© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Transplant Infectious Disease, ISSN 1398-2273
Case report
Rhabdomyolysis associated with cytomegalovirus infection in kidney transplant recipients H.-Y. Jung, K.-H. Kim, S.-C. Park, J.-H. Lee, J.-Y. Choi, J.-H. Cho, S.-H. Park, Y.-L. Kim, H.-K. Kim, S. Huh, C.-D. Kim. Rhabdomyolysis associated with cytomegalovirus infection in kidney transplant recipients. Transpl Infect Dis 2014: 16: 993–998. All rights reserved Abstract: Rhabdomyolysis is a pathological syndrome caused by skeletal muscle cell damage that affects the integrity of the cellular membrane and leads to the release of toxic intracellular constituents into the bloodstream. Although cytomegalovirus (CMV) has rarely been reported as a cause of rhabdomyolysis, CMV infection could be considered as a possible cause because of its clinical significance in kidney transplant recipients (KTRs). We report 2 cases of rhabdomyolysis associated with CMV infection in KTRs. A 64-yearold woman (Case 1) and a 65-year-old man (Case 2), who had each received a kidney from a living unrelated donor, were admitted with complaints of weakness in both legs and myalgia. Laboratory findings revealed highly increased creatine phosphokinase and myoglobinuria. In both cases, no recent alterations of medications had occurred, and other causes of rhabdomyolysis—such as trauma, alcohol, drugs, and electrolyte abnormalities – were excluded. CMV pp65 antigen was positive, and patients were diagnosed with rhabdomyolysis associated with CMV infection. Both patients recovered without complications after ganciclovir treatment. In conclusion, CMV infection should be considered as a possible cause of rhabdomyolysis in KTRs.
Rhabdomyolysis is a syndrome characterized by damage of skeletal muscle, leading to the release of muscle cell elements, such as myoglobin and creatine kinase, into the blood circulation. The clinical presentation of rhabdomyolysis varies from an asymptomatic elevation of muscle enzymes to severe acute kidney injury and hypovolemic shock (1). Acute non-traumatic rhabdomyolysis may be caused by a variety of electrolyte or endocrine disorders, medicine or toxic substance use, acute viral or bacterial infections, inflammatory myopathies, and muscle enzyme deficiencies (2). Although cytomegalovirus (CMV) has rarely been reported as a cause of rhabdomyolysis (3), CMV infection could be considered as a possible cause because of its clinical significance in kidney transplant recipients (KTRs) (4–7). Here, we report 2 cases of
H.-Y. Jung1,2, K.-H. Kim1,2, S.-C. Park1,2, J.-H. Lee1,2, J.-Y. Choi1,2, J.-H. Cho1,2, S.-H. Park1,2, Y.-L. Kim1,2, H.-K. Kim3, S. Huh3, C.-D. Kim1,2 1
Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Korea, 2Clinical Research Center for End Stage Renal Disease in Korea, Daegu, Korea, 3Department of Surgery, Kyungpook National University School of Medicine, Daegu, Korea Key words: rhabdomyolysis; CMV infection; kidney transplantation Correspondence to: Chan-Duck Kim, MD, PhD, Division of Nephrology, Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu 700-721, Korea Tel: +82-53-200-5560 Fax: +82-53-423-7583 E-mail: [email protected]
Received 20 April 2014, revised 5 July 2014, accepted for publication 29 July 2014 DOI: 10.1111/tid.12297 Transpl Infect Dis 2014: 16: 993–998
rhabdomyolysis associated with CMV infection, which, to our knowledge, are the first reported case in KTRs.
Case reports Case 1 A 64-year-old woman was diagnosed with end-stage renal disease due to hypertensive nephrosclerosis and started peritoneal dialysis in May 2010. She eventually received a kidney from her husband in November 2010. In January 2013, she was admitted to our hospital for weakness in both legs and myalgia. Beginning 10 days before admission, she also suffered from nausea, watery diarrhea, and poor appetite. The gastrointestinal
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Jung et al: Rhabdomyolysis in KTRs with CMV infection
(GI) symptoms had improved spontaneously, but the leg weakness had worsened to the point that she was unable to walk. She had been receiving maintenance immunosuppressive therapy consisting of 50 mg of cyclosporine twice daily, 500 mg of mycophenolate mofetil twice daily, and 4 mg of methylprednisolone daily. She had taken these mediations including a statin for at least 2 years without complications, and the dosages had not been changed recently. The patient had no history of alcohol or drug consumption or excessive muscular activity. She was physically active and had no personal or familial history of neurological or muscular disease. Physical examination at admission revealed a temperature of 36.5°C, blood pressure of 107/66 mmHg, regular pulse rate of 87 beats/min, and respiratory rate of 18 breaths/min. Neurological examination revealed flaccid weakness involving the proximal muscles of both lower limbs, but no muscle fasciculation. The patient showed no sensory disturbance. Abdominal examination revealed no tenderness of the renal allograft. Laboratory findings revealed a highly elevated creatine phosphokinase level of 12,036 U/L and myoglobinuria. Blood chemistry examination showed an increased aspartate aminotransferase (AST) level of 492 U/L, an alanine aminotransferase (ALT) level of 286 U/L, a lactate dehydrogenase (LDH) level of
2088 U/L, an aldolase level of 36.2 U/L, and a serum myoglobin level of 20,300 ng/mL. Blood urea nitrogen (BUN) was slightly increased (28.3 mg/dL), and serum creatinine was normal (1.10 mg/dL). There were no electrolyte abnormalities. Motor and sensory nerve conduction studies, performed 2 days after admission and 12 days after the first symptoms, did not show evidence for peripheral neuropathy, especially Guillain-Barre syndrome. Needle electromyogram, performed 5 days after admission, showed polyphasic motor unit action potentials with an early recruit pattern at the right vastus lateralis, tibialis anterior, medial gastrocnemius, and extensor hallucis longus muscles, suggesting a myopathic change. No fibrillation potentials or positive sharp waves were seen at the resting state of the examined muscles. A bone scan, performed 4 days after the admission, showed diffusely increased intense tracer uptake in the buttocks, thighs, and calf muscles, which is compatible with rhabdomyolysis (Fig. 1). No significant elevation of serum antibody was seen against Epstein-Barr virus (EBV) on admission. Serum BK virus polymerase chain reaction (PCR) was unremarkable. However, the number of CMV pp65 antigens was 5/200,000 polymorphonuclear leukocytes (Fig. 2). The pre-transplant CMV immunoglobulin (Ig)M antibodies of donor and recipient were all negative. The pre-transplant CMV IgG antibody titers of donor and
Fig. 1. Bone scan results. A bone scan of Case 1 showed diffusely increased intense tracer uptake in the buttocks, thighs, and calves, which is compatible with rhabdomyolysis.
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recipient were 165 AU/mL and 139 AU/mL, respectively. All of the examination findings indicated that the patient had rhabdomyolysis associated with CMV infection. On the sixth day after admission, ganciclovir (GCV) was administered intravenously. On the 12th day after admission, the clinical status had gradually improved, and other muscle enzymes had gradually decreased. CMV infection was controlled after 16 days
of GCV treatment, and the patient was discharged from the hospital with improved motor function (Fig. 2).
Case 2 A 65-year-old man had been diagnosed with chronic kidney disease as a result of diabetic nephropathy and received a kidney from his wife in May 2008. Since
A Case 1
B Case 2
Fig. 2. Changes in the patients’ clinical course and laboratory data. In both cases, the clinical status gradually improved and muscle enzymes gradually decreased after ganciclovir treatment. CPK, creatine phosphokinase; LDH, lactate dehydrogenase; Cr, creatinine; AST, asparatate aminotransferase. CMV, cytomegalovirus, PMN, polymorphonuclear leukocytes.
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then, his serum creatinine level had remained stable between 1.5 and 1.8 mg/dL. In April 2013, he was admitted to our hospital for weakness in both thighs and myalgia for 3 weeks. He had been experiencing pitting edema in both legs and reddish urine for a week. His concurrent medications included 100 mg of cyclosporine twice daily, 360 mg of mycophenolate mofetil twice daily, and 4 mg of methylprednisolone daily. He had taken these mediations including a statin for at least 2 years without complications, and his medications had not been changed recently. No trauma, alcohol consumption, or drug consumption was reported. He was physically active and had no personal or familial history of neurological or muscular disease. Physical examination at admission revealed a temperature of 36.5°C, blood pressure of 176/76 mmHg, regular pulse rate of 60 beats/min, and respiratory rate of 20 breaths/min. Laboratory findings showed a highly elevated creatine phosphokinase level of 12,551 U/L and myoglobinuria. Blood chemistry examination revealed an elevated AST level of 484 U/L, an ALT level of 614 U/L, an LDH level of 4234 U/L, an aldolase level of 68.5 U/L, and a serum myoglobin level of 15,690 ng/ mL. BUN and serum creatinine levels were increased (43.4 mg/dL and 2.20 mg/dL, respectively). No electrolyte abnormalities were noted. He had no significant elevation of serum antibody against EBV on admission. Serum BK virus PCR was unremarkable. However, CMV PCR was positive, and CMV pp65 antigen count was 10/200,000 polymorphonuclear leukocytes. The pre-transplant CMV IgM antibodies of donor and recipient were all negative. The pre-transplant CMV IgG antibody titers of donor and recipient were 188.4 AU/mL and 91.1 AU/mL, respectively. A diagnosis of rhabdomyolysis associated with CMV infection was made after excluding other causes of rhabdomyolysis. Intravenous GCV was injected for 14 days, which controlled the CMV infection. The clinical status had gradually improved and other muscle enzymes were markedly decreased on day 14. He was discharged on day 22 after admission with full motor function (Fig. 2).
Discussion Acute viral infections associated with rhabdomyolysis include influenza virus, Coxsackie virus, EBV, herpes simplex virus, parainfluenza virus, adenovirus, echovirus, measles virus, varicella zoster virus, human
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immunodeficiency virus, dengue virus, and CMV (3, 8). Influenza virus is the most common viral etiology. In contrast, only a small number of cases have been reported in which CMV infection is related to rhabdomyolysis. We present 2 cases of rhabdomyolysis associated with CMV infection in KTRs who were successfully treated with GCV. Our cases are distinct from all other previous cases, in that all of the previously reported patients were immunocompetent. To the best of our knowledge, this is the first reported cases of rhabdomyolysis associated with CMV infection in KTRs. Although the mechanism of muscle damage as a result of viral infections has not been established, several mechanisms have been proposed. Greco et al. (9) detected myxovirus-like particles by electron microscopy of a muscle specimen from a patient with influenza-associated myositis. Pratt et al. (10) found varicella zoster virus DNA by PCR of muscle specimens from patients with rhabdomyolysis, indicating direct viral invasion of the muscle tissue. Myotoxic cytokines released in response to viral infection were suggested as the possible cause for virus-induced muscle injury in a case of rhabdomyolysis secondary to coxsackie virus myositis (11). Konrad et al. (11) reported that a patient’s serum contained an elevated level of tumor necrosis factor, which induced breakdown of the skeletal muscles in an animal model. Immunologic processes induced by the viral infection have also been postulated as a possible cause of muscle damage (12). Several cases of rhabdomyolysis associated with CMV infection have been reported (3, 8, 13–16) (Table 1). Of all 6 patients in these published cases, 2 patients needed mechanical ventilation, 3 patients received corticosteroid therapy with apparent success, 1 patient received immune globulins therapy, and all of them recovered without sequelae. Muscle biopsies were often close to normal and never showed viral inclusions. Muscle CMV PCR was always negative when performed. Only 1 patient developed renal failure and needed hemodialysis. The 2 patients we present here recovered without complication and did not need hemodialysis or mechanical ventilation (Table 1). Viral particles or virus DNA has been found in muscle specimens from patients with viral infection-associated rhabdomyolysis (9, 10). However, muscle biopsy was not performed in our patients, because muscle biopsy provided no specific diagnostic findings in most of the previously reported viral infection-associated rhabdomyolysis cases or in cases of rhabdomyolysis with other causes, such as inherited metabolic myopathy or polymyositis. Rhabdomyolysis associated with CMV infection was diagnosed on the
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Jung et al: Rhabdomyolysis in KTRs with CMV infection
Summary of reviewed cases of rhabdomyolysis associated with cytomegalovirus (CMV) infection Case no.
1
2
3
4
5
6
7
8
First author (Reference)
Sato (15)
Maeda (14)
Yasumoto (16)
Hughes (13)
Hirohama (8)
Gindre (3)
Jung (PC)
Jung (PC)
Age, years/Gender
31/M
17/F
27/M
21/M
58/F
32/F
64/F
65/M
Immunity
N
N
N
N
N
N
IC
IC
Initial symptoms
Fever, fatigue
Urticaria, dyspnea
Muscle weakness
Fever, myalgia
Myalgia
Myalgia, muscle weakness
Nausea, diarrhea
Myalgia, muscle weakness
Muscle weakness
Proximal
Proximal
Diffuse
Proximal
Proximal
Proximal
Proximal
Proximal
CPK peak level (U/L)
24,380
15,490
74,850
4800
33,744
177,000
18,904
12,551
+ +
+
+
+
NA
+
CMV IgM
+
+
NA
CMV IgG
+
+
+
CMV pp65 Ag
+
NA
NA
NA
NA
NA
NA
CMV PCR
+
NA
+
+ +
Mechanical ventilation
Yes
No
No
No
Yes
Yes
No
No
Hemodialysis
No
No
Yes
No
No
No
No
No
Treatment
CTC
Supportive
CTC
NA
CTC
IVIG, GCV
GCV
GCV
Outcome
Recovered
Recovered
Recovered
Recovered
Recovered
Recovered
Recovered
Recovered
M, male; F, female; PC, present case; N, normal; IC, immunocompromised; CPK, creatine phosphokinase; Ig, immunoglobulin; NA, not available; Ag, antigen; PCR, polymerase chain reaction; CTC, corticosteroids; IVIG, intravenous immune globulins; GCV, ganciclovir.
Table 1
basis of clinical manifestations and laboratory findings after excluding other causes of rhabdomyolysis, such as trauma, alcohol, drugs, and electrolyte abnormalities. Patients in our cases had no history of alcohol or drug consumption and excessive muscular activity. Patients were physically active and had no personal or familial history of neurological or muscular disease. Although patients had taken medications including statins, they had no complications for at least 2 years and no recent alterations of dosage. Previous study (17) demonstrated that the average length of time on a statin before rhabdomyolysis is approximately 1 year. Considering that the patients we presented were taking statins without dosage alteration over 2 years, statins could be excluded as possible causes of rhabdomyolysis. Depending on clinical presentation, diagnosis of our patients was confirmed by the detection of CMV pp65 antigen, which was previously not detected. The pre-transplant CMV serostatus of both the donors and the recipients of presented cases were CMV seropositive and both recipients had a risk of developing CMV superinfection. We could not make an accurate diagnosis about initial GI symptoms of the first case because GI
symptoms were completely improved before admission and we did not have a further examination such as endoscopy. However, we can explain the GI symptoms as a result of viral gastroenteritis considering the clinical course of the patient. A previous report (18) revealed that a patient with rhabdomyolysis following viral gastroenteritis manifested a profound diarrhea resulting in a significant loss of body weight and/or hemodynamic instability. The previous study (18) speculated that hypovolemic ischemic shock, hypercytokinemia related to viral infection, and diarrheainduced electrolyte imbalance such as hypokalemia in a viral gastroenteritis might be associated with rhabdomyolysis. Our first case had no dehydration, hemodynamic instability, or electrolyte imbalance, because GI symptoms were not severe and improved in 3 days. Therefore, the possibility that viral gastroenteritis might be a cause of rhabdomyolysis in our first case and CMV could be an asymptomatic reactivation appeared to be low. If the patient has persistent GI symptoms, endoscopy must be performed in order to differentiate CMV gastroenteritis. CMV infection has more significant clinical importance in KTRs than in immunocompetent patients.
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Several previous studies demonstrated a clinical significance of CMV infection in KTRs. Sagedal et al. (6) found that CMV infection and disease are independent risk factors for clinical acute rejection during the first 100 days post transplantation. They also reported that asymptomatic CMV infection and overt CMV disease during the first 100 days increase the risk of recipient mortality beyond 100 days (7). Arthurs et al. (4) reported that delayed-onset tissue-invasive CMV disease was significantly associated with allograft loss and mortality after kidney transplantation. In the present cases, early diagnosis and treatment with GCV prevented graft dysfunction and reduced mortality. The clinical presentations of CMV infection are varied, and CMV infection primarily results in CMV pneumonitis, hepatitis, encephalitis, and GI disease. However, rhabdomyolysis associated with CMV infection is exceedingly rare. Therefore, the diagnosis of rhabdomyolysis associated with CMV infection can be delayed, which can lead to significant detrimental effects in KTRs. When dealing with KTRs with rhabdomyolysis, CMV infection should be considered as a possible cause of rhabdomyolysis.
4.
5.
6.
7.
8.
9.
10.
11. 12.
13.
Acknowledgements: Author contributions: H.-Y.J. and C.-D.K.: Data analysis, drafting of the article, and critical revision of the article. K.-H.K., S.-C.P., and J.-H.L.: Data collection. J.-Y.C., J.-H.C., S.-H.P., Y.-L.K., H.-K.K., and S.H.: Critical revision of the article.
14.
15.
16.
References 17. 1. Giannoglou GD, Chatzizisis YS, Misirli G. The syndrome of rhabdomyolysis: pathophysiology and diagnosis. Eur J Intern Med 2007; 18 (2): 90–100. 2. Warren JD, Blumbergs PC, Thompson PD. Rhabdomyolysis: a review. Muscle Nerve 2002; 25 (3): 332–347. 3. Gindre H, Feasson L, Auboyer C, Cathebras P. Severe rhabdomyolysis associated with a primary cytomegalovirus
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18.
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infection in an immunocompetent patient. BMJ Case Rep 2013; 2013: pii: bcr2012008140. Arthurs SK, Eid AJ, Pedersen RA, et al. Delayed-onset primary cytomegalovirus disease and the risk of allograft failure and mortality after kidney transplantation. Clin Infect Dis 2008; 46 (6): 840–846. Reischig T, Jindra P, Svecova M, et al. The impact of cytomegalovirus disease and asymptomatic infection on acute renal allograft rejection. J Clin Virol 2006; 36 (2): 146–151. Sagedal S, Hartmann A, Nordal KP, et al. Impact of early cytomegalovirus infection and disease on long-term recipient and kidney graft survival. Kidney Int 2004; 66 (1): 329–337. Sagedal S, Nordal KP, Hartmann A, et al. The impact of cytomegalovirus infection and disease on rejection episodes in renal allograft recipients. Am J Transplant 2002; 2 (9): 850–856. Hirohama D, Shimizu T, Hashimura K, et al. Reversible respiratory failure due to rhabdomyolysis associated with cytomegalovirus infection. Intern Med 2008; 47 (19): 1743–1746. Greco TP, Askenase PW, Kashgarian M. Postviral myositis: myxovirus-like structures in affected muscle. Ann Intern Med 1977; 86 (2): 193–194. Pratt RD, Bradley JS, Loubert C, et al. Rhabdomyolysis associated with acute varicella infection. Clin Infect Dis 1995; 20 (2): 450–453. Konrad RJ, Goodman DB, Davis WL. Tumor necrosis factor and coxsackie B4 rhabdomyolysis. Ann Intern Med 1993; 119 (8): 861. Craighead JE, Huber SA, Sriram S. Animal models of picornavirus-induced autoimmune disease: their possible relevance to human disease. Lab Invest 1990; 63 (4): 432–446. Hughes GS Jr, Hunt R. Cytomegalovirus infection with rhabdomyolysis and myoglobinuria. Ann Intern Med 1984; 101 (2): 276–277. Maeda M, Maeda A, Wakiguchi H, et al. Polymyositis associated with primary cytomegalovirus infection. Scand J Infect Dis 2000; 32 (2): 212–214. Sato K, Yoneda M, Hayashi K, et al. A steroid-responsive case of severe rhabdomyolysis associated with cytomegalovirus infection. Rinsho Shinkeigaku 2006; 46 (5): 312–316. Yasumoto N, Hara M, Kitamoto Y, Nakayama M, Sato T. Cytomegalovirus infection associated with acute pancreatitis, rhabdomyolysis and renal failure. Intern Med 1992; 31 (3): 426–430. Graham DJ, Staffa JA, Shatin D, et al. Incidence of hospitalized rhabdomyolysis in patients treated with lipid-lowering drugs. JAMA 2004; 292 (21): 2585–2590. Minami K, Tamura A, Komori Y, et al. Acute encephalopathy and rhabdomyolysis following rotavirus gastroenteritis. J Paediatr Child Health 2007; 43 (1–2): 90–91.
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Case report
Rhabdomyolysis associated with cytomegalovirus infection in kidney transplant recipients H.-Y. Jung, K.-H. Kim, S.-C. Park, J.-H. Lee, J.-Y. Choi, J.-H. Cho, S.-H. Park, Y.-L. Kim, H.-K. Kim, S. Huh, C.-D. Kim. Rhabdomyolysis associated with cytomegalovirus infection in kidney transplant recipients. Transpl Infect Dis 2014: 16: 993–998. All rights reserved Abstract: Rhabdomyolysis is a pathological syndrome caused by skeletal muscle cell damage that affects the integrity of the cellular membrane and leads to the release of toxic intracellular constituents into the bloodstream. Although cytomegalovirus (CMV) has rarely been reported as a cause of rhabdomyolysis, CMV infection could be considered as a possible cause because of its clinical significance in kidney transplant recipients (KTRs). We report 2 cases of rhabdomyolysis associated with CMV infection in KTRs. A 64-yearold woman (Case 1) and a 65-year-old man (Case 2), who had each received a kidney from a living unrelated donor, were admitted with complaints of weakness in both legs and myalgia. Laboratory findings revealed highly increased creatine phosphokinase and myoglobinuria. In both cases, no recent alterations of medications had occurred, and other causes of rhabdomyolysis—such as trauma, alcohol, drugs, and electrolyte abnormalities – were excluded. CMV pp65 antigen was positive, and patients were diagnosed with rhabdomyolysis associated with CMV infection. Both patients recovered without complications after ganciclovir treatment. In conclusion, CMV infection should be considered as a possible cause of rhabdomyolysis in KTRs.
Rhabdomyolysis is a syndrome characterized by damage of skeletal muscle, leading to the release of muscle cell elements, such as myoglobin and creatine kinase, into the blood circulation. The clinical presentation of rhabdomyolysis varies from an asymptomatic elevation of muscle enzymes to severe acute kidney injury and hypovolemic shock (1). Acute non-traumatic rhabdomyolysis may be caused by a variety of electrolyte or endocrine disorders, medicine or toxic substance use, acute viral or bacterial infections, inflammatory myopathies, and muscle enzyme deficiencies (2). Although cytomegalovirus (CMV) has rarely been reported as a cause of rhabdomyolysis (3), CMV infection could be considered as a possible cause because of its clinical significance in kidney transplant recipients (KTRs) (4–7). Here, we report 2 cases of
H.-Y. Jung1,2, K.-H. Kim1,2, S.-C. Park1,2, J.-H. Lee1,2, J.-Y. Choi1,2, J.-H. Cho1,2, S.-H. Park1,2, Y.-L. Kim1,2, H.-K. Kim3, S. Huh3, C.-D. Kim1,2 1
Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Korea, 2Clinical Research Center for End Stage Renal Disease in Korea, Daegu, Korea, 3Department of Surgery, Kyungpook National University School of Medicine, Daegu, Korea Key words: rhabdomyolysis; CMV infection; kidney transplantation Correspondence to: Chan-Duck Kim, MD, PhD, Division of Nephrology, Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu 700-721, Korea Tel: +82-53-200-5560 Fax: +82-53-423-7583 E-mail: [email protected]
Received 20 April 2014, revised 5 July 2014, accepted for publication 29 July 2014 DOI: 10.1111/tid.12297 Transpl Infect Dis 2014: 16: 993–998
rhabdomyolysis associated with CMV infection, which, to our knowledge, are the first reported case in KTRs.
Case reports Case 1 A 64-year-old woman was diagnosed with end-stage renal disease due to hypertensive nephrosclerosis and started peritoneal dialysis in May 2010. She eventually received a kidney from her husband in November 2010. In January 2013, she was admitted to our hospital for weakness in both legs and myalgia. Beginning 10 days before admission, she also suffered from nausea, watery diarrhea, and poor appetite. The gastrointestinal
993
Jung et al: Rhabdomyolysis in KTRs with CMV infection
(GI) symptoms had improved spontaneously, but the leg weakness had worsened to the point that she was unable to walk. She had been receiving maintenance immunosuppressive therapy consisting of 50 mg of cyclosporine twice daily, 500 mg of mycophenolate mofetil twice daily, and 4 mg of methylprednisolone daily. She had taken these mediations including a statin for at least 2 years without complications, and the dosages had not been changed recently. The patient had no history of alcohol or drug consumption or excessive muscular activity. She was physically active and had no personal or familial history of neurological or muscular disease. Physical examination at admission revealed a temperature of 36.5°C, blood pressure of 107/66 mmHg, regular pulse rate of 87 beats/min, and respiratory rate of 18 breaths/min. Neurological examination revealed flaccid weakness involving the proximal muscles of both lower limbs, but no muscle fasciculation. The patient showed no sensory disturbance. Abdominal examination revealed no tenderness of the renal allograft. Laboratory findings revealed a highly elevated creatine phosphokinase level of 12,036 U/L and myoglobinuria. Blood chemistry examination showed an increased aspartate aminotransferase (AST) level of 492 U/L, an alanine aminotransferase (ALT) level of 286 U/L, a lactate dehydrogenase (LDH) level of
2088 U/L, an aldolase level of 36.2 U/L, and a serum myoglobin level of 20,300 ng/mL. Blood urea nitrogen (BUN) was slightly increased (28.3 mg/dL), and serum creatinine was normal (1.10 mg/dL). There were no electrolyte abnormalities. Motor and sensory nerve conduction studies, performed 2 days after admission and 12 days after the first symptoms, did not show evidence for peripheral neuropathy, especially Guillain-Barre syndrome. Needle electromyogram, performed 5 days after admission, showed polyphasic motor unit action potentials with an early recruit pattern at the right vastus lateralis, tibialis anterior, medial gastrocnemius, and extensor hallucis longus muscles, suggesting a myopathic change. No fibrillation potentials or positive sharp waves were seen at the resting state of the examined muscles. A bone scan, performed 4 days after the admission, showed diffusely increased intense tracer uptake in the buttocks, thighs, and calf muscles, which is compatible with rhabdomyolysis (Fig. 1). No significant elevation of serum antibody was seen against Epstein-Barr virus (EBV) on admission. Serum BK virus polymerase chain reaction (PCR) was unremarkable. However, the number of CMV pp65 antigens was 5/200,000 polymorphonuclear leukocytes (Fig. 2). The pre-transplant CMV immunoglobulin (Ig)M antibodies of donor and recipient were all negative. The pre-transplant CMV IgG antibody titers of donor and
Fig. 1. Bone scan results. A bone scan of Case 1 showed diffusely increased intense tracer uptake in the buttocks, thighs, and calves, which is compatible with rhabdomyolysis.
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recipient were 165 AU/mL and 139 AU/mL, respectively. All of the examination findings indicated that the patient had rhabdomyolysis associated with CMV infection. On the sixth day after admission, ganciclovir (GCV) was administered intravenously. On the 12th day after admission, the clinical status had gradually improved, and other muscle enzymes had gradually decreased. CMV infection was controlled after 16 days
of GCV treatment, and the patient was discharged from the hospital with improved motor function (Fig. 2).
Case 2 A 65-year-old man had been diagnosed with chronic kidney disease as a result of diabetic nephropathy and received a kidney from his wife in May 2008. Since
A Case 1
B Case 2
Fig. 2. Changes in the patients’ clinical course and laboratory data. In both cases, the clinical status gradually improved and muscle enzymes gradually decreased after ganciclovir treatment. CPK, creatine phosphokinase; LDH, lactate dehydrogenase; Cr, creatinine; AST, asparatate aminotransferase. CMV, cytomegalovirus, PMN, polymorphonuclear leukocytes.
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then, his serum creatinine level had remained stable between 1.5 and 1.8 mg/dL. In April 2013, he was admitted to our hospital for weakness in both thighs and myalgia for 3 weeks. He had been experiencing pitting edema in both legs and reddish urine for a week. His concurrent medications included 100 mg of cyclosporine twice daily, 360 mg of mycophenolate mofetil twice daily, and 4 mg of methylprednisolone daily. He had taken these mediations including a statin for at least 2 years without complications, and his medications had not been changed recently. No trauma, alcohol consumption, or drug consumption was reported. He was physically active and had no personal or familial history of neurological or muscular disease. Physical examination at admission revealed a temperature of 36.5°C, blood pressure of 176/76 mmHg, regular pulse rate of 60 beats/min, and respiratory rate of 20 breaths/min. Laboratory findings showed a highly elevated creatine phosphokinase level of 12,551 U/L and myoglobinuria. Blood chemistry examination revealed an elevated AST level of 484 U/L, an ALT level of 614 U/L, an LDH level of 4234 U/L, an aldolase level of 68.5 U/L, and a serum myoglobin level of 15,690 ng/ mL. BUN and serum creatinine levels were increased (43.4 mg/dL and 2.20 mg/dL, respectively). No electrolyte abnormalities were noted. He had no significant elevation of serum antibody against EBV on admission. Serum BK virus PCR was unremarkable. However, CMV PCR was positive, and CMV pp65 antigen count was 10/200,000 polymorphonuclear leukocytes. The pre-transplant CMV IgM antibodies of donor and recipient were all negative. The pre-transplant CMV IgG antibody titers of donor and recipient were 188.4 AU/mL and 91.1 AU/mL, respectively. A diagnosis of rhabdomyolysis associated with CMV infection was made after excluding other causes of rhabdomyolysis. Intravenous GCV was injected for 14 days, which controlled the CMV infection. The clinical status had gradually improved and other muscle enzymes were markedly decreased on day 14. He was discharged on day 22 after admission with full motor function (Fig. 2).
Discussion Acute viral infections associated with rhabdomyolysis include influenza virus, Coxsackie virus, EBV, herpes simplex virus, parainfluenza virus, adenovirus, echovirus, measles virus, varicella zoster virus, human
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immunodeficiency virus, dengue virus, and CMV (3, 8). Influenza virus is the most common viral etiology. In contrast, only a small number of cases have been reported in which CMV infection is related to rhabdomyolysis. We present 2 cases of rhabdomyolysis associated with CMV infection in KTRs who were successfully treated with GCV. Our cases are distinct from all other previous cases, in that all of the previously reported patients were immunocompetent. To the best of our knowledge, this is the first reported cases of rhabdomyolysis associated with CMV infection in KTRs. Although the mechanism of muscle damage as a result of viral infections has not been established, several mechanisms have been proposed. Greco et al. (9) detected myxovirus-like particles by electron microscopy of a muscle specimen from a patient with influenza-associated myositis. Pratt et al. (10) found varicella zoster virus DNA by PCR of muscle specimens from patients with rhabdomyolysis, indicating direct viral invasion of the muscle tissue. Myotoxic cytokines released in response to viral infection were suggested as the possible cause for virus-induced muscle injury in a case of rhabdomyolysis secondary to coxsackie virus myositis (11). Konrad et al. (11) reported that a patient’s serum contained an elevated level of tumor necrosis factor, which induced breakdown of the skeletal muscles in an animal model. Immunologic processes induced by the viral infection have also been postulated as a possible cause of muscle damage (12). Several cases of rhabdomyolysis associated with CMV infection have been reported (3, 8, 13–16) (Table 1). Of all 6 patients in these published cases, 2 patients needed mechanical ventilation, 3 patients received corticosteroid therapy with apparent success, 1 patient received immune globulins therapy, and all of them recovered without sequelae. Muscle biopsies were often close to normal and never showed viral inclusions. Muscle CMV PCR was always negative when performed. Only 1 patient developed renal failure and needed hemodialysis. The 2 patients we present here recovered without complication and did not need hemodialysis or mechanical ventilation (Table 1). Viral particles or virus DNA has been found in muscle specimens from patients with viral infection-associated rhabdomyolysis (9, 10). However, muscle biopsy was not performed in our patients, because muscle biopsy provided no specific diagnostic findings in most of the previously reported viral infection-associated rhabdomyolysis cases or in cases of rhabdomyolysis with other causes, such as inherited metabolic myopathy or polymyositis. Rhabdomyolysis associated with CMV infection was diagnosed on the
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Jung et al: Rhabdomyolysis in KTRs with CMV infection
Summary of reviewed cases of rhabdomyolysis associated with cytomegalovirus (CMV) infection Case no.
1
2
3
4
5
6
7
8
First author (Reference)
Sato (15)
Maeda (14)
Yasumoto (16)
Hughes (13)
Hirohama (8)
Gindre (3)
Jung (PC)
Jung (PC)
Age, years/Gender
31/M
17/F
27/M
21/M
58/F
32/F
64/F
65/M
Immunity
N
N
N
N
N
N
IC
IC
Initial symptoms
Fever, fatigue
Urticaria, dyspnea
Muscle weakness
Fever, myalgia
Myalgia
Myalgia, muscle weakness
Nausea, diarrhea
Myalgia, muscle weakness
Muscle weakness
Proximal
Proximal
Diffuse
Proximal
Proximal
Proximal
Proximal
Proximal
CPK peak level (U/L)
24,380
15,490
74,850
4800
33,744
177,000
18,904
12,551
+ +
+
+
+
NA
+
CMV IgM
+
+
NA
CMV IgG
+
+
+
CMV pp65 Ag
+
NA
NA
NA
NA
NA
NA
CMV PCR
+
NA
+
+ +
Mechanical ventilation
Yes
No
No
No
Yes
Yes
No
No
Hemodialysis
No
No
Yes
No
No
No
No
No
Treatment
CTC
Supportive
CTC
NA
CTC
IVIG, GCV
GCV
GCV
Outcome
Recovered
Recovered
Recovered
Recovered
Recovered
Recovered
Recovered
Recovered
M, male; F, female; PC, present case; N, normal; IC, immunocompromised; CPK, creatine phosphokinase; Ig, immunoglobulin; NA, not available; Ag, antigen; PCR, polymerase chain reaction; CTC, corticosteroids; IVIG, intravenous immune globulins; GCV, ganciclovir.
Table 1
basis of clinical manifestations and laboratory findings after excluding other causes of rhabdomyolysis, such as trauma, alcohol, drugs, and electrolyte abnormalities. Patients in our cases had no history of alcohol or drug consumption and excessive muscular activity. Patients were physically active and had no personal or familial history of neurological or muscular disease. Although patients had taken medications including statins, they had no complications for at least 2 years and no recent alterations of dosage. Previous study (17) demonstrated that the average length of time on a statin before rhabdomyolysis is approximately 1 year. Considering that the patients we presented were taking statins without dosage alteration over 2 years, statins could be excluded as possible causes of rhabdomyolysis. Depending on clinical presentation, diagnosis of our patients was confirmed by the detection of CMV pp65 antigen, which was previously not detected. The pre-transplant CMV serostatus of both the donors and the recipients of presented cases were CMV seropositive and both recipients had a risk of developing CMV superinfection. We could not make an accurate diagnosis about initial GI symptoms of the first case because GI
symptoms were completely improved before admission and we did not have a further examination such as endoscopy. However, we can explain the GI symptoms as a result of viral gastroenteritis considering the clinical course of the patient. A previous report (18) revealed that a patient with rhabdomyolysis following viral gastroenteritis manifested a profound diarrhea resulting in a significant loss of body weight and/or hemodynamic instability. The previous study (18) speculated that hypovolemic ischemic shock, hypercytokinemia related to viral infection, and diarrheainduced electrolyte imbalance such as hypokalemia in a viral gastroenteritis might be associated with rhabdomyolysis. Our first case had no dehydration, hemodynamic instability, or electrolyte imbalance, because GI symptoms were not severe and improved in 3 days. Therefore, the possibility that viral gastroenteritis might be a cause of rhabdomyolysis in our first case and CMV could be an asymptomatic reactivation appeared to be low. If the patient has persistent GI symptoms, endoscopy must be performed in order to differentiate CMV gastroenteritis. CMV infection has more significant clinical importance in KTRs than in immunocompetent patients.
Transplant Infectious Disease 2014: 16: 993–998
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Jung et al: Rhabdomyolysis in KTRs with CMV infection
Several previous studies demonstrated a clinical significance of CMV infection in KTRs. Sagedal et al. (6) found that CMV infection and disease are independent risk factors for clinical acute rejection during the first 100 days post transplantation. They also reported that asymptomatic CMV infection and overt CMV disease during the first 100 days increase the risk of recipient mortality beyond 100 days (7). Arthurs et al. (4) reported that delayed-onset tissue-invasive CMV disease was significantly associated with allograft loss and mortality after kidney transplantation. In the present cases, early diagnosis and treatment with GCV prevented graft dysfunction and reduced mortality. The clinical presentations of CMV infection are varied, and CMV infection primarily results in CMV pneumonitis, hepatitis, encephalitis, and GI disease. However, rhabdomyolysis associated with CMV infection is exceedingly rare. Therefore, the diagnosis of rhabdomyolysis associated with CMV infection can be delayed, which can lead to significant detrimental effects in KTRs. When dealing with KTRs with rhabdomyolysis, CMV infection should be considered as a possible cause of rhabdomyolysis.
4.
5.
6.
7.
8.
9.
10.
11. 12.
13.
Acknowledgements: Author contributions: H.-Y.J. and C.-D.K.: Data analysis, drafting of the article, and critical revision of the article. K.-H.K., S.-C.P., and J.-H.L.: Data collection. J.-Y.C., J.-H.C., S.-H.P., Y.-L.K., H.-K.K., and S.H.: Critical revision of the article.
14.
15.
16.
References 17. 1. Giannoglou GD, Chatzizisis YS, Misirli G. The syndrome of rhabdomyolysis: pathophysiology and diagnosis. Eur J Intern Med 2007; 18 (2): 90–100. 2. Warren JD, Blumbergs PC, Thompson PD. Rhabdomyolysis: a review. Muscle Nerve 2002; 25 (3): 332–347. 3. Gindre H, Feasson L, Auboyer C, Cathebras P. Severe rhabdomyolysis associated with a primary cytomegalovirus
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18.
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