitalization due to COVID-191
    • Patients with underlying chronic medical illness1
    • Unvaccinated patients1
    • Patients who suffered from multisystem inflammatory syndrome while infected with COVID-191
    • Female patients8
    • Type 2 diabetes8
    • Possibly prior Epstein-Barr virus infection8
    • Connective tissue disease8
    • ADHD (attention deficit/hyperactivity disorder)8
    • Chronic urticaria8
    • Lower socioeconomic status8
    • Inadequate rest after acute COVID-19 infection8
    • Possible greater incidence related to earlier COVID-19 variants, although difficult to prove due to possible confounding factors (eg, available vaccinations)9

    Diagnosis

    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

    Workup

    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 weeks2,14,15
      • 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.
      SymptomsLaboratory testAlternative diagnoses in consideration
      FatigueCBCAnemia
      TSHThyroid disease
      Vitamin B12Vitamin B12 deficiency as possible source of anemia
      Vitamin DVitamin D deficiency
      CMPElectrolyte abnormalities, kidney or liver dysfunction
      Hemoglobin A1CNew-onset hyperglycemia or diabetes
      HIV, RPR, hepatitis CAlternative infectious etiologies of symptomatology
      Persistent feversCBCLeukocytosis associated with underlying infection
      Blood culturesEvaluate for bacteremia
      Urine studiesUrinary tract infection
      Stool studiesIf having diarrhea, could be related to parasitosis or bacterial GI infection
      Brain fog

      Memory impairment
      CBCAnemia
      TSHThyroid disease
      CMPElectrolyte abnormalities
      HIV, RPR, hepatitis CAlternative infectious etiologies of symptomatology
      Vitamin D, B12, B1, B6Vitamin deficiencies
      Joint aches

      Muscle pains
      ANAAutoimmune disorder
      ImmunoglobulinsImmunoglobulinopathies
      Small fiber neuropathyVitamin B12Vitamin B12 deficiency
      BMPElectrolyte abnormalities
      ANAAutoimmune diseases
      CBCAnemia, leukopenia
      TSHThyroid disease
      Hemoglobin A1CNew-onset hyperglycemia or diabetes
      HIV, Lyme titers, EBV, hepatitis CAlternative infectious etiologies of symptomatology
      GI symptoms: bloating, dyspepsiaHelicobacter pyloriHelicobacter pylori infection
      SIBO breath testSIBO
      GI symptoms: diarrheaClostridium difficileClostridium difficile infection
      Bacterial stool culturePossible 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 troponinCardiac 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.
      SymptomTestDescription
      FatigueFatigue Assessment ScaleAssessment for level of fatigue



      Can be monitored over time for improvement
      WHO Disability Assessment ScheduleAssessment for how symptomatology is affecting quality of life



      Can be monitored over time for improvement
      PHQ-9Assessment for depression
      GAD-7Assessment for anxiety
      DysautonomiaCOMPASS-31Can help ascertain if patients have dysautonomia and if additional screening, such as autonomic reflex screening, is indicated for patients with a myriad of symptoms
      InsomniaSTOP-BangEvaluation for sleep apnea
      Epworth Sleepiness ScaleAssessment of disability as a result of insomnia and fatigue
      PSQIAssessment etiology of insomnia
      Brain fogMMSEEvaluation for dementia
      MOCA
      HVLTAssessment for short-term memory loss
      Neuropsychiatric symptomsPHQ-9Assessment for depression
      GAD-7Assessment for anxiety
      PTSD Checklist for DSM-5Assessment for PTSD

    Differential Diagnosis

    • Table 3. Differential Diagnosis: PASC.GI, gastrointestinal; PASC, postacute sequelae of COVID-19; PEM, postexertional malaise; POTS, postural orthostatic tachycardia syndrome; PTSD, posttraumatic stress disorder.
      ConditionDescriptionDifferentiated by
      Myalgic encephalitis/chronic fatigue syndrome35More common in females than males (4:1), primarily individuals between ages 40-60 years, occurring in all ethnic groups

      Can also exist as part of patient’s PASC
      Persistent fatigue impairing ability to work, go to school, or have a social life for at least 6 months

      PEM can present as "crashing"

      Nonrestorative sleep

      Must have 1 of the following 2 symptoms in addition to above:
      • Concentration or memory difficulties
      • Orthostatic intolerance
      If symptoms are isolated and not related to other PASC symptoms, unlikely to be PASC

      May have overlap in pathophysiology with PASC
      Central sensitivity syndromes36
      • Fibromyalgia
      • Irritable bowel syndrome
      • Chronic headache
      • Temporomandibular disorders (TMJ)
      • Pelvic pain syndromes
      Persistent pain is unifying across these diagnoses

      Can exist as part of patient’s PASC
      Comorbid features include difficulties with sleep, fatigue, dizziness, cognitive problems, depression, and anxiety

      Difficult to differentiate from PASC and studies show there may be significant overlap37

      Sole diagnosis of central sensitivity syndromes would likely show timeline that preceded COVID infection
      Small fiber neuropathyPain characterized as pins and needles, burning, tingling, or itchiness

      Can exist as part of patient’s PASC
      Comorbid features include orthostatic intolerance, urinary difficulties, GI issues, abnormal sweating, dry eyes or mouth, and palpitations

      Important to rule out other etiologies of small fiber neuropathy:
      • Infectious diseases
      • Vitamin deficiencies
      • Alcohol intake
      • Chemotherapy or other neurotoxic drugs
      • Rheumatologic conditions
      • Vaccine effects
      Can be triggered by COVID infection, but if symptomatology preceded COVID infection, likely symptoms are not related to long COVID
      Orthostatic intolerance syndromes
      • POTS
      • Vasovagal syncope
      • Orthostatic hypotension
      Abnormal autonomic response to position (typically standing)Can be caused by improper secretion of epinephrine and norepinephrine

      Can be related to COVID vaccine as well, though vaccine-related effects have been reported as more transient in nature38

      Can be triggered by COVID infection, but if symptomatology preceded COVID infection, likely symptoms are not related to long COVID
      Myocarditis39Inflammation of cardiac muscle with regional or global cardiac dysfunctionUsually related to viral illnesses, including COVID-19

      Symptoms include:
      • Chest pain
      • Edema
      • Arrhythmias
      • Lightheadedness
      • Flu-like symptoms
      • Fatigue
      • Heart failure
      Can be COVID vaccine related. Typically in young males and usually transient
      Mast cell activation syndrome40Abnormal activation of mast cell degranulation leading to recurrent episodes with varying symptomsSymptoms can include:
      • Tachycardia
      • Hypotension
      • Syncope
      • Pruritis
      • Hives
      • Angioedema
      • Wheezing
      • Shortness of breath
      • Diarrhea
      • Abdominal pain
      Testing can reveal increased mast cell tryptase activity, N-methylcysteine, 11β-prostaglandin, and leukotriene E4 levels

      Can be triggered by COVID infection, but if symptomatology preceded COVID infection, likely symptoms are not related to long COVID
      Uncontrolled mental health condition, including depression, anxiety, PTSD, or ADHDFaulty mood regulation by the brain due to genetics, hormonal changes, life stressors, chronic illness, or other factorsSymptoms can include:
      • Anhedonia
      • No motivation or interest
      • Restlessness
      • Fatigue
      • Difficulties with concentration
      • Irritability
      • Somatic symptoms, including unexplained body pains
      • Sleep difficulties
      • Guilt
      • Easily frightened
      May have overlap in symptoms of PASC and could be worsened by PASC symptomatology

    Treatment

    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
      • POTS24,25
        • 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 adults48,49
          • 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 dyspepsia53,54
      • 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

    Special Considerations

    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 ongoing57,58

    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

    Follow-up

    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 and Prevention

    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
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