Postacute Sequelae of SARS-CoV-2: Musculoskeletal Conditions and Pain

Abstract

Musculoskeletal and pain sequelae of COVID-19 are common in both the acute infection and patients experiencing longer term symptoms associated with recovery, known as postacute sequelae of COVID-19 (PASC). Patients with PASC may experience multiple manifestations of pain and other concurrent symptoms that complicate their experience of pain. In this review, the authors explore what is currently known about PASC-related pain and its pathophysiology as well as strategies for diagnosis and management.

Introduction

Between December 2019 and August 2022, there were over 95 million confirmed cases of COVID-19 in the United States alone, although this is likely an underestimation of the true total infections due to limited testing and underreporting of positive cases.^{1 , 2} Although symptoms of acute COVID-19 often last 3 to 10 days, over half of people have reported experiencing prolonged symptoms^{3 , 4} that can be disabling and impact quality of life.⁵ Postacute sequelae of COVID-19 (PASC) or “long COVID” are terms to describe the ongoing or new symptoms 3 months or more after initial COVID-19 infection.6, 7, 8 Over 200 symptoms have been attributed to PASC, including various pain-related conditions.9, 10, 11 There is also emerging evidence that a range of musculoskeletal conditions and injuries may occur more frequently in patients with PASC compared with people without a history of COVID infection or in those who have recovered completely. Although there are a wide range of painful conditions associated with PASC, in this review the authors focus primarily on musculoskeletal and neuropathic pain as well as the potential impact of COVID on the incidence of musculoskeletal injuries and conditions.

Incidence and prevalence of musculoskeletal pain conditions after COVID

Pain is often not well recognized or attributed to PASC despite being reported by nearly half of patients with COVID-19.¹² Both new pain symptoms and exacerbation of chronic pain conditions have been observed in people with PASC.^{13 , 14} Although there is no established terminology or criteria for diagnosis of post-COVID-19 pain, new-onset chronic pain after COVID-19 infection is considered one of the five most common features of PASC.¹⁵ These symptoms negatively impact daily function, ability to work, and often lead to a higher need for health care services.⁹ It is also important to recognize that many patients with PASC report multiple concurrent pain symptoms, some of which may have different etiologies and treatment strategies. For example, patients commonly report concurrent headaches, chest pain, back and neck pain, myalgias, and arthralgias.^{16 , 17} Although the etiology of chest pain post-COVID is not well understood, chest pain is often musculoskeletal in nature as a secondary effect of coughing and respiratory symptoms rather than from cardiopulmonary or autonomic causes.

It can also be difficult to isolate musculoskeletal pain symptoms from neurologic conditions or other organ-system issues experienced by people with PASC and studies often group pain symptoms into a single category. In addition, the musculoskeletal conditions experienced by patients recovering from COVID-19 vary depending on the underlying conditions, initial severity of infection, and the treatment received for COVID-19.

In one large cohort of people infected with COVID-19 (n = 26,000), 43% of patients had reports of pain in their medical records 2 to 4 months after acute illness.¹² In this cohort, joint pain (21%) and headache (20%) were the most frequently reported pain conditions.¹² A recent meta-analysis (n = 2533) of hospitalized patients with COVID-19 found that 73% of patients had neurologic symptoms including headache, myalgias, and impaired consciousness.¹⁸ Another large meta-analysis of 28,000 patients with COVID-19 found that even among nonhospitalized populations, 16.5% reported headaches in the month after their acute illness and half of those were still experiencing headaches 6 months later.¹⁹ More than half of the patients in this meta-analysis reported some form of musculoskeletal pain 30-days after their acute illness²⁰ and 10% experienced musculoskeletal symptoms 1 year after initial infection.¹⁹ Despite the high prevalence of pain and the impact of pain symptoms on daily life, these symptoms are still not well characterized in PASC literature, and there are few studies specifically addressing the trajectory of painful conditions and effective treatment strategies.²¹

The following sections explore common musculoskeletal pain conditions in PASC, including prevalence, complicating factors, and critical illness considerations.

Myalgias and Arthralgias

Both myalgias and arthralgias are commonly reported in acute COVID and in PASC. Although they are frequently experienced together; patients may report the presence of one or the other in isolation. The prevalence of myalgias in PASC varies greatly between studies, ranging from 3% to over 64% with an estimated pooled prevalence of approximately 19%.^{22 , 23} Myalgia is a common symptom at the initial onset of COVID-19 with up to 36% documented in one meta-analysis of 10 studies (n = 1994).²⁴ However, the presence of myalgias is not significantly associated with severity of COVID-19 and should not be considered a prognostic factor.²³ Regarding arthralgias, two pain categories, “bone and joint pain” and “neck, back, and lower back pain,” were among eight post-COVID-19 symptoms to actually increase over the first year in the ComPaRe long COVID prospective e-cohort. The prevalence of the 45 other symptoms studied either decreased or stayed stable. Specifically, “neck, back, and lower back pain” showed the highest increase in prevalence of all symptoms evaluated over this time period.²⁵

Female patients are at higher risk of experiencing myalgias and arthralgias along with fatigue.^{26 , 27} In addition, high body mass index (BMI) is correlated with higher odds of experiencing myalgias, and arthralgias have been found at 1 month postinfection.²⁰ In a single-center prospective cohort study (n = 300) of hospitalized patients, not requiring intensive care unit (ICU)-level care, myalgias were present in 63% and were more likely to be widespread (40%) than localized (23%) with the lower leg being the most commonly localized area (69% of those reporting localized myalgias). Arthralgias (reported in 59% of patients) were also more likely to be widespread (33%) with the knee being the most common localized joint (51% of 26% localized arthralgias).²⁰

In a meta-analysis of PASC symptom prevalence in hospitalized and nonhospitalized COVID-19 survivors at 60 days after onset or hospitalization, chest pain (24%) and arthralgias (19%) were the most frequently reported symptoms.²⁸ Furthermore, approximately 10% of all patients reported myalgias and arthralgias beyond 90 days which were more prevalent in the nonhospitalized cohort (15% vs 8%).²⁸ At 6 months postinfection, approximately two in five patients had at least one rheumatic or musculoskeletal symptom. Fatigue (approximately one in three), arthralgia (one in five), and myalgia (one in seven) were the most frequent.²⁹ Of note, these symptoms were not among the most frequently reported symptoms at 30 days postinfection, which suggests that although fewer patients in total may experience these symptoms, they tend to be more persistent compared with other commonly reported symptoms, such as ageusia and anosmia.

Neuropathic Pain

Both new onset neuropathic pain and worsening of previously acquired neuropathic pain have been reported following COVID-19.^{30 , 31} Studies have also found that even patients who did not require hospitalization initially experienced worsening of underlying neuropathic conditions for at least several weeks following initial infection, suggesting that worsening neuropathic pain is not limited to those who were critically ill.³⁰ New onset neuropathic pain can have a variety of causes and it is important to recognize that it can be caused by peripheral nerve injuries, polyneuropathies, myopathies, and other neurologic conditions as well as by direct damage to sensory nerve cells from the virus itself.^{30 , 32} Acute ischemic stroke is another sequelae that can occur from SARS-CoV-2 infection and can lead to poststroke-associated neuropathic pain.³⁰

Post-Exertional Malaise

Post-exertional malaise (PEM), which occurs in a large subset of patients with PASC, is one of the hallmark symptoms of myalgic encephalitis (ME) or chronic fatigue syndrome (CFS).²⁹ PEM often presents as worsening fatigue, myalgias, and/or arthralgias 1 to 2 days following an increase in activities involving cognitive and/or physical exertion (including exercise). Triggers are often unknown but can be identified when patients keep detailed diaries of their activities. Although the mechanism of PEM is not fully understood, it is hypothesized to relate to dysfunctional endothelial cells and leakage of blood vessels with subsequent neuroinflammation and may involve dysregulation of the hypothalamic paraventricular nucleus, which affects the function of the hypothalamus and proximal limbic system.³³

Myositis

From a review article in July 2021, there have been at least 23 case reports of myositis attributable to coronavirus (COVID)-19 (C19 M).³⁴ The presentation and severity reported are varied, ranging from dermatomyositis to paraspinal associated myositis to severe rhabdomyolysis.³⁵ Owing to this, it is difficult to know the true incidence as differential with myalgias and modestly elevated creatine kinase (CK) include critical illness myopathy (CIM), neurogenic muscle disease, and true myositis.³⁵ The proposed mechanisms include the SARS-Cov-2 directly entering muscle cells via ACE2 receptor, but this has not been proven when looking at muscle biopsies and so it is favored that myositis is due to the virus triggering an autoimmune response. As such, the timing of myositis has been seen to lag by up to a few weeks and may become more prominent in the PASC period.³⁶ Outcomes also vary with some patients recovering within a few weeks and half within a few weeks to months. This leaves a large portion to have lingering weakness remote from their acute COVID-19 infection.³⁷ For these patients with prolonged C19 M, immunosuppressants such as mycophenolate mofetil, calcineurin inhibitors, and Janus kinase (JAK) inhibitors maybe considered by their rheumatologist.^{34 , 37 , 38}

Dermatomyositis

While not a direct link, an observational study of a single pediatric center showed a rise of 60% compared with average admissions in the same period from 2014 to 2019 for pediatric patients with dermatomyositis in the initial period of the pandemic. ³⁷

Acute viral myositis

Most cases reported were males, aged 33 to 87.³⁴ Initial examination findings are variable from subtle weakness to profound, and patients likely to have an elevated creatine kinase, although creatine kinase levels do not directly correlate with severity or prognosis.³⁴

Paraspinal myositis

Myalgia and back pain are common symptoms reported by patients and characterized as more generalized musculoskeletal symptoms that are likely multifactorial. There has been a case series of nine patients with seven of nine patients with MRI findings showing intramuscular edema and enhancement, consistent with a diagnosis of paraspinal myositis.³⁹ Involvement is seen in bilateral erector spinae and multifidus paraspinal muscles exclusively in the lumbar spine.^{34 , 39} These findings were also associated with a prolonged hospital course (>25 days) and continuation of back pain in the postinfectious period. In this case series, most of these patients underwent MRI due to known “underlying degenerative spine disease and occasional neurogenic symptoms.”³⁴ Although literature suggests this is a more rare finding, it is important to consider that many patients are not receiving advanced imaging for low back pain so prevalence is difficult to ascertain. In a patient with a protracted course of low back pain, paraspinal myositis should be considered on the differential as it may change the treatment options than typical first-line conservative measures for new onset low back pain.

Rhabdomyolysis

Rhabdomyolysis is the rapid breakdown of skeletal muscles, resulting in muscle pain, weakness, and hallmarked by dark urine and elevated serum or plasma creatine kinase levels. Patient presentation is characterized by an acute, symmetric, lower limb-dominant muscle weakness.³⁴ Rhabdomyolysis has been associated with multiple viral infections including influenza, Epstein–Barr, adenovirus, and parainfluenza. Numerous case reports of rhabdomyolysis in patients that tested positive for SARS-COV-2 have been reported, being described as a presenting feature and a late complication.⁴⁰ A systematic review reported incidence ranging from 0.2% to 2.2% in hospitalized COVID-19 patients.⁴¹ In one case series of four patients with rhabdomyolysis, all patients required intubation, suggesting that this is likely a complication associated with severe disease rather than milder initial infections or associated with PASC. Although rhabdomyolysis is likely to be a rare manifestation in critically ill patients with COVID-19, it does have life-threatening implications and can lead to severe acute kidney injury as well as prolonged pain and recovery. Mortality has been reported as high as 30% in patients with COVID-19-related rhabdomyolysis with higher rates in patients with rapidly progressing interstitia lung disease (ILD).⁴¹

Critical Illness Considerations

COVID-19 infections resulting in severe illness and requiring hospitalization with intensive care unit admissions have additional musculoskeletal, neuromuscular, and neurologic conditions to consider given the nature of the treatments and inherent risk of myopathy and peripheral nerve injuries that can occur in this context.¹⁴ Patients who have survived critical illness with COVID-19 are at higher risk of developing chronic pain than those with milder infections, which is likely multifactorial, including not only factors related to their ICU stays, which is an independent risk factor of developing chronic pain, but also due to social determinants of health, the overburdened and stretched health care system, psychological impacts, and social restrictions (loneliness and perception of increased isolation).^{15 , 42} In addition, high BMI, female sex, and myalgias at hospital admission are risk factors for development of chronic pain.¹⁵ Many patients who were critically ill with COVID-19 were also older adults and/or with significant comorbidities, both of which place people at higher risk of developing pain.

Peripheral Nerve Injuries

Often, the treatment itself for hospitalized patients with severe COVID-19 infections puts patients at risk for peripheral nerve and musculoskeletal injuries. For example, positioning patients in the prone position for prolonged periods of time to improve respiratory function places these critically ill patients at risk for brachial plexopathy, joint subluxation, and soft tissue damage.⁴³ Cases of unilateral ankle dorsiflexion weakness or foot drop have been attributed to fibular head and fibular nerve compression due to prone positioning of critically ill and ventilated/sedated patients including those with COVID-19.²⁸ In one study of patients recovering from acute respiratory distress syndrome (ARDS) associated with COVID-19 (n = 83) at a stand-alone rehabilitation center, 14% developed a peripheral nerve injury with 76% occurring in the upper limb and most frequently involving the ulnar nerve (29%).⁴⁴ At least one proning session occurred in 62% of those patients.⁴⁴ In addition to proning, these patients also spent significant time in supine positions while receiving neuromuscular blocking agents, increasing their susceptibility to nerve injuries.^{30 , 44} There were also high rates of diabetes mellitus, obesity, and older-aged patients in this cohort, which each independently places patients at higher risk for developing these types of nerve injuries.⁴⁴

Polyneuropathy

Painful polyneuropathy has been documented in both critically ill and non-critically ill COVID-19 survivors, although is most often associated with critical illness polyneuropathy (CIP).⁴⁵ There have also been documented cases of Guillain–Barre syndrome associated with COVID-19, which is predominately the acute inflammatory demyelinating neuropathy subtype.⁴⁶ In addition, mononeuritis multiplex has also been described after COVID-19 with risk factors including preexisting diabetes, obesity, drug use, and prolonged ICU stay.⁴⁶ Drug-induced polyneuropathy due to neurotoxic drugs such as daptomycin, linezolid, lopinavir, ritonavir, hydroxychloroquine, cisatracurium, clindamycin, and glucocorticoids has also been described as a leading cause of polyneuropathy in patients recovering from COVID-19.⁴⁶ There is little evidence to support the role of infectious neuropathy; rather polyneuropathy in patients with COVID-19 is thought to be secondary to the medications received to treat the infection and associated conditions, critical illness itself, and underlying chronic medical conditions.^{45 , 46}

Critical Illness Polyneuropathy

CIP is characterized by a symmetric, length-dependent sensorimotor axonal polyneuropathy. An observational ICU cohort study (n = 111) found that CIP was associated with increased illness severity and was more frequent among COVID-19 patients compared with a non-COVID-19 cohort.⁴⁷ It has also been observed in the generalized ICU population, CIP often occurs concurrently with CIM.⁴⁸ Incidence is difficult to assess due to numerous circumstances including unknown premorbid status, ongoing severity of illness and inability to perform adequate physical examination, patient’s unable to vocalize symptoms, limited resources and staff availability to perform electrodiagnostics, and mortality. There is likely an underreporting of cases. It is thought that in the generalized ICU population, CIP affects between one-third and one-half of the most severely critically ill patients.^{49 , 50}

Critical Illness Myopathy

CIM is a primary myopathy characterized by the preferential loss of myosin.⁴⁹ It is not secondary to muscle denervation.⁴⁹ CIM impacts patients with severe COVID-19 with prolonged hospitalizations and causes generalized and symmetric muscle weakness impacting limbs as well as respiratory muscles, pain, and weakness-related musculoskeletal injuries. This is thought to be due to muscle wasting from lack of use, impaired contractility, associated neuropathies, and muscle dysfunction with dysregulated autophagy and dysfunctional mitochondrial pathways.^{51 , 52} Needle electromyography (EMG) will demonstrate spontaneous activity in the muscles. Risk factors include sepsis and/or shock, multiple organ failure, prolonged mechanical ventilation, and metabolic disturbances such as hyperglycemia, and age, weight, comorbidities, and exposure to neurotoxic medications.^{51 , 52} One small study of 12 patients with COVID-19 referred for CIM or polyneuropathy electrodiagnostic testing did not find any distinctive features that differentiated patients with COVID-19 patients with CIM from the general ICU-hospitalized patient population experiencing CIM.⁵³ The incidence of CIM in COVID-19 patients has been found to increase with severity of disease.⁴⁷ The incidence of CIM following COVID-19 infection is not well understood but likely mirrors the general population of patients with critical illness treated in the ICU given that it does not seem to be unique to COVID-19.⁵³ It is thought in the ICU population, CIM affects approximately 25% of patients.^{54 , 55}

CIP/CIM Outcomes

For outcomes, we must extrapolate from more well-studied general ICU populations. CIM and CIP are especially important to consider in PASC patients as they often cause a significant loss of function for patients that persists for months to years after critical illness resolves. CIM is thought to have a better prognosis than CIP and combined CIM/CIP cases.^{45 , 48} For patients in an ICU cohort study, 25% with CIM demonstrated earlier markers of electrophysiological signs of recovery and lower degrees of weakness at discharge from the ICU (mean 19 days), compared with none in patients with CIM/CIP patients, despite CIM/CIP patients having a longer ICU length of stay (mean 35 days).⁴⁸ CIM patients, in the CRIMYNE study (n = 92, ICU patients, not COVID-specific) recovered within 6 months, whereas CIP patients had a slower recovery or never recovered fully.⁵⁶

Pathophysiology/proposed mechanisms

The pathophysiology of PASC is thought to involve a prolonged immune system response to initial COVID-19 infection leading to a cascade of inflammatory and/or autoimmune processes.⁵⁷ Studies have demonstrated that laboratory abnormalities suggestive of immunologic dysfunction can be present in patients with PASC several months after acute COVID infection.⁵⁸ Although the etiology is likely multifactorial and uncertainty remains as to the exact mechanism of PASC-related pain, immune-mediated processes may play a key role in the modulation of the inflammatory response that characterizes pain associated with COVID. Examples of potential mechanisms that may contribute to PASC-related pain and musculoskeletal injuries include dysregulation of the renin angiotensin system (RAS) and the resulting impact on macrophage activation, inflammation and neural signaling, mitochondrial dysfunction, fibrin-amyloid microclots, and secondary effects of prolonged illness, including deconditioning and muscle weakness.

Renin Angiotensin System Dysregulation

SARS-CoV-2 infects cells by attaching its spike protein to the angiotensin-converting enzyme-2 (ACE2) receptor. The ACE2 receptor is found on the surface of a variety of cells, including neurons, astrocytes, endothelial, and smooth muscle cells of cerebral blood vessels, and skeletal muscle cells, which explains the uptake of SARS-CoV-2 in the peripheral and central nervous systems and the broad range of symptoms experienced by people infected with SARS-CoV-2.⁵⁹

By attaching to the ACE2 receptor, SARS-CoV-2 prevents degradation of angiotensin II and leads to overactivation of the angiotensin II receptor type I (AT1R). This activation of the AT1R results in downregulation of the ACE2 expression and unchecked inflammation, oxidative stress, vasoconstriction, tissue fibrosis, and a wide range of neurologic complications. This imbalance of the RAS is the primary cause of the “cytokine storm” and cellular damage that causes many of the life-threatening acute complications of COVID-19 such as ARDS and multiorgan system failure. Cytokine storming is an outpouring of pro-inflammatory cytokines including interleukin (IL)-6, tumor necrosis factor (TNF)-α, IL-1β, IL-8, and IL-12, interferon (IFN)-γ inducible protein (IP10; also termed as motif chemokine ligand 10, macrophage inflammatory protein 1A, and monocyte chemoattractant protein 1.⁶⁰ Of these pro-inflammatory cytokines, IL-1β, IL-6, IP10, and TNFα are the ones with the greatest ability to induce direct tissue injury in several organs and systems, including the peripheranl nervous system (PNS) and central nervous system (CNS) (Fig. 1 ).

Fig. 1.

Potential mechanisms of COVID-pain (SARS-CoV-2/COVID-19-induced pain). (A) ACE2/RAS pathway and the direct virus-induced damage. Within the RAS, the virus/receptor (ACE2) interaction involves unbalance of the ACE/Ang II/AT1R and the ACE2/Ang-(1–7)/MasR axes with downregulation of ACE2 levels on cell surfaces, Ang-II accumulation, and impairment of the anti-nociceptive Ang-(1–7) pathway. Therefore, direct damage to sensory neurons and/or glial cells is produced. (B) Macrophage activation. Macrophages and other immune cells can stimulate the production of inflammatory mediators (eg, IL-1β, TNF, and bradykinins). These processes can facilitate the sensory cells injury and can lead to chronic pain through sensitization/activation processes. (C) The exuberant immune-mediated inflammation. It is mostly responsible for systemic damage and the triggering of long-COVID problems (including widespread myalgia and joint pain) via peripheral and central mechanisms. Disease-related and predisposing factors contribute to the determinism of the damage.

(Reproduced from Cascella M, Del Gaudio A, Vittori A, Bimonte S, Del Prete P, Forte CA, Cuomo A, De Blasio E. COVID-Pain: Acute and Late-Onset Painful Clinical Manifestations in COVID-19 - Molecular Mechanisms and Research Perspectives. J Pain Res. 2021 Aug 10;14:2403 to 2412. https://doi.org/10.2147/JPR.S313978. PMID: 34408485; PMCID: PMC8364364.)

The RAS imbalance is also believed to contribute to many of the longer term sequelae of COVID-19 including PASC-related pain. Given that ACE2 receptors are located in muscle tissue, attachment of the spike protein to these receptors can lead directly to inflammation and cellular damage. In addition, ACE2 receptors are also located on the dorsal root ganglia (DRG) in the skin, luminal organs, and meninges and attachment of the SARS-CoV-2 to these receptors can cause an imbalance in the neuromodulation systems of nociception and result in neuropathic pain. A recent study of human tissue donors (organ donors and tissue obtained during vertebrectomy surgeries) found that 25% of the sampled DRG neurons expressed ACE2 and these free nerve endings create an entry point for the SARS-CoV-2 into the peripheral nervous system.⁶¹

Fibrin-Amyloid Microclots

Acute SARS-CoV-19 infection is associated with a variety of clotting abnormalities, including a hypercoagulable state that can cause acute thrombosis and endotheliopathies. In acute infection, markers of coagulopathies, such as the D-dimer, Von Willebrand factor, and fibrinogen levels, have been shown to be important markers of prognosis. In addition, there are a number of studies that have demonstrated the presence of microclots in the lungs as well as high levels of circulating amyloid clots and damage to platelets and erythrocytes in severe acute COVID-19 infections.⁶² There are now increasing reports of these same mechanisms being at play in many of the PASC symptoms, including COVID-related pain. Coagulopathies are known to be associated with a variety of autoimmune and inflammatory conditions, including rheumatoid arthritis. However, the coagulopathies observed in patients with PASC symptoms seem to be somewhat different in that there are high levels of circulating amyloid-containing microclots that are more resistant to fibrinolysis.⁶³ In recent research, these fibrin-amyloid microclots have been observed to entrap inflammatory cells and importantly can pass through microcapillaries and cause blockages. In one study of patients with ME/CFS (which overlaps with PASC in terms of etiology and clinical manifestations), it was noted that they had levels of microclots that were 10-fold that of healthy controls. It is hypothesized that these episodic blockages of the microcapillaries with the fibrin-amyloid microclots may be one cause of some of the transient or migratory pain and neurologic symptoms that many patients with PASC experience.

Autonomic Dysregulation

Patients with PASC often experience symptoms consistent with autonomic dysregulation including instability of heart rate, blood pressure, lightheadedness when standing, chest pain, palpitations, headaches, neuropathic pain, and musculoskeletal pain. Patients may have symptoms consistent with a diagnosis of postural orthostatic tachycardia syndrome (POTS). POTS is triggered by an immunologic stress, which can include a wide range of viral infections, trauma, pregnancy, surgery, or psychosocial stressors. Although the etiology of autonomic dysregulation is not well understood, similar to other PASC symptoms, it is hypothesized to relate to an autoimmune response that involved increased sympathetic activity and potentially denervation which can cause postural central hypovolemia and reflex tachycardia.⁶⁴ It is hypothesized that autonomic dysregulation also causes exacerbation of sensory, autonomic, and small-fiber neuropathies, which may explain the worsening of neuropathic pain in people with POTS or autonomic dysregulation following COVID-19.⁶⁵

Muscle Fatigue Due To Mitochondrial Dysfunction or Deconditioning

Another important potential mechanism for musculoskeletal injuries and pain in patients with PASC is the cumulative effect of chronic illness and inability to tolerate activity on overall strength, endurance, and flexibility. Many people with PASC symptoms have debilitating fatigue and pain that limits their ability to participate in usual activities including exercise. Given the broad range of symptoms that patients with PASC experience as well as the range of severity of organ-level consequences, there has been an increasing interest in understanding how much of what people are experiencing is related to deconditioning versus direct organ damage, mitochondrial dysfunction, or other quantifiable immune system-related processes. One potential way to evaluate this is through the use of cardiopulmonary exercise testing (CPET). In one recent cohort study of people experiencing PASC symptoms, most of the patients were not found to have any evidence of specific end organ damage (including cardiac and pulmonary damage) but had findings consistent with general deconditioning in CPET testing.⁶⁶ Another study of 71 patients with symptoms lasting up to 12 months post-COVID-19 infection found that the reduction in exercise tolerance found through CPET was most consistent with deconditioning and that patients who were initially treated in the ICU setting (more severe acute COVID-19) were much more likely to exhibit signs consistent with deconditioning.⁶⁷ However, there is emerging evidence using CPET data to suggest that at least some patients with PASC experience mitochondrial dysfunction during graded exercise that leads to reductions in fat β-oxidation and an increased buildup of blood lactate. This increase in lactic acid during exercise may play a significant role in the development of PEM.⁶⁸

Impact of postacute sequelae of COVID-19-related musculoskeletal pain conditions on function, quality of life, and return to work

Pain in critical illness requiring ICU level care is a known risk factor for inability to return to work and reduced quality of life for up to 5 years after hospitalization.^{14 , 42} Given the prior research of the long-term impact of critical illness on quality of life and quality-adjusted life years, it has been proposed that ICU admission should be treated as a diagnosis that needs to be monitored and treated lifelong. Although COVID-19 is a new viral illness, research is demonstrating similar impacts of severe COVID-19 requiring ICU admission on long-term quality of life and return to work. In addition, pain seems to be one of the most disabling conditions associated with COVID-19 recovery.

In a single-center prospective study, individuals with critically ill COVID-19 were interviewed 1 month post-hospitalization. Pain was assessed using multiple scales, with 51% reporting new onset pain, 39% with clinically significant pain and those with pain were found to have worsened anxiety and depression scores. Overall, new-onset pain was associated with a lower health-related quality of life.²¹

New functional impairments are also common at 30 days after discharge among survivors of hospitalization for COVID-19, although pain is only one of the contributing factors to these impairments.⁶⁹ One prospective cohort study (n = 92) following individuals between 1 and 6 months after hospitalization, demonstrated that a majority (63%–67%) developed new activities of daily living (ADL) impairment, fatigue, or worsening physical function at 1 month, and of those, only 50% to 79% partially or fully recovered by 6 months.¹⁶

For patients with CIM, compared with their ICU counterparts without CIM, long-term complications include increased mortality, prolonged time to discharge home, and decreased physical function. Studies of ARDS patients showed that even 5 years after ICU discharge, patients still experienced varying degrees of weakness and reduced walk and exercise ability.^{16 , 52}

Return to Work

Although not a pain or musculoskeletal issue, fatigue is a common symptom that persists for many patients who are experiencing PASC. This directly affects patient’s abilities to reintegrate into their community and return to work.^{28 , 69} In a cross-sectional study (n = 55), compared with pre-COVID hospitalization, 52% developed new difficulty with performing basic ADLs and 69% experienced a clinically significant worsening in their fatigue symptom severity.⁶⁹

Evaluation of postacute sequelae of COVID-19-related pain

Navigating the health care system to obtain appropriate care can be a frustrating experience for patients experiencing PASC, particularly due to the wide range of symptoms experienced and limited availability of clinicians with familiarity with PASC conditions. Many clinicians fail to recognize pain symptoms contributing to PASC and are not well trained in current guidelines related to diagnosis, treatment, or the additional hurdles of communicating with insurers or workplaces that may be necessary to help patients manage their pain.⁷⁰

Multidisciplinary post-COVID clinics have been formed across the United States to better care for patients with PASC. In addition, multidisciplinary collaboratives such as the American Academy of Physical Medicine and Rehabilitation PASC Collaborative have been formed to help develop clinical guidance documents, develop standards of care, and advocate for additional resources to care for patients with PASC.⁷¹ However, there are substantial gaps in the knowledge base related to optimal workups, diagnosis, and treatment of PASC symptoms, particularly PASC-related pain. Thus, PASC clinical care and research require interdisciplinary teams to address these gaps and approach PASC in a more holistic manner.^{72 , 73} In addition, the need for this interdisciplinary approach creates an even larger care gap in rural communities that are already disproportionately impacted by COVID-19, but do not have the resources available to address patients with PASC.74, 75, 76 Currently, post-COVID clinics and other medical practices across the country have minimal standardization in how they approach developing care teams and treating the rapidly growing numbers of patients with PASC and PASC-related pain.^{71 , 77}

Despite the limited research available to guide diagnosis and treatment of PASC-related pain, there is a lot that can be drawn from knowledge about other related pain conditions and based on an understanding of etiology of PASC-related pain and concurrent symptoms. The following section describes some specific considerations for the evaluation of PASC-related musculoskeletal symptoms and pain.

History

In addition to a standard comprehensive musculoskeletal and pain history, providers should obtain a detailed history of COVID-19 infection, symptoms, severity, course, duration, hospitalization, and treatments received (including antivirals in both in- and outpatient settings). If patients were treated in the ICU setting, this should be noted and an attempt should be made to understand the treatments received in this setting including positioning, neuromuscular blockades, ventilatory strategies used, and other complications. Patients who were hospitalized, and especially requiring prolonged ICU care, may present with brachial plexopathy, joint subluxation, and soft tissue damage from prolonged positioning. Although pain and musculoskeletal symptoms are often widespread in PASC, it should be noted that the common location for myalgias is the lower leg and for arthralgias is the knees.²⁰ Patients should also be asked about frequency and timing of the most bothersome symptoms as symptoms can fluctuate over time and can be migratory. Understanding if myalgias and arthralgias are localized to specific joints or to specific times during the day can help to target treatments. Exacerbating and relieving factors should be identified whenever possible to help patients develop self-management strategies. This often requires patients to keep diaries of their symptoms and activities to try to identify factors that may be contributing to worsening symptoms. PEM, for example, is often only established after looking for patterns from patient diaries and seeing that it occurs within 1 to 2 days after heavier periods of physical or cognitive activity. As dysautonomia or POTS are common in people with PASC and are associated with pain, it is also important to ask about postural lightheadedness, tachycardia or palpitations, and heart rate and blood pressure instability.

The review of systems should include inquiry into common PASC symptoms, such as musculoskeletal symptoms including joint and muscle pain, fatigue, fever, sleep disturbance, respiratory and cardiovascular symptoms including breathlessness, cough, chest tightness, chest pain, palpitations; neurologic symptoms including “brain fog” (decreased concentration or memory), headache, paresthesias, numbness, dizziness, delirium (in older populations); gastrointestinal symptoms including abdominal pain, nausea, diarrhea, decreased appetite; psychological/psychiatric symptoms including depression and anxiety; ear, nose, and throat symptoms including tinnitus, earache, sore throat, and loss of taste and/or smell.

Examination

Physical examination can follow the standard approach to a comprehensive, history-driven physical examination of musculoskeletal and neurologic systems. In addition, evaluation of vital signs with postural changes, including the 10-minute National Aeronautics and Space Administration (NASA) lean test, can provide additional data in patients experiencing symptoms suggestive of dysautonomia or POTS.⁷⁸ Functional tests that are feasible in the clinic setting such as a 2 or 6 minute walk test with pre- and post-vital signs and timed up and go can also be helpful to measure the impact of their symptoms on endurance, cardiopulmonary function, strength, and balance. Evaluation of mood, affect, and cognitive ability are also important to assess in patients with PASC, particularly if they endorse difficulties in these areas by history.

Laboratory Testing

Laboratory tests can be useful for further evaluating the type of pain patients are experiencing (eg, inflammatory vs mechanical or other), or ruling out alternate causes of pain and related comorbidities. Some examples of laboratory tests that are recommended as part of the general PASC workup include, complete blood count with differential, c-reactive protein, erythrocyte sedimentation rate, complete metabolic panel, magnesium level, thyroid function tests, ferritin, iron panel, vitamin D level, hemoglobin A1c and when pain is present, considering uric acid, rheumatoid factor (RF), anti-cyclic citrullinated peptide (CCP) antibodies, and/or antinuclear antibody (ANA) reflexive panel with titers, among other autoantibodies depending on the patients personal and family history.

Autoantibodies as Potential Laboratory Confounders

Several studies have noted autoantibody positivity in acute COVID-19 infection and beyond.79, 80, 81, 82, 83, 84, 85, 86 Some examples of autoantibodies implicated include ANA, antineutrophil cytoplasmic antibodies, anti-CCP antibodies, RF, antiphospholipid antibodies, anti-interferon antibodies, anti-interleukin antibodies, anti-thyroglobulin, and among many others. ANA positivity—usually found in cases of connective tissue disease (CTD) such as systemic lupus, scleroderma, or mixed CTD—has been reported in up to one-third of acute COVID-19 cases.⁷⁹ ANA positivity has been linked to higher illness severity from COVID-19 (anti-DNA positive predictive value [PPV] 86%) and increased complications, including ICU stays.⁸¹ Furthermore, persistent autoantibody positivity has been noted for several months after acute COVID infection. One recent study reported ANA titers greater than 1:160 in 43% of patients 12 months after onset of COVID-19 symptoms.⁸⁰ Given that PASC pain can sometimes mimic other diagnoses, such as ANA-associated CTD, ordering ANA tests has been recommended as part of the workup for PASC pain symptoms.⁷⁷ Caution should be taken, however, when contemplating ordering immunologic laboratory testing to workup PASC-related pain as the clinical relevance of autoantibody positivity post-COVID infection remains poorly understood. It is unclear if a positive test represents new onset of a rheumatologic condition, latent autoimmunity, worsening of a previously diagnosed inflammatory condition, PASC as a new autoimmune condition itself, other immunologic dysfunction, or simply an incidental finding, as benign ANA (eg, anti-dense fine speckled-70 antibodies) can be found in up to 20% of healthy individuals without autoimmune disease.^{87 , 88} Furthermore, although autoantibody positivity may be alarming as it is classically seen in cases of CTD, transient autoantibody production may be driven by the downstream activation of autoreactive B and T cells triggered by cytokines or by the B and T cells themselves recognizing viral antigens (molecular mimicry).⁸⁶ Therefore, careful interpretation of autoantibody laboratory tests during acute viral infections and even several months after suspected recovery is advised.

Diagnostic Testing

If patients have signs of peripheral neuropathy on physical examination and/or by history, nerve conduction/EMG testing is appropriate. If small fiber neuropathy is suspected, a single fiber EMG and/or skin biopsy may be required to diagnose. In the setting of clinical suspicion for obstructive sleep apnea (OSA), sleep studies may be indicated, as untreated OSA may aggravate acute and chronic pain conditions.⁸⁹ CPET, if available, may also be particularly useful in distinguishing mitochondrial dysfunction from deconditioning or cardiopulmonary causes of exercise intolerance and PEM.

Rehabilitation/treatment strategies

Much of the approach to PASC rehabilitation and therapeutics will overlap with typical pain- and musculoskeletal-related strategies. However, special consideration is needed for concurrent neurologic, autonomic, inflammatory, and cardiopulmonary symptoms and dysfunction. In addition, it is important to recognize the impact of insomnia, mental health issues and coping strategies on the experience of post-COVID pain and PASC.

Rehabilitation Strategies

Rehabilitation approaches can consider gradual return to activity as tolerated, although no validated protocols exist at this time. Physical therapy can play an integral role in structured rehabilitation addressing deconditioning, poor balance, and moving safely in pain and fatigue, as well as addressing specific pulmonary and cardiovascular considerations such as shortness of breath and POTS/dysautonomia. For patients at risk for PEM, it is important that activity-based rehabilitation be mindful of the potential impact of exertion on PEM and to not exceed the threshold of activity that triggers PEM for a given patient. Over time, this threshold can be gradually increased in many patients. In general, restorative exercises such as breathing exercises, stretching, yoga, and gentle low-intensity aerobic exercise tend to be more well tolerated than high-intensity aerobic exercise or weight training. High-intensity aerobic exercise and weight training are associated with temporary increases in inflammation and cortisol levels, which may exacerbate pain conditions and trigger PEM.⁹⁰ In addition, for patients with postural tachycardia, recumbent exercises tend to be more well tolerated.

Respiratory issues are common in PASC and may be interpreted as barriers to physical activity by patients. Home breathing exercises can help alleviate some respiratory symptoms that limit ability to engage in physical activity. This may include pursed lip breathing or incentive spirometry. Breathing and conditioning exercises can be done during the same session or separately.

Lifestyle Recommendations for Postacute Sequelae of COVID-19 Recovery and Pain Management

Given the emerging research that suggests that PASC-related pain may be mediated by an inflammatory response, reducing inflammation through diet and lifestyle may help with recovery and symptom management.⁵⁷ Anti-inflammatory lifestyle strategies include an anti-inflammatory diet,^{91 , 92} such as the Mediterranean diet, smoking cessation, limiting alcohol intake, regular exercise/activity, good quality sleep, stress management, and weight management. As part of interdisciplinary care for PASC, nutritionists can be particularly helpful for some patients to engage in health eating and weight-loss strategies, particularly those with coexisting medical conditions or dietary restrictions.

Quality sleep may be supported by interventions such as education on sleep hygiene, evaluation for sleep apnea, and medications such as melatonin. Patients may also experience depression, anxiety, regret, trauma, re-experiencing hospitalization, and loneliness following COVID-19 infections. Evaluation and treatment for concurrent mental health issues are important to support pain management. Rehab psychology and counseling are an important component of management of chronic pain conditions, particularly when there are concurrent mental health issues that may impact recovery.

Clinician-moderated support groups that focus on behavioral strategies to manage PASC-related symptoms, including pain, are one strategy developed for PASC and currently being evaluated. These interventions may be particularly helpful in providing patients with peer support in a moderated setting in which they are guided to evidence-based strategies for self-management of symptoms and have previously been found to be effective in ICU recovery.⁹³

Pain Medications in Postacute Sequelae of COVID-19-Related Pain

The approach to medication management of PASC-related pain can be similar to typical pain management strategies but with important considerations specific to PASC. For example, patients with PASC may be particularly sensitive to the sedating and cognitive impairment side effects of commonly used pain medications such as gabapentin and other anticonvulsants, sedating antidepressants, muscle relaxants, and opioids as many experience a PASC-related “brain fog.” Interestingly, low-dose naltrexone (LDN) has shown promise in its use for PASC-related pain, fatigue, and mood, though data are limited to small non-randomized studies, and more rigorous evaluation is needed.⁹⁴ Side effects of LDN include diarrhea and fatigue and may limit use.⁹⁴ In addition, cost and availability of pharmacies able to compound LDN may be additional barriers to use.

Disability and Return to Work Considerations

Considering the broad constellation of symptoms of PASC and PASC-related pain conditions on daily function, patients benefit from a comprehensive approach to disability accommodations. Symptoms can fluctuate during the day or over time, which can make it challenging for employers to understand how to make reasonable accommodations. In addition, the delayed responses to overexertion seen in PEM can make it more challenging to communicate the need for accommodations to prevent these worsening symptoms of pain and/or fatigue. Return to work evaluations should consider work intensity, duration, responsibilities, and physical and mental demands. When available, vocational counseling can be particularly important to help patients navigate return to work strategies, appropriate work accommodations, and the disability system.

Health equity considerations

It is well-documented that COVID-19 has had disparate impact on lower socioeconomic and minority communities.⁵⁶ This includes not only a higher risk of experiencing COVID-19 infection but more severe illness and higher rates of death. Although research in this area is sparse, these increased risks likely extend further into the impact on pain and musculoskeletal health issues. The social determinants of health, including access to care, insurance status, financial security, housing stability, and health literacy have a direct impact on many of the comorbidities and risk factors for worse outcomes following infection with COVID-19, such as obesity, hypertension, renal disease, and diabetes.

In addition, for some of the most pervasive and impactful symptoms, including fatigue, myalgias, and arthralgias, female patients are at higher risk than men. Fatigue is often one of the largest contributors to a delay in return to work or need for reduced work hours and can therefore cause further financial stress, particularly in women.

Furthermore, given that PASC is still an emerging public health issue, most PASC care is clustered in urban, academic settings, which disproportionately limits access to care to those living outside of those communities or without the means to travel to these clinics. The rapid expansion of telemedicine has increased the ability to provide care to patients in less accessible communities, but still requires that patients have financial and geographic access to Internet connection and technical skills to manage a telecommunication platform.

Financial considerations should also be considered when offering diagnostics and counseling to patients. Laboratory tests, advanced imaging, medications, therapies, and procedures such as electrodiagnostics are costly for an uninsured or underinsured patient or may not be covered by a patient’s insurance. There is also the added financial burden if the patient or their caregiver has to take time off work to attend appointments. Furthermore, most of the supplements that we can offer patients are not covered by insurance and specialty medications, such as LDN have the added burden of needing a specialty compounding pharmacy, which can be challenging.

Research gaps

Although there is rapidly emerging research related to the etiology, risk factors and experiences of people with PASC, there are critical gaps in our understanding of PASC-related pain. Although we are starting to better understand the pathophysiology of PASC-related pain, it is clear that more research is needed as there are many different phenotypes of pain and likely many different associated causes of PASC-related pain and different phenotypes. In addition, there is even more limited data on health disparities, particularly as they relate to the experience of pain and access to treatment for PASC-related pain conditions. There are emerging data suggesting that musculoskeletal injuries may be increased after COVID-19 particularly among athletes, but this relationship is not clear and needs further exploration.95, 96, 97 In addition, although there are a number of evidence-based treatment strategies for many of the painful conditions experienced in PASC, there are very few ongoing clinical trials of treatments specifically for PASC-related pain.

Summary

Pain is common in people who are recovering from COVID-19, and patients may experience a wide range of painful conditions including musculoskeletal-related and neuropathic pain. Patients may experience multiple different painful conditions and other concurrent symptoms that complicate their experience of pain. Although the pathophysiology of pain in PASC is still largely unproven, it likely relates to a variety of immune system changes including inflammation, the presence of auto-antibodies, autonomic dysregulation, and changes in clotting. A thorough history and diagnostic evaluation are important given the myriad symptoms, concurrent conditions, and exacerbating factors that can impact recovery from pain. Despite the limited availability of clinical trials of specific treatment strategies for PASC-related pain, there are many rehabilitation strategies that can be used to address COVID-related pain and a number of emerging and promising treatments that are under evaluation.

Disclosures

None.

Clinics care points

• •Painful musculoskeletal conditions are common in patients with post-acute sequelae of COVID-19 (PASC).
• •Many patients with PASC experience multiple concomitant pain symptoms.
• •Pathophysiology of pain in PASC is still unproven but a variety of immune system changes including inflammation, the presence of autoantibodies, mitochondrial dysfunction, autonomic dysregulation, and changes in clotting have been hypothesized.
• •Treatment strategies should be holistic and take into consideration other concurrent PASC symptoms and a biopsychosocial treatment approach.