Myalgia As a Symptom at Hospital Admission by Severe Acute Respiratory Syndrome Coronavirus 2 Infection Is Associated With Persistent Musculoskeletal Pain as Long-term Post-COVID Sequelae

A Case-control Study

César Fernández-de-las-Peñas; Jorge Rodríguez-Jiménez; Stella Fuensalida-Novo; María Palacios-Ceñ; Víctor Gómez-Mayordomo; Lidiane L. Florencio; Valentín Hernández-Barrera; Lars Arendt-Nielsen

Disclosures

Pain. 2021;162(12):2832-2840. 

In This Article

Discussion

This study describes the prevalence of long-term post-COVID symptoms depending on the presence of myalgia as a symptom at hospital admission. We found that this acute symptom was associated with the presence of preexisting musculoskeletal pain and also with the development of musculoskeletal pain as post-COVID sequelae. The prevalence of persistent musculoskeletal pain after COVID-19 reached 38%. No differences in persistent fatigue, dyspnoea, anxiety/depressive levels, or sleep quality between patients experiencing or not experiencing myalgia at hospital admission were found.

Myalgia as COVID-19–Related Symptom at Onset of the Infection

Evidence supports that clinical presentation of SARS-CoV-2 infection is heterogeneous because these patients exhibit a plethora of symptoms at onset, with fever, cough, fatigue, and dyspnoea being the most prevalent.[4] Rubio-Rivas et al.[38] identified 4 clusters of patients with COVID-19, where individuals presenting with myalgia, arthralgia, or headache at the acute phase presented lower rates of hospital mortality.[38] The association of pain at the acute phase of COVID-19 with a decrease in mortality has been also recently observed by Knox et al.[29]

We found that the presence of myalgia as a symptom at hospital admission was more prevalent in individuals with preexisting musculoskeletal pain conditions, but this was not exclusive, because 15% of patients not suffering myalgia at hospital admission also reported previous history of musculoskeletal pain before the infection. The location of preexisting musculoskeletal pain conditions should be considered during the screening of patients with acute COVID-19, and they must be differentiated from the location of the new viral-related pain symptoms. Erçalık et al.[19] observed that spinal pain was the most frequent painful location experienced by patients before COVID-19, whereas headache and more generalized pain, including the extremities, were the most prevalent during the infection. In our study, we also observed that spinal pain was the most frequent painful location experienced by patients before infection, but also the most common location of post-COVID musculoskeletal pain. By contrast, most patients of our research reported that myalgia experienced as a symptom of SARS-CoV-2 infection at hospital admission was perceived as generalized diffuse muscle pain and clearly different from their preexisting musculoskeletal pain symptoms.

Musculoskeletal Pain as Post-COVID Sequelae

We reported an overall prevalence of musculoskeletal post-COVID pain of 38% of patients, 7 months after hospitalisation. Current data are much higher than those previously reported 6 months after hospital discharge (3%).[25] Most of the other studies providing prevalence data of post-COVID pain included shorter follow-up periods;[5,9,26] therefore, comparisons should not be made. Also, differences in populations, preexisting comorbidities, preexisting history of musculoskeletal pain (data not reported in previous studies), follow-up periods, or clinical course of the disease could explain these discrepancies. Our study is the first focussing on persistent post-COVID pain, considering the presence of preexisting musculoskeletal pain before hospitalisation and the presence of myalgia at the acute phase.

Identification of patients at risk of developing post-COVID musculoskeletal pain could lead to better therapeutic strategies.[28] Our findings have clinical implications because preexisting musculoskeletal pain may predispose to exacerbation of preexisting conditions or also to the development of new pain conditions.[6] Our results support both assumptions because 50% of individuals with preexisting musculoskeletal pain reported an exacerbation of their preexisting symptoms 7 months after infection (exacerbated COVID-19–related pain), and the remaining 50% developed new musculoskeletal post-COVID pain (new-onset COVID-19–related pain). The results from this study support the fact that musculoskeletal pain can appear as new long-term post-COVID sequelae or as exacerbated post-COVID pain sequelae. Further studies are needed to characterize the nature of post-COVID musculoskeletal pain.

In addition, the development of musculoskeletal post-COVID pain was associated with the presence of myalgia as a symptom at the onset of the SARS-CoV-2 infection and hospital admission. It is possible that early consideration of myalgia at onset may help clinicians identify subjects at risk of developing musculoskeletal post-COVID pain. This is a relevant topic because myalgia is not considered one of the most bothersome symptoms by COVID-19, when compared with other related symptoms such as dyspnoea, fever, or chest pain. Therefore, it is possible that this symptom is underreported by some patients at hospital admission. Our results support the relevance of properly identifying this symptom at infection onset because it was associated with a higher risk of developing musculoskeletal post-COVID pain.

Mechanisms of Musculoskeletal Pain as Post-COVID Sequelae

The main hypothesis explaining the association between musculoskeletal pain and SARS-CoV-2 infection is the prolonged proinflammatory response associated with COVID-19. This cytokine storm leads to a rapid hyperactivation of T cells, macrophages, and natural killer cells, stimulating the overproduction of proinflammatory mediators.[33] These events could promote mechanisms associated with muscle pain, eg, atypical responses of the mast cells,[3] increase of inflammatory interleukin-6,[14] and an overexpression of angiotensin-converting enzyme 2 at central and peripheral nervous systems.[40] Current hypotheses suggest that pain may result from viral neurotropic properties, the activation of nociceptive neurons, involvement of peripheral nervous system, and muscle and autoimmune reactions, having the potential to increase the incidence of chronic pain.[31] However, no evidence of a direct association between these mechanisms, eg, angiotensin-converting enzyme 2 overexpression, and COVID-19 is still confirmed.[34] It is possible that these cytokine-mediated responses lead to a hyperexcitability of the peripheral and central nervous systems, promoting the development of post-COVID pain symptoms.[13] In fact, it is possible that cytokine storm could lead to the ability of SARS-CoV-2 infection for triggering nociplastic pain.[12] In such a scenario, the presence of viral-induced myalgia as a symptom at the acute phase could activate a cascade of events that, in predisposing subjects, may lead to development of new musculoskeletal post-COVID pain symptoms or to a worsening of a preexisting pain symptom, as it was observed in our study.

In addition, emotional and social factors related to COVID-19 can also promote the development of musculoskeletal post-COVID pain or the exacerbation of preexisting painful conditions,[27] exacerbated by the barriers encountered in accessing adequate medical care for patients with chronic pain during the worldwide COVID-19 lockdown.[17] Surprisingly, we did not observe differences in the presence of anxiety/depressive levels and sleep quality depending on the presence or absence of myalgia as a symptom at infection. In addition, anxiety and depressive levels or sleep quality was not either associated with the presence of preexisting musculoskeletal pain or the development of musculoskeletal post-COVID pain (data not shown). The fact that the anxiety/depressive levels were small in our sample could explain these results. Furthermore, other psychosocial mechanisms including catastrophic social alarm, hospitalization-related posttraumatic stress disorder or uncertainty about prognosis may also play a role because these factors also interplay with central mechanisms that contribute to chronic pain.[2] For instance, it has been previously found that those patients recalling higher pain and distress during ICU admission are at higher risk of developing chronic pain after hospital discharge.[36] Our sample of patients requiring ICU admission was small to make conclusions. Future studies determining the association between emotional factors and the development of musculoskeletal post-COVID pain are needed.

Limitations

Although this is the largest study with the longest follow-up period to date focussing on musculoskeletal post-COVID pain and also considering the presence of viral-induced myalgia at hospital admission, potential limitations should be recognized. First, we just included hospitalised COVID-19 survivors; therefore, we cannot extrapolate these results to nonhospitalised patients. Second, we only included Caucasian participants; therefore, ethnic differences could not be investigated. Furthermore, because musculoskeletal pain exhibits a female predominance, future studies assessing sex differences are needed. Third, we did not collect laboratory measures, eg, biomarkers of inflammation, or estimations of severity of the infection, eg, cycle thresholds of the polymerase chain reaction, which could help to further characterize musculoskeletal post-COVID pain. Nevertheless, Hickie et al.[23] observed that postinfectious symptoms are not related to the inflammatory response at the acute phase, but rather by the intensity of these symptoms at baseline. Similarly, we did not collect data about the intensity or severity of musculoskeletal pain; therefore, we were not able to determine the proportion of patients showing disabling pain symptoms. Future studies characterising the severity of musculoskeletal post-COVID pain are now needed. Fourth, data were collected over the telephone, a procedure with a well-known potential bias in survey studies. Nevertheless, it should be noted that previous studies investigating post-COVID symptoms have also used similar methods for the recruitment of data.[5,9,25,26] Finally, the cross-sectional design of the study does not allow to determine the evolution of musculoskeletal post-COVID pain during the follow-up period after hospital discharge, making it difficult to exclusively attribute to SARS-CoV-2 its development 7 months after the infection and hospitalisation. Longitudinal studies investigating the evolution of post-COVID sequelae are needed. Finally, it should be noted that differentiating myalgias and arthralgias can be difficult for both patients and clinicians; therefore, it is possible that the term myalgias and arthralgias would have been more appropriate.

In conclusion, this study reported that 65% of COVID-19 survivors exhibited long-term post-COVID symptoms. The prevalence of musculoskeletal post-COVID pain was 38%. Myalgia as a symptom at the acute phase was more frequent in individuals with preexisting musculoskeletal pain conditions. The presence of viral-induced myalgia at hospital admission was associated with the development of musculoskeletal post-COVID pain. Overall, 50% of patients with preexisting musculoskeletal pain conditions showed exacerbation of their symptoms and the remaining 50% developed new musculoskeletal post-COVID pain. No differences in dyspnoea, anxiety/depressive levels, or sleep quality were found between patients with and without myalgia at the acute phase of the infection.

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