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long Covid-19; post-acute sequelae of COVID-19 (PASC); post-Covid syndrome

- Persistent symptoms &/or delayed or long-term complications of SARS-CoV2 infection beyond 4 weeks from the onset of symptoms. - chronic condition that occurs after SARS-CoV-2 infection, present for >= 3 months as a continuous, relapsing & remitting, or progressive disease affecting one or more organ systems (definition) [140] Classification: 1) late complications of Covid-19 after hospital discharge [23] 2) subacute or ongoing symptomatic COVID-19 - symptoms & abnormalities present from 4-12 weeks beyond acute COVID-19 3) chronic or post COVID-19 syndrome - symptoms & abnormalities persisting or present beyond 12 weeks after onset of acute COVID-19 not attributable to alternative diagnosis [17] 4) long Covid-19 has 3 forms a) largest group has a cluster of symptoms in the nervous system - fatigue, brain fog, headaches - most common subtype among Alpha variant & Delta variant, which was dominant in 2021. b) 2nd form has respiratory symptoms - chest pain, dyspnea, suggesting lung injury - most common type for original Wuhan coronavirus strain c) 3rd forms diverse range of physical symptoms, - heart palpitations, myalgias, pain, skin & hair disorders - some with severe & debilitating multi-organ symptoms [88] Etiology: - idiopathic [86] - comprehensive evaluation of cases did not find cause [86] - may overlap with post-intensive care syndrome, or multisystem inflammatory disorder - testing positive for SARS-CoV2 is a risk factor for long Covid-19 [50] - disruption of intestinal flora is linked with susceptibility to long COVID-19 [58] - higher BMI & female sex are risk factors for long Covid-19 [109] - theories - a virus cryptic reservoir that could reactivate at any time - viral remnants that trigger chronic inflammation - autoimmune antibodies that cause ongoing symptoms - reduced circulating serotonin levels [134] - risk factors [118] - female sex, older age, higher body mass index, smoking - preexisting comorbidities - previous hospitalization or ICU admission - SARS-CoV2 vaccination with 2 doses lowers risk [118] Epidemiology: - 20% of Covid-19 survivors age 18-64 & 25% of Covid-19 survivors > 65 experience at least one symptom of long Covid-19 [81,85,97] - younger patients more likely to have long Covid-19 than older patients [85] - more common in older patients [99,100] - women more likely to have long Covid-19 than men [85,99,100] - 50-90% of hospitalized discharged COVID-19 patients report persistent symptoms 1-2 months later - 37% of patients report at least one symptom 3-6 months after infection with SARS-CoV2 [51] - 30% of patients report persistent symptoms 9 months later [10] - nearly 1/2 of persons hospitalized with Covid-19 report at least 1 lingering symptom 1 year later [47] - appears to affect even those who experienced more mild disease [5] - 15% of patients with mild COVID-19 symptoms still had symptoms 8 months later [27] - 13% of patients with Covid-19 note somatic complaints 90-150 days later [90] - 5% of Covid-19 survivors continue to experience symptoms 18 months later [107] - older people, people with asthma, & people evaluated for hospitalization are more likely to report long-term symptoms [19] - women in their 40s & 50s at higher risk of long Covid-19 after hospitalization with COVID-19 [22] - children may experience long Covid-19 [11] - estimated prevalence of long Covid-19 in children at 6 months after initial infection range from 0% to 27% [43] - Omicron ~1/2 as likely to cause long Covid-19 as Delta (~5%) [84] - ~ 19 million Americans suffer from long Covid-19 (Dec 2022) [112] - long Covid-19 may persist as a mass diabling event [126,127] - less common in the Omicron era than earlier eras but still substantial even among vaccinated persons [145] Pathology: - replication-competent SARS-CoV2 has not been isolated after 3 weeks [17] - possible contributions from - cellular damage - a robust innate immune response - inflammatory cytokine production - Covid-19 related anosmia likely due to peripheral inflammation [41] - a pro-coagulant state - mechanisms associated with 'brain fog' - activation of TGF-beta signaling & oxidative overload [61] - microtubule-associated protein tau hyperphosphorylation [61] - RyR2 in COVID-19 brains expressed a 'leaky' phenotype resulting in cognitive & behavioral deficits [61] - kynurenine pathway activation is associated with mild cognitive impairment [83] - cognitive impairment associated with kynurenine pathway metabolites: - quinolinic acid, 3-hydroxyanthranilic acid, & kynurenine - diminished circulating serotonin levels [134] - viral RNA-induced interferons (IFN) type I reduce serotonin levels - reduced peripheral serotonin levels reduce vagal signaling - reduced vagal signaling impairs cognition 'brain fog' [134] - inflammation of vagus nerve - dyspnea, fatigue, & decreased exercise tolerance due to impaired extraction of oxygen in skeletal muscle vs pulmonary or cardiac dysfunction [71] - diaphragm weakness identified in patients with dyspnea post hospitalization, especially after mechanical ventilation, despite normal pulmonary & cardiac function [120] - post Covid-19 fatigue associated with - reduced intracortical facilitation within the primary motor cortex - autonomic dysfunction - skeletal muscle myopathy [72] - SARS-CoV2 associated with axon pathology & microvasculopathy in the olfactory bulb & olfactory tract [76] - not a result from direct viral injury - may be associated with local inflammation - complement activation may last for 6 months [135] - reactivation of cytomegalovirus & Epstein-Barr virus play a role - complement activation may induce inflammation, thrombosis & endothelial dysfunction [135] - inflammation & endothelial dysfunction may play a role in long Covid-19 [78] - neurologic symptoms of long COVID may result from antigenic imprinting, a misdirected immune response to SARS-CoV2 [121] - long Covid-19 & chronic fatigue syndrome share pathophysiology [123] Clinical manifestations: - presentation with symptoms 4-12 weeks after the start of acute symptoms - COVID-19 symptoms not resolved after 12 weeks - symptoms & excess risk for new disease persist for 2 years after acute COVID-19 [129] - common symptoms are fatigue, cough, & headache [1,100] - fatigue, dyspnea, arthralgia, & chest pain most common [4] - among patients with mild COVID-19, most common prolonged symptoms were anosmia, fatigue, ageusia, & dyspnea [17,27] - anosmia & ageusia most unique features of long Covid-19 [79] - sense of smell can be altered > 5-6 months after COVID-19 [12,55] - 86% recovery from anosmia within 6 months, 96% within 12 months [41] - dyspnea a unique feature of Covid-19 [79] - 25-36% report dyspnea after 6 months [5,31] - vaccinated people at lower risk of dyspnea vs unvaccinated people [113] - 75% have >= 1 persistent symptom 6 months after hospitalization [3] - fibromyalgia [48] - fatigue or muscle weakness (63%) - myalgias (55%) [21], arthralgias [62] - sleep disorder, insomnia (26-29%) [31] - anxiety or depression (23%) [3,47]; 52% at 4 months [20,40] - persons with headache during acute infection at elevated risk of post-acute COVID-19 depression [20,40] - symptoms of chest pain, cough, muscle aches & hair loss tend to resolve within 1 year [113] - myalgic encephalomyelitis/chronic fatigue syndrome - cognitive impairment especially impairment of memory, reasoning & planning [138] - "brain fog" [52,59] &/or executive dysfunction [7] - cognitive impairment correlates with persistent anosmia in older adults [44] - anosmia more predictive of cognitive impairment than Covid-19 disease severity [98] - poor memory & attention persists months after mild COVID-19 recovery [57] - 70% report memory problems: 78% difficulty concentrating, 69% "brain fog", 68% forgetfulness, 60% word finding difficulty [73] - cognitive deficits not mediated by depression or anxiety [130] - cognitive slowing determined by visual reaction time & number vigilance [136] - neurocognitive impairment, confusion [100] - 60% of hospitalized patients & 67% of non-hospitalized patients report symptoms after 2 years, fatigue, pain, & memory loss most common [104] - 1 year after ICU treatment for COVID-19 - physical symptoms in 74% - mental symptoms in 26% - cognitive symptoms in 16% [62] - fluctuating symptoms ("good & bad days") - no clear pattern of either migraines or tension headaches - paresthesias, tingling or numbness - dysautonomia, including light-headedness, palpitations - diarrhea & other GI disturbances [30] - dysuria [79] - dizziness, generalized pain, blurred vision, tinnitus [21] - > 50% of Covid-19 survivors with long Covid-19 symtoms after 6 months [53] - chest imaging abnormality - general functional impairments - fatigue or muscle weakness - decline in quality of life [17,47] - more than 50 long-term effects of COVID-19 [45] * a PASC score includes postexertional malaise, fatigue, brain fog, dizziness, gastrointestinal symptoms, palpitations, changes in sexual desire or capacity, loss of or change in smell or taste, thirst, chronic cough, chest pain, & abnormal movements [122] Laboratory: - lipid panel: hyperlipidemia common [42] - higher median CSF C-reactive protein & serum amyloid A in long COVID patients with cognitive symptoms [75] - elevated plasma fibrinogen relative to plasma C-reactive protein is associated with both objective & subjective cognitive deficits [130] - elevated plasma D-dimer relative to plasma C-reactive protein is associated with subjective cognitive deficits & occupational impact - may be mediated by fatigue & dyspnea [130] - differences in circulating myeloid & lymphocyte populations vs controls - exaggerated humoral responses directed against SARS-CoV2 vs controls [132] - higher antibody responses directed against non-SARS-CoV2 viral pathogens, particularly Epstein-Barr virus vs controls [132] - serum cortisol lower in patients with long Covid-19 vs controls [132] Special laboratory: - pulmonary function tests* - diffusion capacity* - 6 minute walk test* [5] - pulse oximetry at rest & during ambulation [56] - echocardiogram as indicated - cardiopulmonary exercise stress testing [95] - factors associated with exertional intolerance - deconditioning (common) - dysfunctional breathing - chronotropic incompetence - abnormal peripheral oxygen extraction (common) [95] * impairment at 6 months in patients without hypoxia during acute COVID-19 - 52% with DLCO reduced to < 80% - 16% with DLCO reduced to < 60% [14] * 22% with limited mobility based on short physical performance battery evaluating - balance, walking speed & standing up from a chair [14] Radiology: - chest X-ray (as indicated) - thromboembolic workup (as indicated) - doppler ultrasound of lower extremities - VQ scan vs pulmonary CT angiography for pulmonary embolism - high-resolution CT of chest for interstitial lung disease (as indicated) - CT imaging findings may persist at 3 months & 1 year after Covid-19 [82,119] - ground-glass opacities & curvilinear bands (reticulations) most common - no correlation of long Covid-19 symptoms & persistent imaging findings [82] - CT imaging findings uncommon 1 year after hospitalization for Covid-19 [102] - 6 months, 40% of patients with normal CT scans; 93% with normal scans at 1 year - ground-glass opacities 100% at baseline; at 1 year, only 2% - pulmonary fibrosis found in 2% of long Covid-19 patients at 1 year [102] - brain MRI before & after Covid-19 shows loss of grey matter in primary or secondary cortical gustatory & olfactory areas, in the left hemisphere [38] - brain MRI shows changes in frontal lobe & brainstem [108] - frontal lobe changes primarily in white matter regions - also changes in the orbital-inferior frontal gyrus - cluster of changes in the right ventral diencephalon region of the brain stem [108] - resting-state fluctuation amplitudes from functional MRI identifies chronic cerebrovascular disease after hospitalization for Covid-19. Complications: - hypoxia, persistent oxygen requirement [17] - respiratory failure [39,68] - air trapping suggesting obstruction of small airways [34] - pulmonary fibrosis [5,17] - interstitial lung disease - pulmonary hypertension [36] - pulmonary embolism (RR=2) [81] - sleep apnea - increased risk of cardiovascular disease - risk elevated at least 1 year after even mild cases of Covid-19 [63] - risk elevated even for those < 65 years & lacked risk factors [63] - heart failure [63] including stress cardiomyopathy [39] - hypertension [39,42,68] & stroke [63] - myocarditis or pericarditis [8] - cardiac arrhythmia [39] - postinfectious, immune-mediated myopathy [35] - inflammation of skeletal muscles associated with duration of illness - more pronounced than cardiac inflammation [35] - microvascular angina, chest pain - palpitations, cardiac arrhythmias: atrial fibrillation, atrial flutter - dysautonomia including POTS [15,33,87,111] - mast cell activation syndrome - thromboembolic disease: - pulmonary embolism, cerebral venous thrombosis [68] - risk for venous thromboembolism persists for months after Covid-19 [77] - risk greater for hospitalized patients [77] - risk of thromboembolic disease declines more rapidly for arterial thromboses than venous thromboses, but remains elevated up to 49 weeks after COVID-19 diagnosis [91] - myelopathy, neuropathy, cognitive disorders - inflammatiom of vagus nerve resulting in dysphagia & dyspnea [66] - renal impairment (chronic kidney disease) [17,49] - autoimmune disease [140] - new onset diabetes mellitus - subacute thyroiditis [28] - GI motility disorders, dyspepsia, GERD, peptic ulcer disease, functional intestinal disorders, acute pancreatitis, hepatitis, biliary disease. abnormal liver function tests [116] - steatosis [117] - new onset allergies, anaphylaxis - dysphonia [8] - alopecia [17] - 1/3 of survivors diagnosed with neuropsychiatric disorder within 6 months [24] - PTSD (30% of survivors of severe COVID-19) [9,40] - long-term neuropsychiatric complications common after hospitalization [25] - 39% of hospitalized patients, 50% after ICU admission [26] - cognitive deficits, hyposmia, & postural tremor most common [25] - intracranial hemorrhage; ischemic stroke; parkinsonism; Guillain-Barre syndrome; nerve, nerve root & plexus disorders; myoneural junction & muscle disease; encephalitis; dementia; psychosis, mood disorders, & anxiety disorders; insomnia [26,92] - epilepsy, seizures [105], migraine [92] - small-fiber neuropathy after mild SARS-CoV2 common, beginning within 1 month of COVID-19 onset [69] - brain-related abnormalities seen on imaging [70] - reduction in grey matter thickness & tissue-contrast in the orbitofrontal cortex & parahippocampal gyrus - changes in markers of tissue damage in regions functionally-connected to the primary olfactory cortex - reduction in global brain size [70] - severity of acute COVID-19 is associated with chronic cerebrovascular disease, cognitive impairment & mental health disorder [65,70] - cerebrovascular pathology observed in the lateral lobes, frontal lobe, temporal lobe & parietal lobe [65] - over-stimulation of the immune system, possibly triggered by ongoing vascular injury & repair may result in persistent post-COVID cognitive changes [74] - increased risk of anxiety disorders, depressive disorders, stress disorders & adjustment disorders, opioid abuse & nonopioid substance abuse disorders, neurocognitive decline, sleep disorders [68] - mortality* 7%, readmission* 15% within 60 days of acute COVID-19 [17] - mortality* 12%, readmission* 29% within a mean of 140 days of acute COVID-19 [23] - rates that were 3.5 & 7.7 times higher than in matched controls - 30 day mortality in hospitalized patients 46 times that of non-hospitalized [42] - new-onset diagnoses of respiratory diseases were 27 times more common after hospitalization than in controls [23] - major adverse cardiovascular events, chronic liver disease, chronic kidney disease, & diabetes mellitus were also more common [23] - higher mortality & health resource utilization [29] - sequalae of respiratory disorders, nervous system & neurocognitive disorders, mental health disorders, metabolic disorders, cardiovascular disorders, gastrointestinal disorders, malaise, fatigue, musculoskeletal pain, & anemia [29] - increased use of pharmaceuticals: analgesics, antidepressants, anxiolytics, antihypertensives, & oral hypoglycemics - in children & adolescents acute pulmonary embolism (RR=2.0), myocarditis & cardiomyopathy (RR=2.0), venous thromboembolic event (RR=1.9),renal failure (RR=1.3), & type 1 diabetes (RR=1.2) [93] - older age (> 60 years, female sex, history of cancer, history of tobacco use, high BMI, higher number of symptoms during acute phase associated with slower resolution of symptoms [103] - viruses, including rhinovirus (common cold) & influenza virus can trigger relapse [143[ Management: - a healthy lifestyle prior to Covid-19 infection is associated with a diminished risk of long Covid-19 [115] - COVID-19 vaccination safe [32] - improvement in symptoms in 23% 1 month after Pfizer or AstraZeneca vaccine [32] - improvement in symptoms in 36%, some with complete resolution of symptoms [16] - of benefit even after Covid-19 infection [67,110] - vaccination prior to Covid-19 provides partial protection against long Covid-19 [80,94,99,100,110,118] - Covid-19 vaccines prevent new onset long Covid-10 & flare-ups for people with long Covid-19 [125] - Covid-19 vaccination was associated with 30-50% lower risk for long COVID-19 in all age groups [139] - treatment with Paxlovid during the acute phase of Covid-19 within 5 days of a positive SARS-CoV-2 test is associated with reduced risk of long Covid-19 regardless of vaccination status or history of prior infection [106,114,118] - see NICE guidelines [2] - monitoring of pulmonary symptoms with pulse oximetry at rest & during ambulation - pulmonary rehabilitation as indicated [56] - fatigue [46]; healthy diet; exercise (rule of tens) - brain fog & fagigue may respond to low-dose (5 mg QD) naltrexone* [96] - Hematology: - consider extended thromboprophylaxis [17] - Neuropsychiatry - screening for PTSD, anxiety, sleep disorder - screening for depression - screening for cognitive impairment [17] - cognitive rehabilitation as indicated - sleep interventions to improve cognitive symptoms [56] - assess potential impact of medications on cognitive function [56] - noninvasive brain stimulation using alternating microcurrents appears to rapidly & effectively improve cognitive & visual deficits related to long Covid-19 [64] - hyperbaric oxygen may improve neurocognitive function [89] - Nephrology: - follow-up with nephrology after discharge with Covid-19 & acute renal failure [17 - primary care - early rehabilitation - patient education - enrollment in research studies - engagement with patient advocacy groups [17] - set achievable goals through shared decision-making [37] - approach treatment by focusing on specific symptoms [37] - high-intensity interval training increases left ventricular mass - pulmonary diffusing capacity is unaffected [128] - not beneficial - Coenzyme Q10 500 mg QD is not beneficial [101] - Paxlovid [141,142] - low-dose lithium aspartate, 10-15 mg/day, for 3 weeks of no benefit for fatigue or cognitive dysfunction [144] - a higher dose 40-45 mg/day may offer symptomatic benefit (2 patients) * naltrexone is available in 50 mg pills - low-dose naltrexone must be purchased through a compounding pharmacy [96] Notes: - on the other hand, a French nun survives Covid-19 to celebrate her 117th birthday with red wine [6] - new name post-acute sequelae of COVID-19 (PASC) from Anthony Fauci [13] - ICD10 codes associated with long Covid-19 [18]

Related

COVID-19 ICD10 codes associated with long Covid-19

General

syndrome

References

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  18. ICD10Monitor Arriving Soon: Code U09.9, Post-COVID-19 Condition https://www.icd10monitor.com/arriving-soon-code-u09-9-post-covid-19-condition
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