Learning Objectives: After participating in this continuing professional development activity, the provider should be better able to:
1. Distinguish the various symptoms reported during and after coronavirus disease-2019 (COVID-19) infection.
2. Differentiate potential mechanisms of persistent pain after COVID-19 infection.
3. Explain the need for holistic surveillance and follow-up management for individuals affected by COVID-19.
The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing the outbreak of coronavirus disease-2019 (COVID-19) was declared to be a global pandemic on March 11, 2020, by the World Health Organization. The vast number of deaths across the world due to COVID-19 infection has been devastating, along with the short- and long-term physical, psychological, social, and financial burden of affected individuals and their loved ones. This article summarizes current data on reported symptoms during and after COVID-19 infection, explores the mechanisms of persistent pain and other comorbid symptoms after recovery from COVID-19, and explains the need for interdisciplinary care involving holistic assessment of individuals and families affected by COVID-19.
Pathophysiology of COVID-19 Infection
SARS-CoV-2 is a single-stranded RNA virus that belongs to the Orthocoronavirinae subfamily.1 It consists of 16 nonstructural proteins and 4 structural components: spike glycoprotein (S), envelope protein, membrane glycoprotein, and nucleocapsid phosphoprotein (N) (Figure 1).2 However, the viral types can differ across infections at different times and at least 116 mutations have been identified. The S proteins are critical for binding to the host cell surface receptors, whereas the N proteins are essential for viral survival and expansion.3
Similar to SARS-CoV, the pathogen responsible for the SARS epidemic of 2003, SARS-CoV-2 spike protein engages angiotensin-converting enzyme 2 (ACE2) as an entry receptor. SARS-CoV-2 cell entry requires priming of the spike protein by the cellular enzyme, transmembrane protease serine 2 (TMPRSS2) or other proteases.4 Compared with SARS-CoV, the SARS-CoV-2 has shown high affinity of binding to ACE2, which may be related to the increased transmissibility observed throughout the pandemic.
SARS-CoV-2 is transmitted through exposure to respiratory droplets from a person with COVID-19 that are inhaled or deposited on the host's mucous membranes. Respiratory droplets may be airborne or can land on surfaces and objects, which when exposed to a host cell with the entry receptor ACE2 in the presence of TMPRSS2 interacting with its spike protein to gain entry.5 Upon binding to the ACE2 receptor, the SARS-CoV-2 spike protein is activated through proteolytic cleavage by TMPRSS2, inserted into the cell membrane, and fuses the viral and cellular membranes so that transfer of the viral RNA into the host cell cytoplasm can occur, followed by viral replication.6,7
The involvement of other receptors has been examined with at least 2 reports demonstrating that the SARS-CoV-2 spike protein can bind to the b1b2 domain of the neuropilin-1 receptor (NRP-1), which could potentiate its entry into cells.8,9 These studies provided evidence that blocking NRP1 with a monoclonal blocking antibody could be effective as an antiviral intervention, even though the ACE2 receptor remains a source of viral transmission.10 However, this finding was also of interest in the area of pain treatment because both the spike protein and vascular endothelial growth factor-A (VEGF-A), a pronociceptive and angiogenic factor, can bind to the NRP-1 receptor.
In the case of VEGF-A binding to NRP-1, sensory neuron firing increases along with mechanical allodynia, thermal hyperalgesia, and pronociceptive behaviors.11 However, SARS-CoV-2 spike protein hijacked NRP-1 signaling and mitigated VEGF-A-mediated pain.11 Preventing VEGF-A/NRP-1 signaling using SARS-CoV-2 spike or the NRP-1 inhibitor [EG00229] was analgesic, thus providing a potential new avenue for targeted drug therapeutics.
In addition to varying entry routes into host cells, questions remain regarding how SARS-CoV-2 gains access into the central nervous system (CNS), referred to as neurotropism or the ability to infect nerve tissue. The nasal-olfactory nerve route, blood-nervous stem barrier breakdown, blood-nerve barrier or blood-cerebrospinal fluid barrier permeability, lymphatic drainage system of the brain, retrograde transmission from the enteric, lung, or kidney nerve routes, or macrophage/monocyte cargo routes have all been suggested pathways by which the SARS-CoV-2 virus reaches the CNS.12
For now, general precautions (masks, social distancing, and frequent handwashing) remain in place to control the virus, as COVID-19 vaccinations are taking place worldwide. Testing for COVID-19 infection remains a critical component of the COVID-19 detection and surveillance efforts. Of concern, the accuracy of antibody testing for seroconversion of immunoglobulin M and immunoglobulin G proteins varies over time and is not recommended until at least 14 days after the onset of symptoms, because it takes 1 to 3 weeks for the body to begin producing antibodies.
In a comparison of 5 SARS-CoV-2 antibody detection tests currently on the market, it was found that several of the tests did not provide meaningful interpretation of severity and infection status.13 Although the FDA has approved some antibody tests, their utility in population surveillance of COVID-19 is yet to be widely implemented.
Symptom Variability in Acute COVID-19 Infection
Although variability in symptom manifestations is not completely understood, the primary pathophysiologic mechanisms of acute COVID-19 infection include endothelial damage and microvascular injury, immune system dysregulation with potential for a hyperinflammatory state, and hypercoagulability resulting in risk of thrombosis and macrothrombosis.14
Although primarily considered as respiratory-based diseases, survivors of the SARS epidemic of 2003 and the Middle East respiratory syndrome outbreak of 2012 also exhibited multiple-organ involvement with some reporting long-term symptoms. Similar trends have been evolving after COVID-19 infection and current research is attempting to understand who is likely to be at risk.
Based on testing sensitivity, specificity, positive predictive value, and negative predictive value of individual symptoms and symptom combinations, a study involving 8214 individuals tested for COVID-19 found that the individual symptoms most associated with positivity of SARS-CoV-2 were fever [odds ratio (OR), 5.34; P < 0.001], anosmia (OR, 4.08; P < 0.001), ageusia (OR, 2.38; P = 0.006), and cough (OR, 2.86; P < 0.001).15
Using data from 44 studies including 26,884 participants, a total of 84 signs and symptoms related to COVID-19 infection were identified (Table 1).16 Because the probability estimates depend on the disease prevalence in a specific area, symptom presentations can vary. However, the data may be helpful in triaging patients for testing and/or treatment.
Limitations of the review included the lack of studies among children and older adults and high risk of selection bias because of studies that included patients who were already admitted to the hospital with COVID-19.
As seen from the meta-analysis on the top 6 most frequent symptoms (Table 1), most symptoms had a low sensitivity and a high specificity for diagnosis of COVID-19(+) status. A combination of signs and symptoms, such as combining cough and fever with other symptoms, increased sensitivity but lowered specificity.
From the data analysis, the authors concluded that neither the presence nor absence of a single sign or symptom is accurate to rule in or rule out COVID-19. However, the presence of anosmia and/or ageusia may be a useful red flag of COVID-19 because of their high specificity, whereas fever or cough may be useful in identifying the need for further testing. The possibility that specific symptoms could correspond with more severe infection has been discussed with symptoms of chest pain, myalgia, and abdominal pain being suggested as precursors to severe illness.17
Post-Acute COVID-19 Syndrome
Since the beginning of the COVID-19 pandemic, patient reports of persistent symptoms lasting long past the stages of recovery have been acknowledged and research studies have been launched to systematically quantify what is now known as post-acute COVID-19 syndrome, post-COVID syndrome, or long COVID, with sufferers referred to as COVID-19 long haulers.
Among 183 patients with a median age of 57 years (range 25-85 years), 72.7% reported persistent COVID-19 symptoms at 35 days post-hospitalization, with the most frequent symptoms being fatigue (55%), dyspnea (45.3%), musculoskeletal pain (51%), and cough (41.8%).18 Older patients and women had a statistically significant higher odds of experiencing persistent symptoms. A meta-analysis of 15 publications that examined symptoms of COVID-19 reported that 80% (95% CI, 65-92) of individuals with a confirmed COVID-19 diagnosis continued to have at least 1 symptom for at least 2 weeks after acute infection, with fatigue, anosmia, lung dysfunction, and neurologic disorders being the most common.19
In a study of 50 SARS-CoV-2 laboratory-positive and 50 laboratory-negative individuals who reported symptoms of COVID-19 but were never hospitalized for pneumonia or hypoxemia, the characterization of their neurologic symptoms lasting over 6 weeks was documented, as they returned for follow-up visits at a neuro-COVID-19 clinic.20 The most frequently reported symptoms were fatigue (85%), brain fog (81%), headaches (68%), numbness/tingling (60%), dysgeusia (59%), anosmia (55%), and myalgias (55%).
Anosmia was the only symptom that was more frequent in SARS-CoV-2(+) individuals compared with SARS-CoV-2(-) individuals. Among the entire sample, there was no association identified between time from disease onset and subjective assessment of recovery, with all participants exhibiting impaired quality of life in the fatigue and cognitive domains. In addition, the SARS-CoV-2(+) individuals demonstrated worse performance in attention and working memory cognitive tasks compared with a demographic-matched US population (P < 0.01).
In an Italian study that assessed 238 patients who were hospitalized with COVID-19, the presence of lung function anomalies, exercise function impairment, and psychological symptoms were studied at 4 months after discharge from the hospital.21 Of 219 patients able to complete pulmonary function tests including diffusing lung capacity for carbon monoxide (DLCO), 51.6% had a DLCO of less than 80% of the estimated value and 15.5% had a DLCO of less than 60% of the estimated value.
The Short Physical Performance Battery score and the 2-minue walking test were outside the reference range of expected performance for age and sex in 22.3% and 40.5% of patients, respectively. Posttraumatic stress (PTS) symptoms were reported by 17.2% of patients and male sex was the only independent factor associated with PTS symptoms. In addition, dyspnea persisted in 10% of patients, alternations in taste and/or smell in 17% of patients, and arthralgia and myalgia in 33% of patients at 4 months post-hospital discharge. The findings suggest that long-term follow-up of patients with severe COVID-19 disease will be required, especially to determine whether patients with reduced DLCO are at increased risk of progressive lung fibrosis and impaired motor function.
In a study to describe the long-term health (6-month follow-up) consequences of patients with COVID-19 who were discharged from the hospital, 1733 patients were interviewed.22 Among the cohort, fatigue or muscle weakness (63%) and sleep difficulties (26%) were most common, with 23% reporting anxiety or depression. In addition, 22% reported hair loss, 11% agnosia, 9% ageusia, and 7% difficulty with mobility. The median 6-minute walking distance was less than the lower limit of normal range and pulmonary diffusion impairment had an increasing prevalence associated with the severity of COVID-19 illness during the acute stage, meaning that those who had more significant acute COVID-19 disease symptoms experienced more severe impairments in physical functioning and pulmonary function.
In terms of renal abnormalities, 13% who had normal kidney function during acute infection had an estimated glomerular filtration rate lower than 90 mL/min per 1.73 m2 at follow-up.
In a study using electronic health records from community-dwelling individuals with polymerase chain reaction (PCR)-confirmed COVID-19 infection (n=1407), the symptoms reported during the acute phase were examined as predictors of persistent symptoms at day 61+ post-recovery.23 Importantly, patients hospitalized for COVID-19 were excluded from the study to determine whether those with mild to moderate symptoms were also experiencing post-acute COVID-19 syndrome.
Approximately 68% of the group reported symptoms during acute infection with 32% being asymptomatic. During the acute phase of illness (days 0-10 from time of a positive result on a COVID-19 test), the analysis identified 5 symptom clusters:
1. Dyspnea-anxiety (dyspnea, anxiety, tachycardia, headache, and abdominal pain);
2. Cough-fatigue (cough, fatigue, muscle pain, dysgeusia, and nausea);
3. Fever-headache (fever, headache, muscle pain, tachycardia, and abdominal pain);
4. Chest pain-tachycardia (chest pain, tachycardia, anxiety, muscle pain, and insomnia); and
5. Diarrhea-abdominal pain (diarrhea, abdominal pain, fatigue, nausea, and headache).
At day 61 or greater post-infection, persistent symptoms were reported by 27% of participants, and this group was composed of individuals across all age and racial/ethnic categories with a majority being women. The most common symptoms reported by the long-hauler group included chest pain, dyspnea, anxiety, abdominal pain, cough, low back pain, and fatigue. Symptom clusters in the post-acute COVID-19 stage included:
* Chest pain-cough (chest pain, cough, insomnia, tachycardia, and syncope);
* Dyspnea-cough (dyspnea, cough, heart palpitations, diarrhea, and tachycardia);
* Anxiety-tachycardia (anxiety, tachycardia, heartburn, diarrhea, and alopecia);
* Abdominal pain-nausea (abdominal pain, nausea, diarrhea, headache, and fever); and
* Low back pain-join pain (low back pain, joint pain, fatigue, muscle pain, and nausea).
Positive predictors of persistent symptoms using demographic variables (age and sex), presence of symptoms, and other variables revealed that asymptomatic presentation, heart palpitations, chronic rhinitis, dysgeusia, and chills held the highest likelihood of developing persistent symptoms.
In this study, people in the age range of 50 to 59 years (+/- 20 years) represented more than 72% of the long-hauler population. An important finding from this study was that the symptom clusters identified among long haulers vary compared with those identified during initial COVID-19 infection. As asymptomatic individuals often do not receive follow-up care, the finding that 32% of long haulers were asymptomatic during acute SARS-CoV-2 infection is concerning and suggests that long-term management of COVID-19 should include surveillance of all individuals who were infected or likely to be infected, because not all people had access to testing and the window for antigen testing may have passed.
Underlying Mechanisms of Pain With COVID-19
Myalgia is one of the most common symptoms associated with COVID-19 infection, and it is thought to result from the inflammatory response due to viral invasion with release of cytokines such as interleukin-6 (IL-6) that are known to cause hyperalgesia.24,25 Patients with SARS-CoV-2 infection exhibit elevated cytokine levels including IL-6, IL-10, and tumor necrosis factor-[alpha], especially with moderate to severe disease.
With systemic inflammation and a massive increase in proinflammatory cytokines in circulation, leukocytes, including T- and B-lymphocytes, enter the CNS through the choroid plexus to defend against invading pathogens.26 However, SARS-CoV-2 may also directly infect CNS structures after transnasal and transsynaptic invasion into the olfactory bulb and then into the brain stem, or by endocytosis of the circumventricular organs (subfornical organ, paraventricular nucleus, nucleus of the tractus solitarius, and rostral ventrolateral medulla) that are highly concentrated with ACE2 receptors and lack the blood-brain barrier.
Microglia, which are resident immune cells in the CNS, are constantly surveying the brain parenchyma for pathogens and are capable of initiating inflammatory responses, activating inflammasomes, secreting inflammatory mediators, and clearing debris.27 The recognition of specific inflammatory ligands leads to activation of inflammasomes by microglia and astroglia and neurons in specific pathologic circumstances.
These inflammatory ligands may be pathogen-associated molecular patterns, or PAMPs, composed of pathogen-specific carbohydrates and lipoproteins (lipopolysaccharides or nucleic acids) or damage-associated molecular patterns, or DAMPs, which are derived from host cells (dying cells and tumor cells). Once activated, PAMPs and DAMPs bind to pattern recognition receptors, including toll-like receptors and cytoplasmic NOD-like receptors (NLRs), to activate the intracellular inflammasome complex and facilitate the host CNS defense system.
Inflammasomes such as NLRP3, NLRP1b, and NLR family CARD domain-containing protein 4 (NLRC4) are expressed in the brain and circulate throughout the CNS. There is increasing evidence that inflammasome NLRP3 is involved in pain facilitation.28,29 CNS activation of microglia by the invading virus may be involved in regulating the development and maintenance of pain by causing microglial release of pain-related proinflammatory mediators and initiating inflammasomes. Importantly, sensitization of spinal neurons after the activation of microglia often persists for weeks, which may influence the maintenance of pain mechanisms.29
Post-acute COVID-19 survivors often report fatigue, diffuse myalgia, depressive symptoms, and sleep disturbances, which may be associated with the pathophysiologic events described earlier. In addition, headaches and cognitive impairment, or brain fog, may be related to the inflammatory response to COVID-19.
Although neurologic symptoms have been reported since the beginning of the pandemic,30 there has been very little research focused on identifying specific treatment targets. Concern is rising that a significant number of survivors will be burdened by neuropathic pain, cognitive impairment, and debilitating fatigue, with the challenge of getting patients back to their predisease state of functioning and quality of life.31 With the paucity of data on the number of people who are currently suffering with chronic pain related to COVID-19 infection, there is a clear need for research in this area both to identify people affected and to assess potential strategies for managing pain and other symptoms.
Models of Care for Management of Post-Acute COVID-19 Syndrome
To address the needs of patients and families affected by post-acute COVID-19 syndrome, health care systems across the nation have been responding by setting up post-COVID recovery programs with multidisciplinary team management.32,33
Based on the patient's disease course and symptoms, referrals may be made to pulmonary medicine, cardiology, neurology, and/or kidney specialists for diagnostic evaluation and follow-up care.
Psychologists and counselors may be needed to address mental health issues and symptom management, including anxiety and sleep disturbances.
Due to potential cardiac and pulmonary sequelae from COVID-19 infection, long-term surveillance and monitoring of symptoms are recommended to detect impaired function and provide treatment when indicated.
The full implications of COVID-19 on neurologic, cardiopulmonary, renal, and musculoskeletal functions remain unknown at this time. Thus, holistic assessments and follow-up are needed to gather data on population health outcomes among those with and without post-acute COVID-19 syndrome.
Rehabilitation specialists, including physical and occupational therapists, can be instrumental in helping patients to regain physical functioning and progress in carrying out activities of daily living and, if possible, return to employment. Social workers are also essential members of the team, helping to identify resources for basic living needs, health care coverage, and employment opportunities, and access to advocacy and/or support groups. Although many of these clinics are located in large health care networks, linking care received with the patient's primary care provider can help to provide continuity of care during the process of recovery.
Of interest, recent reports have documented that at least some long COVID-19 sufferers are improving after receiving any of the 4 available COVID vaccinations.34 Research is ongoing to identify the mechanisms of this phenomenon, and currently 2 theories have evolved:
Theory 1: Post-acute COVID-19 syndrome is caused when fragments of the virus are not cleared and continue to maintain an environment of low-grade inflammation. The vaccine induces an immune response, thereby boosting the body's ability to fight off the residual infection.
Theory 2: Post-acute COVID-19 syndrome is caused by the autoimmune response in which immune cells damage the body's organs and tissues. The vaccine activates the innate immune system and reduces autoantibodies, temporarily resulting in symptom improvement.
Conclusion
The COVID-19 pandemic continues to be a major public health challenge for people around the world. Acute symptoms of COVID-19 range from asymptomatic status to severe COVID-19 pneumonia with multiorgan involvement that place these patients at high risk for morbidity and mortality.
Post-acute COVID-19 symptoms can include a wide range of symptoms including fatigue, dyspnea, musculoskeletal pain, cough, anosmia, ageusia, and brain fog. Importantly, the severity of acute symptoms and illness does not predict the development and severity of post-acute COVID-19 syndrome. In response, health care systems must be prepared to meet the needs of people with post-acute COVID syndrome through careful surveillance measures, research, and multidisciplinary management of pain and other symptoms.
References