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Journal of Shoulder and Elbow Surgery

Can adhesive capsulitis of the shoulder be a consequence of COVID-19? Case series of 12 patients

      Keywords

      Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) has spread explosively throughout the world, resulting in a pandemic new respiratory disease identified as coronavirus disease 2019 (COVID-19). Since March 2020, the viral infection has affected at least 192 countries or regions, causing about 2.5 million deaths and infecting more than 112 million people.
      Johns Hopkins University
      Coronavirus resource center.
      Patients with COVID-19 can be classified into 3 groups according to the severity of the viral infection: (1) asymptomatic and mild COVID-19 patients, who account for the majority of cases (approximately 80%), (2) severely ill patients (14%), and (3) critical patients (6%).
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      COVID-19 symptoms differ in the 3 groups.
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      Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention.
      Patients with mild symptoms generally suffer from nasal congestion, fever, anosmia and dysgeusia, a sore throat, cough, headache, malaise, and myalgia. Patients with a severe presentation frequently require hospitalization owing to pneumonia and acute respiratory distress syndrome. The symptoms in critical patients include respiratory failure, septic shock, multiorgan dysfunction syndrome, and disseminated intravascular coagulation.
      • Wu Z.
      • McGoogan J.M.
      Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention.
      Systemic manifestations of COVID-19 result from a combination of the direct effects of the SARS-CoV-2 on infected target cells and of the indirect effects due to the host’s inflammatory response to the virus. In particular, the indirect effects are associated with a cytokine storm and a systemic inflammation that involve any organ or system, including the musculoskeletal system.
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      Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
      The main musculoskeletal manifestations that as of this writing have been associated with COVID-19 are myalgias and generalized weakness, which are reported as early, transient features in 15%-45% of symptomatic patients and resolve on average within 10-15 days.
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      Arthralgia is another common symptom, which is often combined with myalgias.
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      Lastly, high blood creatinine kinase levels are often present in severe and critical patients.
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      Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
      Less is known about joint symptoms, with no studies having yet been published on inflammation of the synovial tissue or joint fibrosis related to COVID-19.
      Among the inflammatory diseases involving the shoulder and associated with an overexpression of inflammatory cytokines is adhesive capsulitis (AC).
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      Inflammatory cytokines are overexpressed in the subacromial bursa of frozen shoulder.
      Described for the first time in 1872 by Duplay
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      Scapulo-humeral periarthritis and shoulder stiffness resulting from it..
      and subsequently also defined as frozen shoulder by Codman,
      • Codman E.A.
      The shoulder. Rupture of the supraspinatus tendon and other lesions in or about the subacromial bursa.
      AC is characterized by shoulder pain and stiffness combined with reduced active and passive range of motion and may severely impair a person’s quality of life.
      Several studies
      • Hand G.C.
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      • Matthews T.
      • Carr A.J.
      The pathology of frozen shoulder.
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      • Kanbe K.
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      • Chen Q.
      Inducement of mitogen-activated protein kinases in frozen shoulders.
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      • et al.
      Inflammatory cytokines are overexpressed in the subacromial bursa of frozen shoulder.
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      Hyaluronan modulates cell proliferation and mRNA expression of adhesion-related procollagens and cytokines in glenohumeral synovial/capsular fibroblasts in adhesive capsulitis.
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      • Tom J.
      • Warren R.F.
      • Wickiewicz T.L.
      Immunolocalization of cytokines and their receptors in adhesive capsulitis of the shoulder.
      have shown that the beginning of the pathologic process in AC is characterized by a glenohumeral inflammation followed by synovial and periarticular fibrosis.
      • Hand G.C.
      • Athanasou N.A.
      • Matthews T.
      • Carr A.J.
      The pathology of frozen shoulder.
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      • Kanbe K.
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      • Chen Q.
      Inducement of mitogen-activated protein kinases in frozen shoulders.
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      • Min B.W.
      • Bae K.C.
      • et al.
      Inflammatory cytokines are overexpressed in the subacromial bursa of frozen shoulder.
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      • Shirachi I.
      • Higuchi F.
      • et al.
      Hyaluronan modulates cell proliferation and mRNA expression of adhesion-related procollagens and cytokines in glenohumeral synovial/capsular fibroblasts in adhesive capsulitis.
      ,
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      • Tom J.
      • Warren R.F.
      • Wickiewicz T.L.
      Immunolocalization of cytokines and their receptors in adhesive capsulitis of the shoulder.
      Based on reports that the inflammatory reaction in AC
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      • Ha E.
      • Cho C.H.
      • Song K.S.
      • Min B.W.
      • Bae K.C.
      • et al.
      Inflammatory cytokines are overexpressed in the subacromial bursa of frozen shoulder.
      ,
      • Rodeo S.A.
      • Hannafin J.A.
      • Tom J.
      • Warren R.F.
      • Wickiewicz T.L.
      Immunolocalization of cytokines and their receptors in adhesive capsulitis of the shoulder.
      shows several similarities to that in COVID-19, and that synovial cells may be targeted by the SARS-CoV-2,
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      Defining inflammatory cell states in rheumatoid arthritis joint synovial tissues by integrating single-cell transcriptomics and mass cytometry.
      we hypothesized that COVID-19 might be related to the development of AC in the shoulder. Here, we present our case series of patients with AC evaluated at our hospital.

      Materials and methods

      The study group included 12 consecutive, prospectively enrolled, subjects with AC. The diagnosis, which was made by the senior author (C.A.) after clinical and radiologic examination, was based on a reduction in both active and passive range of motion (ROM) of the shoulder, evaluated in the sitting and supine positions; no strength reduction in intra-extrarotation; exclusion of the posterosuperior
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      and anterior
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      rotator cuff tendon tears; a radiographic evaluation, that is, true anteroposterior view (with the central ray tangential to the glenoid surface) and a Velpeau axillary view (with the patient's arm held in internal rotation, the ray is superior to inferior and the patient leaning backward); and an MRI of the involved shoulder.
      All the patients were evaluated between November 15, 2020, and January 15, 2021, at the shoulder surgery unit at our hospital, and all reported shoulder stiffness and pain arising after COVID-19, with no apparent cause.
      At the time of our examination, none of the patients enrolled reported the following: a recent shoulder trauma; previous diagnosis of AC in either shoulder; a previous ROM limitation or a rotator cuff tear; severe glenohumeral osteoarthritis; cervical spine symptoms and rheumatologic and/or autoimmune pathologies.
      The total number of patients and those with AC evaluated during the study period were noted. Clinical information on gender, age, affected side, time of AC onset after COVID-19 diagnosis, severity of COVID-19, shoulder functional limitation, and pain intensity was recorded. All comorbidities, as possible risk factors for development of AC, were noted.
      Passive shoulder ROM was evaluated in terms of forward elevation, abduction, and external rotation (with the arm at the side and elbow flexed at 90°). The visual analog scale (VAS) was used to assess pain intensity.
      • Jensen M.P.
      • Karoly P.
      Pain-specific beliefs, perceived symptom severity, and adjustment to chronic pain.
      All the patients signed an informed consent form in accordance with the Declaration of Helsinki.

      Results

      During the study period, a total of 1120 patients were evaluated at our shoulder surgery unit. Of these, 146 had an AC of the shoulder. The study sample was composed of 12 patients: 8 female and 4 male. The patients’ mean age was 57 years (range: 42-73). All the clinical data are presented in Table I.
      Table IClinical data of the study sample
      Pt no.SexAgeSideAC onset
      AC onset after COVID-19 diagnosis in terms of months.
      COVID-19 severityPassive ROM
      Reduction of motion compared with the uninjured contralateral side. Values are in degrees, expressed as mean (reduction of motion compared with the uninjured contralateral side).
      VAS score
      FEAbdER
      1F73L2Mild100 (60)90 (60)10 (35)5
      2F42R2Asymptomatic70 (110)50 (130)0 (50)8
      3F50R2.5Asymptomatic110 (60)80 (90)10 (30)6
      4M49L3Mild150 (25)100 (80)20 (25)4
      5F54R3Asymptomatic140 (40)100 (75)10 (40)5
      6F57R2Mild160 (10)130 (40)30 (10)3
      7M59L1.5Asymptomatic70 (95)40 (120)0 (40)8
      8F61R3Asymptomatic170 (10)150 (25)35 (15)3
      9F65L2Mild130 (35)100 (60)15 (25)6
      10M57Both1.5AsymptomaticR: 100; L: 110R: 90; L: 90R: 10; L: 157
      11M62L2.5Mild120 (50)100 (70)30 (15)5
      12F51L2Asymptomatic80 (100)40 (140)5 (45)7
      Pt, patient; F, female; M, male; L, left; R, right; AC, adhesive capsulitis; ROM, range of motion; FE, forward elevation; Abd, abduction; ER, external rotation (with the arm at the side and elbow flexed at 90°); VAS, visual analog scale for pain.
      AC onset after COVID-19 diagnosis in terms of months.
      Reduction of motion compared with the uninjured contralateral side. Values are in degrees, expressed as mean (reduction of motion compared with the uninjured contralateral side).
      The right shoulder was involved in 5 subjects and the left shoulder in 6 subjects, whereas 1 patient reported symptoms in both shoulders. AC arose 1.5-3 months after the COVID-19 diagnosis (mean time to onset: 2 months).
      According to severity, COVID-19 in 7 of the patients was asymptomatic, whereas in the remaining 5 patients symptoms were mild. None of the patients were severely or critical ill. As for other comorbidities, 2 patients had well-compensated diabetes mellitus.
      The decrease in range of motion was as follows: mean forward elevation of the affected side was 116° (range: 70°-170°), with a mean reduction compared with the uninjured shoulder of 54° (range: 10°-110°); the mean abduction was 89° (range: 40°-150°) and mean external rotation was 15° (range: 0°-35°), with a mean reduction compared with the contralateral side of 81° (range: 25°-140°) and 30° (range: 10°-50°), respectively. The mean pain intensity was 5.6 (range: 3-8).
      Table II shows all the mean ROM and VAS values in the patients with asymptomatic and mild-symptomatic COVID-19.
      Table IIROM and pain intensity in asymptomatic and mild symptomatic COVID-19 patients
      Passive ROM
      Reduction of motion compared with the uninjured contralateral side. Values are in degrees, expressed as mean (reduction of motion compared with the uninjured contralateral side).
      VAS score, mean
      FEAbdER
      Asymptomatic patients (n = 7)106 (69)80 (97)11 (37)6.3
      Mild patients (n = 5)132 (36)104 (62)21 (22)4.6
      ROM, range of motion; FE, forward elevation; Abd, abduction; ER, external rotation (with the arm at the side and elbow flexed at 90°); VAS, visual analog scale for pain.
      Reduction of motion compared with the uninjured contralateral side. Values are in degrees, expressed as mean (reduction of motion compared with the uninjured contralateral side).

      Discussion

      The initial pathologic process in AC is known to be a synovial inflammation associated with a hypervascular hyperplasia. This is followed by fibroblast hyperactivity and subsequent fibrosis in the synovium and glenohumeral capsular tissue,
      • Lho Y.M.
      • Ha E.
      • Cho C.H.
      • Song K.S.
      • Min B.W.
      • Bae K.C.
      • et al.
      Inflammatory cytokines are overexpressed in the subacromial bursa of frozen shoulder.
      ,
      • Rodeo S.A.
      • Hannafin J.A.
      • Tom J.
      • Warren R.F.
      • Wickiewicz T.L.
      Immunolocalization of cytokines and their receptors in adhesive capsulitis of the shoulder.
      located above all in the coracohumeral ligament and to the rotator interval area.
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      Expression of growth factors, cytokines and matrix metalloproteinases in frozen shoulder.
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      ,
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      • Gotoh M.
      • Nakama K.
      • Shirachi I.
      • Higuchi F.
      • et al.
      Hyaluronan modulates cell proliferation and mRNA expression of adhesion-related procollagens and cytokines in glenohumeral synovial/capsular fibroblasts in adhesive capsulitis.
      Active and passive motion limitations are characteristic in patients with AC and occur with varying degrees of severity.
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      Lastly, the pain in AC is most frequently reported in the anterior surface of the shoulder with irradiation downward, to the antero-lateral aspect of the arm as far as its distal third (dermatomes C5-C6).
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      In our series, the asymptomatic patients displayed a greater ROM impairment and a greater intensity of pain than mild-symptomatic patients, though a statistical evaluation is unreliable owing to the limited size of the sample.
      As regards the correlation between COVID-19 and the frozen shoulder, we hypothesize that both direct and indirect effects of the viral disease may contribute to the pathogenesis of AC.
      Cellular penetration of SARS-CoV-2 occurs via the angiotensin-converting enzyme 2 (ACE2) receptor and the serine protease TMPRSS2 (transmembrane protease, serine 2).
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      With regard to human skeletal muscle tissue, many cells express TMPRSS2, including smooth muscle cells, muscle stem cells, pericytes, vascular cells, and endothelial cells. However, among these, only pericytes and smooth muscle cells express the ACE2 receptor.
      By contrast, several cells in the synovium, including fibroblasts and monocytes, express both ACE2 and TMPRSS2.
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      This finding may be one of the main direct effects of the SARSCoV-2 on the synovium and fibroblasts and, therefore, be related to fibrosis of the capsular and pericapsular tissues in the AC.
      In addition to direct infection of the cells outside of the respiratory tract, COVID-19 is characterized by indirect effects resulting from the host’s response to the viral infection. These indirect effects are associated with a cytokine storm and a systemic inflammation that may impact nearly every organ system, including the musculoskeletal tissues.
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      In strong analogy with COVID-19, the inflammatory cascade implicated in abnormal tissue repair and fibrosis of the shoulder AC is supported by similar cytokines and growth factors, particularly IL-1, IL-6, and TNF-α.
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      • Ha E.
      • Cho C.H.
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      • et al.
      Inflammatory cytokines are overexpressed in the subacromial bursa of frozen shoulder.
      ,
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      • Hannafin J.A.
      • Tom J.
      • Warren R.F.
      • Wickiewicz T.L.
      Immunolocalization of cytokines and their receptors in adhesive capsulitis of the shoulder.
      Moreover, several authors
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      have shown that expression levels of TNF-α, IL-1, and IL-6 are high in the joint capsule, in the subacromial bursa, and in joint fluid in patients with frozen shoulder. These data lend support to the hypothesis that indirect effects of viral infection may be involved in the development of AC.
      Lastly, it should be borne in mind that, in addition to the direct and indirect effects of SARS-CoV-2, viral infection may be related to the development of AC resulting from the marked changes in lifestyle induced by the pandemic, especially those due to quarantine. Indeed, we believe that a sedentary lifestyle is associated with a number of side effects, as is confirmed by extensive reports indicating that lack of physical activity results in and exacerbates musculoskeletal discomfort and pain.
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      • Ansari N.N.
      • Kargarfard M.
      • et al.
      Prevalence rate of neck, shoulder and lower back pain in association with age, body mass index and gender among Malaysian office workers.
      The main limitations of our study are as follows: the limited size of the study group, although it should be borne in mind that we enrolled highly selected patients who had recently suffered from COVID-19 and who had AC of the shoulder with no other apparent causes; SARSCoV-2 was not specifically detected in the shoulder tissues of our patients, nor can we provide incontrovertible data supporting the correlation between overexpression of inflammatory mediators of COVID-19 and the development of AC of the shoulder; the lack of a short- and long-term evaluation of patients regarding the evolution and treatment of AC; the absence of a control group consisting of patients with AC that did not occur after COVID-19.
      Despite the possibility that there may be a correlation between COVID-19 and AC for the reasons we have provided, this case series cannot describe a cause-and-effect relationship.

      Conclusion

      We present our series of 12 patients with AC of the shoulder that developed shortly after COVID-19. We hypothesize that AC may be related to the infectious disease and that both direct and indirect effects of SARS-CoV-2 infection may be involved in its development, as may the sedentary lifestyle forced on these patients by this disease.
      Future research will be needed to evaluate the short- and long-term natural history and treatment of these patients as well as to compare them with patients with AC that did not occur concurrently with COVID-19.

      Disclaimer

      The authors, their immediate families, and any research foundations with which they are affiliated have not received any financial payments or other benefits from any commercial entity related to the subject of this article.

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