Severe rhabdomyolysis associated with a primary cytomegalovirus infection in an immunocompetent patient

Abstract

Virus-induced rhabdomyolysis rarely induces respiratory failure. We discuss here a case of severe rhabdomyolysis with acute respiratory failure secondary to a cytomegalovirus (CMV) primary infection. We report a case of severe acute rhabdomyolysis, leading to respiratory failure and mechanical ventilation, associated with CMV primary infection in a young and otherwise healthy woman. We excluded other aetiologies such as metabolic myopathies, electrolyte disorders or Guillain-Barré syndrome with exhaustive researches. After 1 year, the patient recovered completely, apart from a slight muscle deconditioning. In this report, we compare our patient with five other similar cases found in the literature; our patient had the most severe presentation. The mechanism of acute viral-induced rhabdomyolysis remains elusive.

Background

Acute non-traumatic rhabdomyolysis may be caused by a variety of electrolyte or endocrine disorders, medicine or toxic use, acute infections (viral or bacterial), inflammatory myopathies and muscle enzyme deficiencies.¹ Cytomegalovirus (CMV) has rarely been reported as a cause of rhabdomyolysis. Although severe rhabdomyolysis may lead to acute kidney injury, it rarely induces respiratory failure. We discuss here a case of severe rhabdomyolysis with acute respiratory failure secondary to a CMV primary infection.

Case presentation

A 32-year-old woman was admitted to the emergency room for back pain and proximal muscle weakness. She was physically active and had no personal or familial history of muscle disorder. She had given birth to a healthy baby 3 weeks before. She had no history of alcohol or drug consumption. She initially presented with muscle pain and weakness, shortness of breath, tachycardia and tea-coloured urine, but displayed no signs of organ failure (normal blood pressure, temperature and oxygenation). Neurological examination showed proximal muscle weakness, without sensitive or deep tendon reflexes abnormalities. Laboratory findings were elevated muscle enzymes (CK 120 000 IU/l (N 20–120), AST 3599 IU/l (N 0–45), ALT 1024 IU/l (N 0–45), LDH 10 678 IU/l (N 300–620)), moderately elevated C reactive protein (38 mg/l (N<5)), oliguria but no renal failure (creatine 35 μmol/l, K⁺ 4.8 mmol/l). Muscle weakness got worse during the following days, and the patient experienced respiratory distress, which led to her transfer to the intensive care unit. Chest x-ray was normal. Gas analysis showed signs of alveolar hypoventilation (pH 7.40; PaCO₂ 46 mm Hg (N: 35–45); PaO₂ 164 mm Hg (N>70), HCO₃− 30 (N: 22–26)). She first received non-invasive ventilation, but as the gas analysis worsened with marked hypercapnia (PaCO₂ 61 mm Hg), mechanical ventilation was later used for 14 days. Biological findings showed extremely elevated CK (177 000 IU/l) and myoglobinuria (4 009 500 μg/l). No renal or cardiac failure developed under intensive saline hydration (200 ml/h). Thyroid function was normal. Cerebrospinal fluid was unremarkable. High antibody titres against CMV (IgM 1/128, IgG positive), with a very high viral count for CMV-PCR (51 800 copies/ml), were demonstrated. HIV testing was negative. Immunologic testing did not reveal autoantibodies associated with inflammatory myositis, but showed the presence of antiganglioside antibodies (anti-GM2 IgM). A diagnosis of severe rhabdomyolysis secondary to CMV primary infection was retained, and the patient was treated with ganciclovir (for 21 days) and intravenous immune globulins for 5 days (25 g/day). She received no corticosteroid therapy. Supportive care included parenteral nutrition and physiotherapy. Nosocomial complications were methicillin-sensitive Staphylococcus aureus pneumonia and Escherichia coli urinary tract infection, which evolved well under antibiotic treatment.

Investigations

A muscle biopsy was performed on the 15th day after admission, and showed only non-specific findings such as mild variation in fibre size and rare necrotic fibres. No viral inclusions, negative CMV-PCR, and no inflammatory, metabolic or structural impairment were observed. Histochemical, immunohistochemical, oxidative and glycolytic enzyme reactions were performed. Glycogenoses, mitochondrial myopathies and lipid related disorders were specifically sought. Some of them were excluded by normal laboratory work-up for maltase acid activity, carnitine palmitoyltransferase II activity and spectrometric profile of plasmatic acylcarnitines.

An electroneuromyographic study, performed 1 month after the first symptoms, did not show argument for peripheral neuropathy, especially Guillain-Barré syndrome (GBS). Needle examination was also normal, without myopathic pattern.

Outcome and follow-up

On the 21st day, the clinical status had gradually improved, hyperCKemia and other rhabdomyolysis markers were significantly reduced (CK 4454 IU/l, AST 278 IU/l, ALT 446 IU/l, LDH 1767 IU/l), CMV infection was controlled (viral count 450 copies/ml), and she was extubated. One month after the first symptoms, she was referred to a rehabilitation centre. At that time, muscle weakness had markedly improved. One year after the first symptoms, the patient, who was experiencing mild fatigue, underwent a complete muscle work-up, which only revealed slight deconditioning, without any argument for metabolic myopathy.

Discussion

We report here a case of reversible respiratory failure owing to a severe rhabdomyolysis caused by CMV primary infection, in an otherwise healthy patient. A variety of inherited and acquired disorders affecting muscle membranes, ion channels and muscle energy supply may cause rhabdomyolysis.¹ Multiple contributing factors are commonly found, and in a significant proportion of cases, no aetiology can be identified. Although viral infections are among the common triggers of rhabdomyolysis, the mechanisms of infection-induced rhabdomyolysis remain unclear. Proposed mechanisms include direct viral invasion of muscle cells, toxin generation, hyperthermic or drug injury.² Like anaesthesia, fasting or strenuous exercise, a virus-induced rhabdomyolysis may reveal a structural or metabolic myopathy.¹

Respiratory distress was considered as a consequence of muscle weakness, as the patient presented with alveolar hypoventilation and chest x-ray excluding interstitial pneumonitis or left cardiac failure. No signs of renal failure developed in our case under intensive fluid therapy, and we did not use forced alkaline diuresis or furosemide/mannitol administration. The relevance of urine alkalinisation in the management of rhabdomyolysis remains debated.³ The incidence of acute kidney injury in acute rhabdomyolysis is probably less than 50% and may be even rarer in the absence of sepsis, dehydration or acidosis in patients with myopathies.³ Serum creatine was the only renal biomarker measured in our case.

We found only five other cases of CMV-induced rhabdomyolysis without coinfection or strenuous exercise in the medical literature.^4–8 The published cases were pretty similar to our case (table 1). All the patients were immunocompetent; two patients needed mechanical ventilation, three of them received corticosteroid therapy with apparent success, and all of them recovered without sequelae. Muscle biopsies were often close to normal and never showed viral inclusions. Only one patient developed renal failure and needed haemodialysis.⁶ Muscle CMV-PCR was always negative when performed. Our patient had the highest CK level and the best proven CMV primary infection. The history of our patient did not suggest a structural or metabolic myopathy, and we performed an extensive work-up to exclude such underlying diseases. Taken together, these findings suggest that CMV primary infection may cause severe rhabdomyolysis leading to respiratory failure in previously healthy subjects.

Table 1.

Comparison of reported cases of CMV-associated rhabdomyolysis

	Case 1 4	Case 2 5	Case 3 6	Case 4 7	Case 5 8	Our case
Age, sex	31, M	17, F	27, M	21, M	58, F	32, F
Immunity	N	N	N	N	N	N
Initial symptoms	Fever and fatigue	Urticaria and dyspnoea	Muscle weakness	Fever and myalgia	Myalgia	Myalgia and muscle weakness
Muscle weakness	Proximal	Proximal	Diffuse	Proximal	Proximal	Proximal
Maximum CK level (UI/l)	24380	15490	74850	4800	33744	177000
CMV-IgM	+	+	ND	+	−	+++
CMV-IgG	+	+	+	−	+	+
CMV-Ag	+	ND	ND	ND	ND	ND
CMV-PCR	−	ND	ND	ND	−	+
Muscle biopsy
Necrotic fibres	Yes	Yes	Yes	ND	No	Rare
Lymphocytic infiltration	No	Yes	Yes	ND	No	No
Mechanical ventilation	Yes	No	No	No	Yes	Yes
Treatment	CTC	Supportive	CTC	?	CTC	IVIg, ganciclovir
Total recovery	3 months	7 months	3 months	?	24 days	6 months

CTC, corticosteroids; F, female; IVIg, intravenous immune globulins; M, male; N, normal; ND, not determined.

However, given the atypical clinical presentation, and the fact that CMV infection may induce GBS, we should consider an association between rhabdomyolysis and GBS to explain the clinical course of this case. Such a hypothesis seems unlikely, because of normal cerebrospinal fluid and the absence of compatible findings on the delayed electroneuromyographic study. Like Hirohama et al,⁸ we found anti-GM2 antibodies (IgM type), which have been associated with CMV-associated GBS.⁹ However, recent studies suggest that anti-GM2 may be associated with CMV infection, regardless of neurological involvement.¹⁰ The normality of muscle biopsy in most cases of CMV-induced rhabdomyolysis suggests an indirect mechanism of muscle injury rather than a direct viral invasion of skeletal muscles.

Besides the supportive therapy, there is no evidence for a particular treatment of CMV-induced rhabdomyolysis. We discussed steroid therapy, which had previously been considered effective in a few cases, but in an intensive care setting with a high risk of nosocomial infection, we preferred to administer intravenous immune globulins (by analogy with CMV-associated GBS) and ganciclovir, the latter being questionable in a presumed immunocompetent patient.

Learning points.

• Cytomegalovirus primary infection may induce acute rhabdomyolysis in otherwise healthy patients.

• Although severe rhabdomyolysis usually leads to acute kidney injury, it may also induce respiratory failure.

• The mechanism of acute viral-induced rhabdomyolysis remains elusive.