Long COVID: A review of long-term consequences of COVID-19

Background

As of April 4, 2022, the severe acute respiratory syndrome coronavirus-2 (SARS CoV-2) virus causing coronavirus disease 2019 (COVID-19) has accounted for a total of 492,362,635 cases and 6,150,346 deaths across the world.¹ Though COVID-19 can lead to severe comorbidities in acute illness, for those who survive, long COVID appears to be the most prevalent and prolonged complication thus far. Long COVID has been described under different terms such as “post-acute sequelae of COVID-19 (PASC)”, “long-haul COVID”, “post-COVID-19 syndrome”, or “chronic COVID”. Long COVID has affected people across the world and various definitions have since emerged to identify the impact of this condition (Table 1).^2–4 The Centers for Disease Control and Prevention’s National Center for Health Statistics (CDC/NCHS) has assigned an ICD-10 code for post COVID-19 condition (U09.9) to aid with diagnosis and assess the prevalence of this condition.⁵

Prevalence and Epidemiology

Sudre et al conducted prospective observation cohort study including populations from the UK (88%), the United States (US) (7.3%) and Sweden (4.5%) reporting an estimate on persistent symptoms after 28 days (13%), 56 days (4.5%), and 90 days (2.6%) of COVID-19 diagnosis.⁶ In another study, 33%-98% reported at least one new or persistent symptom after acute COVID-19 infection.⁷ A comprehensive systematic review with meta-analysis on long-term effects of COVID-19 described the most common long COVID symptoms with their estimated prevalence as fatigue (58%), headache (44%), attention disorder (27%), hair loss (25%), and dyspnea (24%).⁸ Additionally, cough (10%-13%), chest pain (5%-42.7%), anxiety/depression (14.6%-23%), and olfactory/gustatory deficits (13.1%-67.5%) have been described as commonly reported symptoms.⁷ Multiple other long COVID symptoms with less frequency have been reported in studies affecting various organ systems. Thus far only one study has assessed long COVID effects one-year post-acute illness reporting fatigue (28%), dyspnea (18%), myalgia (26%), depression (23%), anxiety (22%), memory loss (19%), concentration difficulties/brain fog (18%), and insomnia (12%) as common persistent symptoms.⁹ There are no published studies with >1 year follow up period for patients with COVID-19, however, a study of SARS-CoV patients reported persistence of fatigue among 50% of survivors up to 4 years post-acute illness.¹⁰ The full clinical spectrum of long COVID-19 arranged by organ systems is described in Table 2.

Risk factors

Women, older adults, pre-existing medical conditions (specifically hypertension and chronic lung conditions), hospitalization during onset of symptoms, more than 5 symptoms in the first week of acute illness, shortness of breath and chest pain have been identified as significant risk factors for development of long COVID.¹¹ Most studies have observed progression to long COVID may occur irrespective of severity of initial illness. One recently published study identified higher viral load during acute illness, presence of autoantibodies, reactivation of Epstein-Barr virus (EBV) and type 2 diabetes as important risk factors associated with long COVID.¹² Notably, a rapid review performed in the UK reported vaccination against SARS CoV-2 virus prior to development of infection or immediately after acute illness has shown to decreased likelihood of development of long COVID compared to unvaccinated individuals.¹³

Pathophysiology

There is a lack of clear understanding on pathophysiology behind development of long COVID. Multiple theories have been established (mostly based on autopsy studies) speculating a combination of pathological changes as causative factors for multisystem involvement in long COVID.¹⁴ Direct viral invasion has been proposed as a primary cause for long-term consequences affecting tissues expressing angiotensin-converting enzyme-2 entry receptors such as vascular endothelial cells, olfactory cells, mucous membrane of the mouth, lungs (type II alveolar epithelial cells), heart (myocytes), gastrointestinal tract epithelial cells, hepatic cells, pancreatic β cells, renal podocytes, skeletal muscle and synovial tissue, and testicular cells. High viral load and direct invasion results in cascade of proinflammatory cytokine release, activation of lymphocytes (CD8 T-cell), neutrophils causing inflammatory damage to tissues, coagulopathy, cell death and risk for infarction and fibrosis. There is no clear evidence on SARS CoV-2 neurotropism resulting in brain entry, however, damage to blood-brain barrier or entry through the olfactory nerve tract could be possible mechanisms for direct injury. SARS CoV-2 spike protein mediated neuroinflammation has also been postulated as a possible mechanism. Predominantly systemic inflammatory response rather than direct viral injury has been proposed to play significant role in neurocognitive complications. In some cases, prolonged low-level SARS CoV-2 viremia resulting in sustained CD8 T cell stimulation has been reported as a possible mechanism for long COVID. Other proposed mechanisms include immune system dysregulation with SARS CoV-2 mimicking antigen presenting cells causing formation of auto reactive antibodies as seen in autoimmune conditions.

Diagnosis

It is uncertain whether the condition of long COVID represents unique consequences of SARS CoV-2 infection as many of these symptoms can be seen after other serious viral infections, sepsis and ICU stays. Thus, diagnosis of long COVID is challenging as it is considered as a diagnosis of exclusion based on established clinical definitions. Commonly, multiple visits are needed to rule out other causes and confirm a long COVID diagnosis. The initial patient visit commonly includes a comprehensive assessment including history, physical examination, cognitive, and psychological evaluation.^15,16

Studies recommend all patients should undergo baseline anxiety and depression screening. Additional assessment tools can be used during baseline evaluation to determine impact of long COVID on quality of life/functional status, dyspnea scale, cognitive assessment, mini mental status examination, fatigue severity scale, et cetera, depending on reported ongoing symptoms. No specific laboratory tests are recommended for establishing long COVID diagnosis. Confirmation of COVID-19 infection with repeat viral test or antibody test is not recommended. Basic standard laboratory tests such as complete blood count, liver function, and kidney function tests can be performed during initial assessment. Additional laboratory studies can be performed based on reported symptoms, clinical assessment, and follow up of any abnormalities identified during hospitalization (Table 2). A few studies have stated abnormal levels of C-reactive protein (increased), D-dimer (increased) and lymphocyte count (decreased) serve as inflammatory biomarkers of long COVID; however, other studies have not supported this finding.¹⁷ Based on the initial assessment, laboratory test results and ruling out of any new medical condition diagnosis or exacerbation of an underlying co-morbidity, diagnosis of long COVID can be established.

Management

As there is incomplete understanding on pathophysiology, management of long COVID is not well defined. It is commonly recommended to see long COVID patients in a multidisciplinary outpatient clinic setting with a goal to improve patient’s function and quality of life.^4,15,16 This approach could be challenging for population of Mississippi.

In the state of Mississippi (MS), the COVID-19 pandemic has had its worst impact on rural, uninsured population with untreated or undiagnosed chronic medical conditions. A substantial percentage of this population lacks access to healthcare and does not have established primary care providers (PCP). Such disparities have caused further delay in seeking healthcare assessment, including initiation of long COVID management. Expanding care to all Mississippians would require fundamental reform to improve healthcare equity. The essential first step for management for Mississippians affected with long COVID would be to establish care with a local PCP. Primary care providers can perform a comprehensive evaluation to unmask any undiagnosed medical conditions, identify exacerbation of chronic diseases, and rule out long COVID diagnosis. Appropriate pharmacological treatment for known medical conditions should be prescribed based on clinical assessment and laboratory studies (diabetes, thyroid disease, vitamin deficiencies). Periodic reassessment should be performed by PCP for improvement or resolution of symptoms. Patients without symptom resolution and with underlying systemic involvement should be referred to appropriate specialists for further evaluation. Primary care providers can continue to co-ordinate care with specialists until there is satisfactory response to management.

There is no established pharmacological or non-pharmacological treatment option for management of long COVID. Currently recommended medications (remdesivir, nirmatrelvir/ritonavir, molnupiravir, monoclonal antibodies) for treatment of acute COVID illness do not play any role in management of long COVID. Treatment of pulmonary complications with immunomodulatory drugs or anti-fibrotic drugs is debatable and should only be prescribed at the discretion of a pulmonologist. Ultimately, rehabilitation is the cornerstone therapy and strongly recommended for improvement in organ function (cardiac, pulmonary, neurocognitive, physical, mental health) and for patient well-being. Based on positive findings from COVID-19 vaccination data, vaccination should be encouraged in unvaccinated long COVID survivors to reduce risk for re-infection and potentially long-term complications.¹³ Routine follow up via face-to-face or virtual visits is recommended to monitor the patient’s progress, implement timely and appropriate interventions and provide support during their road to recovery. As prognosis of long COVID is largely unknown, resources for peer support groups and online forums should be shared with patients during ongoing care. Long COVID is recognized as a disability under the Americans with Disabilities Act (ADA) in patients with impairments affecting function and quality of life.¹⁸ Additionally, it is worth relating to patients that many large studies looking at persistence of COVID symptoms over time show gradual resolution of symptoms for most patients.¹⁹

Future directions

As healthcare professionals continue on their third year of this pandemic journey, the next wave of healthcare burden in form of long COVID is already creeping up on us. A clear lack of understanding of pathophysiology of long COVID, its prognosis and diagnostic challenges has resulted in limited management options. Further research studies focusing on understanding, prevention and treatment of this disabling disease are needed. Among multiple ongoing studies, Research COVID to Enhance Recovery (RECOVER) is a multicenter study funded by National Institutes of Health that is currently underway in the US and enrolling participants. It is imperative for healthcare facilities and providers to recognize this upcoming healthcare disaster and be prepared to invest resources in establishing multidisciplinary clinics, rehabilitation programs and support groups for the care of long COVID patients.

Contribution of Taxonomy Statement (CRedIT)

Both authors performed the literature search and contributed equally in drafting and revision of the manuscript.