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Rhabdomyolysis in an Infant With Primary Human Herpesvirus 6 Infection

Fujino, Masayuki MD*; Ohashi, Masahiro MD*; Tanaka, Kenichi MD*; Kato, Tomochika MD*; Asano, Yoshizo MD; Yoshikawa, Tetsushi MD

The Pediatric Infectious Disease Journal: November 2012 - Volume 31 - Issue 11 - p 1202–1203
doi: 10.1097/INF.0b013e318266b3c9
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We report here the first case of rhabdomyolysis at the time of primary human herpesvirus 6 infection. The patient was a previously healthy 1-year-old girl who developed rhabdomyolysis 4 days after the onset of the primary human herpesvirus 6 infection. No other etiologic agent that might cause rhabdomyolysis was identified.

From the *Department of Pediatrics, Toyokawa Municipal Hospital, Toyokawa; and Department of Pediatrics, Fujita Health University School of Medicine, Toyoake, Aichi, Japan.

Accepted for publication June 26, 2012.

The authors have no funding or conflicts of interest to disclose.

Address for Correspondence: Masahiro Ohashi, MD, Department of Pediatrics, Fujita Health University Hospital, Toyoake, Aichi, Japan 470–1192. E-mail: mohashi@fujita-hu.ac.jp.

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CASE REPORT

A previously healthy 1-year-old Japanese girl had a high fever (39.0°C) on March 11, 2009 (day 1 of illness). The rapid diagnostic test for influenza A and B antigens by immunochromatographic method was negative on day 2 of illness. She was admitted to our hospital on day 4 of illness due to short generalized clonic seizures.

She had tachycardia (heart rate, 160 beats per minute) and tachypnea (respiratory rate, 48 beats per minute); however, no other abnormal findings, including remarkable muscle weakness, were observed at the time of admission to the hospital. Clinical course and kinetics of creatine kinase and myoglobin are summarized in Figure 1. A mild elevation of C-reactive protein (2.98 mg/dL), aspartate aminotransferase (177 U/L) and lactate dehydrogenase (512 U/L) were detected in the patient’s serum. In addition, a marked elevation of muscle enzymes, namely, creatine kinase (9896 U/L), myoglobin (2060 ng/mL) and aldolase (23.1 U/L) were also observed. Moreover, the patient’s creatine kinase value peaked at 12,654 U/L on day 5 of illness, and gradually decreased to normal by day 12 of illness. Serum creatinine value was within normal range during the observation period. Although urinalysis revealed occult blood, no red blood cells were detected by microscopic examination. Based on these clinical findings, the patient was diagnosed with rhabdomyolysis, and was treated with hydration and the administration of bicarbonate and osmotic diuretics. On day 6 of illness, the patient’s body temperature returned to normal. The appearance of a skin rash on the patient’s trunk and face prompted a diagnosis of exanthem subitum. The patient was followed for 6 months after being discharged from the hospital, and normal development and muscle functions were observed.

FIGURE 1

FIGURE 1

At the time of admission to the hospital, no bacteria were isolated from any of the patient’s clinical specimens including throat swabs, urine and stool specimens and cerebrospinal fluid. Rotavirus antigen was not detected in the stool, and serologic tests for herpes simplex viruses, cytomegalovirus, Epstein-Barr virus and parainfluenza virus were all negative. However, seroconversion to human herpesvirus 6 (HHV-6) IgG antibody (<8–256 by indirect immunofluorescent assay) was demonstrated indicating a primary HHV-6 infection. Moreover, HHV-6 DNA was also detected in serum collected at the time of admission.1 Based on mass spectrometric analysis (amino acid and acylcarnitines TandemMass Spectrometry kit) there was no evidence of metabolic disease in the patient’s urine and serum specimens. Additionally, neither antibiotic nor vaccine was administered in this patient in the month before the hospitalization.

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DISCUSSION

Rhabdomyolysis is defined as a clinical and biochemical syndrome resulting from skeletal muscle injury characterized by elevation of serum creatine kinase concentrations and myoglobinuria, leading to the involvement of other organ systems.2 This disease could be caused by various factors, including exhaustive exercise, heatstroke, trauma, drugs, toxins, metabolic disorders and several viral and bacterial infections. The clinical course of our patient was consistent with rhabdomyolysis. No obvious external factors such as trauma, heatstroke and drugs were identified in our patient. Furthermore, it is unlikely that the patient had a metabolic disorder based on the history, physical examination and mass spectrometric analysis. Although several viral infections, including influenza viruses, parainfluenza virus, adenoviruses and herpesviruses, have been identified as causative agents for rhabdomyolysis,3,4 the possibility of these viral infections was excluded by virologic examinations in this patient.

Primary HHV-6 infection causes exanthema subitum, which is generally a benign infantile febrile disease.5 It is well known that exanthema subitum rarely results in complications such as seizure, encephalitis, hepatitis, virus-associated hemophagocytic syndrome and myocarditis.6–8 Most of the etiologic agents of rhabdomyolysis were ruled out in this patient. Moreover, this patient displayed a typical clinical course of exanthem subitum, and primary HHV-6 infection was determined based on a serologic assay and serum polymerase chain reaction. Thus, these data strongly suggest that HHV-6 was involved in rhabdomyolysis in this patient. To our knowledge, this is the first case of rhabdomyolysis in a patient with primary HHV-6 infection.

There are 2 possible mechanisms of muscle damage induced by viral infections: one is the direct invasion of the virus into the muscle, and another is the induction of myotoxins by cytokines.9 Direct muscular damage by HHV-6 infection has been suggested in fatal cases of HHV-6–associated myocarditis.8 On the other hand, HHV-6 increases the synthesis of several cytokines including tumor necrosis factor-α,10 which is capable of causing acute proteolysis in a variety of organs including the liver, central nervous system and skeletal muscle.11 Although intensive care, including dialysis, is sometimes necessary for the treatment of rhabdomyolysis, this was not required for our patient. Further studies to elucidate the pathophysiology of HHV-6–associated rhabdomyolysis are necessary, and may shed light on the therapeutic efficacy of antiviral drugs or anticytokine drugs for treatment of this disease.

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REFERENCE

1. Tanaka N, Kimura H, Hoshino Y, et al. Monitoring four herpesviruses in unrelated cord blood transplantation. Bone Marrow Transplant. 2000;26:1193–1197
2. Warren JD, Blumbergs PC, Thompson PD. Rhabdomyolysis: a review. Muscle Nerve. 2002;25:332–347
3. Singh U, Scheld WM. Infectious etiologies of rhabdomyolysis: three case reports and review. Clin Infect Dis. 1996;22:642–649
4. Ebbeson RL, De Kock MJ, Penny N, et al. Rhabdomyolysis, acute renal failure, and compartment syndrome in a child with parainfluenza type 1 infection. Pediatr Infect Dis J. 2009;28:850–852
5. Asano Y, Yoshikawa T, Suga S, et al. Clinical features of infants with primary human herpesvirus 6 infection (exanthem subitum, roseola infantum). Pediatrics. 1994;93:104–108
6. Asano Y, Yoshikawa T, Kajita Y, et al. Fatal encephalitis/encephalopathy in primary human herpesvirus-6 infection. Arch Dis Child. 1992;67:1484–1485
7. Huang LM, Lee CY, Lin KH, et al. Human herpesvirus-6 associated with fatal haemophagocytic syndrome. Lancet. 1990;336:60–61
8. Yoshikawa T, Ihira M, Suzuki K, et al. Fatal acute myocarditis in an infant with human herpesvirus 6 infection. J Clin Pathol. 2001;54:792–795
9. Qin H, Cha SC, Neelapu SS, et al. Generation of an immune microenvironment as a novel mechanism for myotoxins to potentiate genetic vaccines. Vaccine. 2010;28:7970–7978
10. Ohashi M, Sugata K, Ihira M, et al. Human herpesvirus 6 infection in adult living related liver transplant recipients. Liver Transpl. 2008;14:100–109
11. Flores EA, Bistrian BR, Pomposelli JJ, et al. Infusion of tumor necrosis factor/cachectin promotes muscle catabolism in the rat. A synergistic effect with interleukin 1. J Clin Invest. 1989;83:1614–1622
Keywords:

human herpesvirus 6; rhabdomyolysis; cytokines

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