Enterovirus related metabolic myopathy: a postviral fatigue syndrome
Abstract
Objective: To detect and characterise enterovirus RNA in skeletal muscle from patients with chronic fatigue syndrome (CFS) and to compare efficiency of muscle energy metabolism in enterovirus positive and negative CFS patients.
Methods: Quadriceps muscle biopsy samples from 48 patients with CFS were processed to detect enterovirus RNA by two stage, reverse transcription, nested polymerase chain reaction (RT-NPCR), using enterovirus group specific primer sets. Direct nucleotide sequencing of PCR products was used to characterise the enterovirus. Controls were 29 subjects with normal muscles. On the day of biopsy, each CFS patient undertook a subanaerobic threshold exercise test (SATET). Venous plasma lactate was measured immediately before and after exercise, and 30 minutes after testing. An abnormal lactate response to exercise (SATET+) was defined as an exercise test in which plasma lactate exceeded the upper 99% confidence limits for normal sedentary controls at two or more time points.
Results: Muscle biopsy samples from 20.8% of the CFS patients were positive for enterovirus sequences by RT-NPCR, while all the 29 control samples were negative; 58.3% of the CFS patients had a SATET+ response. Nine of the 10 enterovirus positive cases were among the 28 SATET+ patients (32.1%), compared with only one (5%) of the 20 SATET- patients. PCR products were most closely related to coxsackie B virus.
Conclusions: There is an association between abnormal lactate response to exercise, reflecting impaired muscle energy metabolism, and the presence of enterovirus sequences in muscle in a proportion of CFS patients.
Full Text
The Full Text of this article is available as a PDF (486K).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Wessely S, Chalder T, Hirsch S, Pawlikowska T, Wallace P, Wright DJ. Postinfectious fatigue: prospective cohort study in primary care. Lancet. 1995 May 27;345(8961):1333–1338. [PubMed] [Google Scholar]
- White PD, Thomas JM, Amess J, Grover SA, Kangro HO, Clare AW. The existence of a fatigue syndrome after glandular fever. Psychol Med. 1995 Sep;25(5):907–916. [PubMed] [Google Scholar]
- Berelowitz GJ, Burgess AP, Thanabalasingham T, Murray-Lyon IM, Wright DJ. Post-hepatitis syndrome revisited. J Viral Hepat. 1995;2(3):133–138. [PubMed] [Google Scholar]
- Ayres JG, Flint N, Smith EG, Tunnicliffe WS, Fletcher TJ, Hammond K, Ward D, Marmion BP. Post-infection fatigue syndrome following Q fever. QJM. 1998 Feb;91(2):105–123. [PubMed] [Google Scholar]
- Kerr JR, Barah F, Mattey DL, Laing I, Hopkins SJ, Hutchinson IV, Tyrrell DA. Circulating tumour necrosis factor-alpha and interferon-gamma are detectable during acute and convalescent parvovirus B19 infection and are associated with prolonged and chronic fatigue. J Gen Virol. 2001 Dec;82(Pt 12):3011–3019. [PubMed] [Google Scholar]
- Wallace HL, 2nd, Natelson B, Gause W, Hay J. Human herpesviruses in chronic fatigue syndrome. Clin Diagn Lab Immunol. 1999 Mar;6(2):216–223.[PMC free article] [PubMed] [Google Scholar]
- Nakaya T, Takahashi H, Nakamur Y, Kuratsune H, Kitani T, Machii T, Yamanishi K, Ikuta K. Borna disease virus infection in two family clusters of patients with chronic fatigue syndrome. Microbiol Immunol. 1999;43(7):679–689. [PubMed] [Google Scholar]
- Evengård B, Briese T, Lindh G, Lee S, Lipkin WI. Absence of evidence of Borna disease virus infection in Swedish patients with Chronic Fatigue Syndrome. J Neurovirol. 1999 Oct;5(5):495–499. [PubMed] [Google Scholar]
- Joyce E, Blumenthal S, Wessely S. Memory, attention, and executive function in chronic fatigue syndrome. J Neurol Neurosurg Psychiatry. 1996 May;60(5):495–503.[PMC free article] [PubMed] [Google Scholar]
- Archard LC, Khan MA, Soteriou BA, Zhang H, Why HJ, Robinson NM, Richardson PJ. Characterization of Coxsackie B virus RNA in myocardium from patients with dilated cardiomyopathy by nucleotide sequencing of reverse transcription-nested polymerase chain reaction products. Hum Pathol. 1998 Jun;29(6):578–584. [PubMed] [Google Scholar]
- Leff RL, Love LA, Miller FW, Greenberg SJ, Klein EA, Dalakas MC, Plotz PH. Viruses in idiopathic inflammatory myopathies: absence of candidate viral genomes in muscle. Lancet. 1992 May 16;339(8803):1192–1195. [PubMed] [Google Scholar]
- Leon-Monzon M, Dalakas MC. Absence of persistent infection with enteroviruses in muscles of patients with inflammatory myopathies. Ann Neurol. 1992 Aug;32(2):219–222. [PubMed] [Google Scholar]
- Fox SA, Finklestone E, Robbins PD, Mastaglia FL, Swanson NR. Search for persistent enterovirus infection of muscle in inflammatory myopathies. J Neurol Sci. 1994 Aug;125(1):70–76. [PubMed] [Google Scholar]
- Gow JW, Behan WM, Clements GB, Woodall C, Riding M, Behan PO. Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome. BMJ. 1991 Mar 23;302(6778):692–696.[PMC free article] [PubMed] [Google Scholar]
- Behan WM, Behan PO. The role of viral infection in polymyositis, dermatomyositis and chronic fatigue syndrome. Baillieres Clin Neurol. 1993 Nov;2(3):637–657. [PubMed] [Google Scholar]
- McArdle A, McArdle F, Jackson MJ, Page SF, Fahal I, Edwards RH. Investigation by polymerase chain reaction of enteroviral infection in patients with chronic fatigue syndrome. Clin Sci (Lond) 1996 Apr;90(4):295–300. [PubMed] [Google Scholar]
- Lane RJ, Burgess AP, Flint J, Riccio M, Archard LC. Exercise responses and psychiatric disorder in chronic fatigue syndrome. BMJ. 1995 Aug 26;311(7004):544–545.[PMC free article] [PubMed] [Google Scholar]
- Lane RJ, Barrett MC, Woodrow D, Moss J, Fletcher R, Archard LC. Muscle fibre characteristics and lactate responses to exercise in chronic fatigue syndrome. J Neurol Neurosurg Psychiatry. 1998 Mar;64(3):362–367.[PMC free article] [PubMed] [Google Scholar]
- Lane RJ, Barrett MC, Taylor DJ, Kemp GJ, Lodi R. Heterogeneity in chronic fatigue syndrome: evidence from magnetic resonance spectroscopy of muscle. Neuromuscul Disord. 1998 May;8(3-4):204–209. [PubMed] [Google Scholar]
- Wong R, Lopaschuk G, Zhu G, Walker D, Catellier D, Burton D, Teo K, Collins-Nakai R, Montague T. Skeletal muscle metabolism in the chronic fatigue syndrome. In vivo assessment by 31P nuclear magnetic resonance spectroscopy. Chest. 1992 Dec;102(6):1716–1722. [PubMed] [Google Scholar]
- McCully KK, Natelson BH, Iotti S, Sisto S, Leigh JS., Jr Reduced oxidative muscle metabolism in chronic fatigue syndrome. Muscle Nerve. 1996 May;19(5):621–625. [PubMed] [Google Scholar]
- Fulcher KY, White PD. Strength and physiological response to exercise in patients with chronic fatigue syndrome. J Neurol Neurosurg Psychiatry. 2000 Sep;69(3):302–307.[PMC free article] [PubMed] [Google Scholar]
- Nashef L, Lane RJ. Screening for mitochondrial cytopathies: the sub-anaerobic threshold exercise test (SATET). J Neurol Neurosurg Psychiatry. 1989 Sep;52(9):1090–1094.[PMC free article] [PubMed] [Google Scholar]
- Sharpe MC, Archard LC, Banatvala JE, Borysiewicz LK, Clare AW, David A, Edwards RH, Hawton KE, Lambert HP, Lane RJ, et al. A report--chronic fatigue syndrome: guidelines for research. J R Soc Med. 1991 Feb;84(2):118–121.[PMC free article] [PubMed] [Google Scholar]
- Zhang H, Yousef GE, Ouyang X, Archard LC. Characterization of a murine model of myocarditis induced by a reactivated coxsackievirus B3. Int J Exp Pathol. 1994 Apr;75(2):99–110.[PMC free article] [PubMed] [Google Scholar]
- Klump WM, Bergmann I, Müller BC, Ameis D, Kandolf R. Complete nucleotide sequence of infectious Coxsackievirus B3 cDNA: two initial 5' uridine residues are regained during plus-strand RNA synthesis. J Virol. 1990 Apr;64(4):1573–1583.[PMC free article] [PubMed] [Google Scholar]
- Chang KH, Auvinen P, Hyypiä T, Stanway G. The nucleotide sequence of coxsackievirus A9; implications for receptor binding and enterovirus classification. J Gen Virol. 1989 Dec;70(Pt 12):3269–3280. [PubMed] [Google Scholar]
- Cann AJ, Stanway G, Hughes PJ, Minor PD, Evans DM, Schild GC, Almond JW. Reversion to neurovirulence of the live-attenuated Sabin type 3 oral poliovirus vaccine. Nucleic Acids Res. 1984 Oct 25;12(20):7787–7792.[PMC free article] [PubMed] [Google Scholar]
- Zhang H, Soteriou B, Knowlson S, Theodoridou A, Archard LC. Characterisation of genomic RNA of Coxsackievirus B3 in murine myocarditis: reliability of direct sequencing of reverse transcription-nested polymerase chain reaction products. J Virol Methods. 1997 Dec;69(1-2):7–17. [PubMed] [Google Scholar]
- Komaroff AL, Buchwald DS. Chronic fatigue syndrome: an update. Annu Rev Med. 1998;49:1–13. [PubMed] [Google Scholar]
- Wadler S. The role of interferons in the treatment of solid tumors. Cancer. 1992 Aug 15;70(4 Suppl):949–958. [PubMed] [Google Scholar]
- Curti BD, Smith JW., 2nd Interleukin-1 in the treatment of cancer. Pharmacol Ther. 1995 Mar;65(3):291–302. [PubMed] [Google Scholar]
- Bennett AL, Chao CC, Hu S, Buchwald D, Fagioli LR, Schur PH, Peterson PK, Komaroff AL. Elevation of bioactive transforming growth factor-beta in serum from patients with chronic fatigue syndrome. J Clin Immunol. 1997 Mar;17(2):160–166. [PubMed] [Google Scholar]
- Moss RB, Mercandetti A, Vojdani A. TNF-alpha and chronic fatigue syndrome. J Clin Immunol. 1999 Sep;19(5):314–316. [PubMed] [Google Scholar]
- Penttila IA, Harris RJ, Storm P, Haynes D, Worswick DA, Marmion BP. Cytokine dysregulation in the post-Q-fever fatigue syndrome. QJM. 1998 Aug;91(8):549–560. [PubMed] [Google Scholar]
- Kerr JR, Barah F, Mattey DL, Laing I, Hopkins SJ, Hutchinson IV, Tyrrell DA. Circulating tumour necrosis factor-alpha and interferon-gamma are detectable during acute and convalescent parvovirus B19 infection and are associated with prolonged and chronic fatigue. J Gen Virol. 2001 Dec;82(Pt 12):3011–3019. [PubMed] [Google Scholar]
- Harris RJ, Storm PA, Lloyd A, Arens M, Marmion BP. Long-term persistence of Coxiella burnetii in the host after primary Q fever. Epidemiol Infect. 2000 Jun;124(3):543–549.[PMC free article] [PubMed] [Google Scholar]
Abstract
Objective: To detect and characterise enterovirus RNA in skeletal muscle from patients with chronic fatigue syndrome (CFS) and to compare efficiency of muscle energy metabolism in enterovirus positive and negative CFS patients.
Methods: Quadriceps muscle biopsy samples from 48 patients with CFS were processed to detect enterovirus RNA by two stage, reverse transcription, nested polymerase chain reaction (RT-NPCR), using enterovirus group specific primer sets. Direct nucleotide sequencing of PCR products was used to characterise the enterovirus. Controls were 29 subjects with normal muscles. On the day of biopsy, each CFS patient undertook a subanaerobic threshold exercise test (SATET). Venous plasma lactate was measured immediately before and after exercise, and 30 minutes after testing. An abnormal lactate response to exercise (SATET+) was defined as an exercise test in which plasma lactate exceeded the upper 99% confidence limits for normal sedentary controls at two or more time points.
Results: Muscle biopsy samples from 20.8% of the CFS patients were positive for enterovirus sequences by RT-NPCR, while all the 29 control samples were negative; 58.3% of the CFS patients had a SATET+ response. Nine of the 10 enterovirus positive cases were among the 28 SATET+ patients (32.1%), compared with only one (5%) of the 20 SATET- patients. PCR products were most closely related to coxsackie B virus.
Conclusions: There is an association between abnormal lactate response to exercise, reflecting impaired muscle energy metabolism, and the presence of enterovirus sequences in muscle in a proportion of CFS patients.