Rhabdomyolysis Induced by Parainfluenza 2 Virus in a Healthy 18-Year-Old Male Patient: A Case Study

Introduction

Rhabdomyolysis is a medical condition defined by the cellular breakdown of skeletal muscle fibers leading to the release of basic muscle components into the bloodstream [1]. The disorder can result in life-threatening renal failure if undiagnosed and untreated. It can have a variety of underlying causes, including infections that directly affect muscle tissue. There are a diverse group of human viral pathogens documented that can cause rhabdomyolysis, including influenza types A and B [2], HIV [3], enteroviruses [4], Epstein-Barr [5], cytomegalovirus [6], adenovirus [7], herpes simplex [8], parainfluenza [9], and varicella virus [10]. In childhood and early adulthood, viral myositis is the single most prevalent cause of rhabdomyolysis, affecting 38% of cases [11], with influenza virus being the most common [1], implicated in nearly 33% of known viral-induced rhabdomyolysis cases[12]. Rhabdomyolysis characteristically presents with 3 findings: myalgias, muscle weakness, and myoglobinuria, manifested as tea-colored urine. However, over 50% will report they have no muscle weakness or myalgia, with the only initial symptom being discolored urine [13]. Serum creatine kinase (CK) concentration, primarily the CK-muscle-muscle isoenzyme (MM) subtype, is the most sensitive lab test for muscle damage in a patient with rhabdomyolysis. CK has both a rapid surge in measured serum concentration with skeletal muscle necrosis and a slow clearance, making it a useful laboratory measurement to follow during treatment and recovery of rhabdomyolysis [10]. In contrast to rhabdomyolysis, benign viral myositis cases do not have a rapid surge in CK values or a reduction in renal function [14]. To date, there are very few cases demonstrating the association between parainfluenza virus infection and rhabdomyolysis [9]. The purpose of this report is to document parainfluenza 2 as the etiology of a case of clinically disabling rhabdomyolysis in an 18-year-old male patient with no comorbidities and his rapid recovery with supportive care.

Case Report

An 18-year-old male patient was brought to the hospital after experiencing a concerning decline in his physical condition. He had a 5-day period of increasing sore throat, and generalized myalgias, which he dismissed as a common “cold”. After the 5 days, the condition progressed to severe skeletal muscle weakness, especially in his lower extremities, with elements of pain including his back and generalized pain. He ultimately refused to walk, and his urine turned a distinct clear brown color; therefore, he was brought to the Emergency Department (ED). His past medical history and family history were negative. There was no known history of familial myopathy or muscle metabolic myopathy. His social history was negative. There was no history of toxic or poison exposure and no history of autoimmune myopathies. He denied use of tobacco, alcohol, and drugs. He was on no medications. He was not overly active physically and had no recent physical trauma. He reported recent travel and no risk factors for hepatitis B virus (HBV), HIV, hepatitis C virus (HCV), or SARS-CoV-2 infection. On physical examination, he was afebrile and mentally intact. There was no edema, rash, or lymphadenopathy. His abdomen was soft and non-distended and had minimal guarding. The joints appeared normal and had full mobility, limited only by the pain of the examination. There was diffuse tenderness to palpation over the lower extremities, and he refused to bear weight. His pulses were negative for ischemia, and there was no evidence of compartment syndrome. No edema was obvious, and his extremities were warm to the touch. The spinal examination revealed muscle tenderness and pain on movement in the lumbosacral region. Reflexes were normal. The laboratory investigation revealed leucocytes of 8000 cells/μL (reference range, 4500–11 000 cells/μL), with lymphocytes of 61.4% (reference range, 24–54%), absolute neutrophil count of 1000 neutrophils per μL, (reference, men, 2500 to 7000/μL), erythrocyte sedimentation rate, 37 mm/h (reference, men, 0–12 mm/h); C-reactive protein, 3.2 mg/dL (reference, <1.0 mg/dL; hemoglobin, 12.9 g/L (reference, men, 13.5–17.5 g/dL), red blood cells (RBC), 4.5 million RBC/μL; (reference, 4.35–5.65 million μL, and platelet count of 358 000/μL, (reference, 150 000–450 000 platelets/μL of blood). Urinalysis revealed protein, 2+; blood, 1+; glucose negative; nitrite negative; leukocyte esterase negative; pH 5; and ketone, 1+. Microscopic examination of the sediment revealed 3 to 4 white blood cells per high-power field but no RBCs. Serum biochemical analysis revealed blood urea nitrogen (BUN), 28 mg/dL (reference, 7–20 mg/dL); creatinine, 0.8 mg/dL (reference, 0.6–1.1 mg/dL); alkaline phosphatase, 161 IU/L (reference, 44–147 IU/L); alanine aminotransferase (ALT), 30 U/L (reference, 7–55 U/L); and aspartate aminotransferase (AST), 125 U/L (reference, 8–48 U/L).

The diagnosis of rhabdomyolysis was made by measuring the serum enzymes: CK, 6859 U/L (reference, 10–70 U/L); CK-MB, 3 U/L (reference <10 U/L); and lactate dehydrogenase (LDH) 5734U/L (reference, 100–350 U/L). Additional laboratory test results indicated that the initial blood and urine culture was negative. Since the only antecedent risk factor detectable in his case was probably the concurrent “cold” it was logical that a viral illness was the trigger. Because parainfluenza 2 is an upper respiratory virus but is an extremely rare cause of rhabdomyolysis, an entire panel of known viral illnesses was obtained. Ultimately, he was seronegative for Epstein-Barr virus, herpes virus, cytomegalovirus, HIV, respiratory syncytial virus, enterovirus, adenovirus, influenza A and B, Legionella, and Mycoplasma pneumoniae. Parainfluenza type 2 virus was identified by a nasopharyngeal respiratory polymerase chain reaction panel. Initially, the patient received symptomatic treatment, which involved acetaminophen, methocarbamol, and intravenous fluids. Once the serum CK returned >5× normal in the clinical setting, the diagnosis of rhabdomyolysis was felt to be accurate, and further investigation for underlying abnormalities was not pursued. To prevent renal damage, aggressive intravenous therapy was started initially with a rate of 1.5 L/h to maintain a urinary output of 200 mL/h. A pulse oximeter was used to measure oxygen saturation, and vital signs were monitored closely. In addition, over the course of the first 2 days, a significant increase in oral fluid intake was implemented to promote continued diuresis. Fortunately, there was no necessity for urine alkalization or the administration of diuretics, as his kidney function was nearly normal. Urine myoglobin was not obtained, because the clinical response was reassuring for an accurate diagnosis and favorable response. In addition, neither muscle imaging nor biopsy was implemented, because his symptoms improved, and there was no renal involvement. His improvement was rapid and the diagnosis was firm; consequently, interferon-1 (IFN-1) levels were not performed. He and his mother were counseled about the importance of IFN-1 on viral immunity, and the rare genetic mutations reported that result in a defective interferon response. Since he improved clinically and was discharged home after 5 days, no other autoimmune-acquired or inherited myositis conditions were considered that may have contributed to the patient’s presentation. Over time, his CK values demonstrated a gradual decline, ultimately returning to their reference range (Figure 1). Within 5 days, the patient’s symptoms showed marked improvement, and his urine appeared macroscopically clear. Furthermore, dipstick testing revealed no evidence of protein or blood in the urine. Physical therapy was not indicated, and he was told to follow up with his primary care provider for recurrent lengthy colds associated with myalgias.

Discussion

Rhabdomyolysis is a serious medical condition marked by the breakdown of skeletal muscle tissue. Intracellular elements of skeletal muscles, including myoglobin and the key enzymes CK, aldolase, LDH, ALT, and AST are released into the systemic circulation. Recognizing this condition promptly is vital to avoid irreversible kidney damage and compartment syndrome. The factors contributing to rhabdomyolysis are varied and include physical trauma that damages muscles, an intense or prolonged exercise that exceeds the body’s capacity to recover, certain drug reactions, particularly to substances that exert toxic effects on muscle tissue, metabolic disorders, electrolyte imbalances, connective tissue diseases, toxic substances, and infections [1]. The extent of muscle damage can be estimated by the level of serum CK. Borgetta studied 505 adult patients and found that higher CK levels at the time of admission were linked to renal failure, need for dialysis, necessity of mechanical ventilation, and increased length of hospital stay [15]. Awareness and timely intervention can make a significant difference in outcomes, even in patients with asymptomatic elevated serum CK [16]. The diagnosis requires a complete history and physical examination, since the presentation is often variable. Muscle soreness, malaise, fever, and mental status changes can be the initial presenting findings [17]. Laboratory values, including elevated serum CK level and CK-MM subtype, serum, and urine myoglobin, are characteristically present. Occasionally, magnetic resonance imaging to demonstrate high signal intensity, suggestive of acute myositis, or a skeletal muscle biopsy is used [18]. Genetically susceptible patients are at increased risk, likely through mutant genes related to the type IFN-1 pathway. The incidence of these mutations is unknown as the 6 genes encoding IFN-1 are not routinely genotyped in rhabdomyolysis cases. The readily available capacity to analyze selected single-nucleotide polymorphisms in the 6 possible genes possibly should be offered, considering the potential consequences [19]. The exact mechanisms behind viral-induced rhabdomyolysis remain poorly understood. This patient had no known predisposing risk factors other than parainfluenza. Various theories have been proposed, including direct viral invasion, toxicity, and immunological factors, such as the deposition of immune complexes or cross-reactivity [20]. Viral particles are absent in muscle biopsy, suggesting the inflammatory cascade is initiated by an indirect mechanism, most likely an inflammatory-mediated process [21]. Cellular toxicity resulting in cell death could reflect the deposition of immune-mediated complexes [9]. There is evidence that in individuals with certain genetic predispositions, parainfluenza virus infection can lead to increased production of IFN-1 through the induction of interferon regulatory factor-3. IFN-1 has been identified as a potential trigger for rhabdomyolysis [21]. Regardless of the specific cause of the rhabdomyolysis, however, all causes follow a similar pathway to muscle cell destruction. Cellular adenosine triphosphate depletion occurs as a result of metabolic demands of overwhelming infection or trauma. Adenosine triphosphate-dependent cell wall pump malfunction leads to increased cell wall permeability [22]. Ultimately, the normally low intracellular calcium rises, along with an influx of water, sodium, and chloride. This results in the activation of intracellular proteolytic enzyme activity and osmotic swelling that starts the myocyte degeneration process. As the skeletal muscle cells die, myoglobin, CK, AST, and other intracellular components leak into the systemic circulation [23]. If the concentration of myoglobin exceeds the protein binding capacity, the myoglobin can precipitate during glomerular filtration, resulting in renal damage [24]. The first case of rhabdomyolysis linked to parainfluenza was documented in 1976 by McKinlay and Mitchell, involving an 8-year-old child who experienced a benign and self-limiting illness [9]. Since that time, isolated case reports demonstrate that other members of the viral family Paramyxoviridae can result in rhabdomyolysis, besides parainfluenza 2. One patient with parainfluenza 3 died after developing necrotizing rhabdomyopathy, and 1 patient with parainfluenza 1 with spastic quadriplegia developed rhabdomyolysis complicated by acute renal failure [21]. A total of 11 cases of rhabdomyolysis have been reported in patients with an antecedent parainfluenza infection, based on a PubMed database in the English language. All cases presented with rhabdomyolysis within 1 to 5 days after the onset of fever or upper respiratory tract symptoms. Myalgias involved predominantly the calves and thighs in all children but one, for which no specific description of muscle involvement was available [26]. This finding is consistent with our patient, who had 5 days of myalgia that ultimately resulted in a nonambulatory state. The median CK level was 7563 U/L (reference range, 1566–50 000, mean 15 508 U/L), compared with a median of 4100 U/L (reference 230–1 000 000) in 36 children with influenza [20]. Our patient’s serum CK measured 6859 U/L. The explanation for why the patient’s CK level was almost twice the median of child-related cases, with an earlier recovery period compared with the median, is not readily apparent. Possibly, it reflects the fact that he had no significant kidney damage before treatment was implemented and, therefore, no disruption in his glomerular filtration rate. It may also reflect a slightly larger size of an adolescent male patient with more skeletal muscle mass to release CK.

This case has limitations with regard to the parainfluenza virus as the causative agent in rhabdomyolysis. The comparative difference that each separate viral pathogen generates toward skeletal muscle damage is not published. This is probably because viral-associated rhabdomyolysis is rare, especially in parainfluenza, and the muscle damage most likely reflects a pathway influenced by the time to diagnosis and treatment rather than to the inciting viral event. Thus, even knowledge of the identity of the specific viral etiology may not be a critical element in the ultimate outcome. The only data available to compare the effects of different viruses are represented in case reports and anecdotes. However, it appears that Influenza A is particularly pathogenic. Fadila reported in 2015 that there had been 12 reported cases in the English-language literature, and 67% had acute kidney injury [12]. The median time to clinical recovery was 12 days, with a range of 4 to 52 days and an average of 18.8 days. Our patient’s CK level returned to normal by day 12, and he was entirely asymptomatic by day 14. He had no complications. Among the 7 children evaluated, 3 developed acute renal failure, and 2 of these patients required renal replacement therapy [26].

Conclusions

This case describes a healthy, active young male patient who dismissed 5 days of generalized malaise and 2 days of progressively debilitating skeletal muscle malfunction before his mother brought him to a healthcare center. The case reviews the multiple causes of rhabdomyolysis and the rare association with parainfluenza. The importance of this case is that the time from symptom onset to diagnosis typically reflects the level of muscle damage, which is measured by an easily obtained serum CK level. Missing or delaying the diagnosis can be calamitous to normal kidney function and thus, life threatening. Supportive care and intense hydration in rhabdomyolysis is typically successful if the kidneys are undamaged. Consequently, based on this case, health providers should be concerned and open to evaluating patients who call with a typical “extended flu or cold” or symptoms of “prolonged flu-like symptoms with muscle soreness” and concurrent or delayed myalgia. Future protocols of patients with viral-induced rhabdomyolysis could include routine analysis of selected single-nucleotide polymorphisms in the 6 possible genes encoding INF-1 searching for mutations.