Rhabdomyolysis is a life-threatening disorder that manifests with myalgia, fatigue, and pigmenturia, with a mortality rate as high as 59%. Acute renal failure which occurs in 13-50% of cases. Myalgia and fatigue are common constitutional symptoms in patients with viral infection such as COVID-19. These symptoms are relatively common in viral illnesses making suspicion of rhabdomyolysis unlikely in most cases. This paper discussed a 74-year-old man with COVID-19 who presented with myalgia, dark colored urine and acute kidney injury associated with elevated creatine kinase. Patient was managed with careful hydration and renal replacement therapy which subsequently improved patient’s symptoms and decrease in creatine kinase. High index of suspicion is key to diagnose rhabdomyolysis in patients with focal muscle pain and fatigue to prevent complications such as acute kidney injury, arrhythmia, disseminated intravascular coagulation, and death. We recommend inclusion of muscle injury markers such as total creatine kinase and creatine kinase MM in patients presenting with prominent myalgia. Prompt initiation of hemodialysis in patients who are oliguric and presenting with rhadbdomyolysis showed good response in some cases presented. Referral to Nephrology should never be delayed when suspecting rhabdomyolysis in a patient.
Key words: Rhabdomyolysis, COVID-19, myalgia
Word Count: 223
Rhabdomyolysis is a life-threatening disorder that manifests with myalgia, fatigue, and pigmenturia. Complications include acute renal failure which occurs in 13-50% of cases and has a mortality rate as high as 59%. 
The pathogenesis of rhabdomyolysis in infection with SARS-CoV-2 is unknown, however, possible mechanisms may include direct muscle invasion by SARS-CoV-2 and exaggerated immunologic response to the virus causing collateral muscle damage.  The instigating factors of rhabdomyolysis include autoimmune myopathies, septicemia, electrolyte abnormalities, substance abuse, alcohol use, or infection such as viral infections, most prominently from influenza. 
The clinical triad of myalgia, muscle weakness and pigmenturia is present in less than 10% of cases.  Myalgia and fatigue are common constitutional symptoms in patients with viral infection such as COVID-19. These symptoms are relatively common in viral illnesses making suspicion of rhabdomyolysis unlikely in most cases. Creatine kinase and myoglobin levels are important indexes for rhabdomyolysis; however, they are not tested routinely.
Reports from other countries have been published describing cases of rhabdomyolysis in patients with COVID-19. In this case report, we aim to describe a critical COVID-19 patient presenting with muscle pain and dark colored urine associated with markedly elevated creatinine kinase on his 22nd day of illness.
A 74-year-old Filipino male presented at the emergency room with one week history of non-productive cough associated with intermittent fever, dyspnea, poor appetite, joint pains and body weakness. He self-medicated with paracetamol and Vitex negundo tablets. Worsening of symptoms led to consult and subsequent admission. He was a diabetic, hypertensive for ten years with good compliance to his maintenance medications: clopidogrel, lisinopril, carvedilol, simvastatin, carvedilol and amlodipine. He also had a previous acute myocardial infarction. He was a non-smoker and a social alcoholic beverage drinker. Upon examination, he was restless with the following vital signs: blood pressure 150/100 mmHg, heart rate 100 bpm, respiratory rate 31 cpm, temperature 36.7?C and oxygen saturation of 39%. He had symmetric chest wall expansion with bibasal crackles. There was no abdominal tenderness and distention, or muscle tenderness noted. Other systemic findings were unremarkable.
Baseline diagnostic tests revel a positive SARS-COV2 RNA test, leukocytosis with segmenter predominance (82%), decreased eGFR (31.17 ml/min/m2), and slightly elevated aspartate aminotransferase and alanine aminotransferase (AST 67.94 U/L, ALT 50.2 U/L). Inflammatory markers such as CRP (x) and LDH (836.83 U/L) were also increased. Arterial blood gas revealed an uncompensated metabolic acidosis with severe hypoxemia. While, urinalysis revealed proteinuria. Chest radiography showed pneumonia on both lungs (Figure 1). Coagulation test, blood culture and hepatitis profile were unremarkable.
Treatment and Outcome
Due to respiratory distress, endotracheal intubation was done. Remdesivir, dexamethasone, enoxaparin, piperacillin-tazobactam and azithromycin were administered. Hemodialysis with hemoperfusion was offered but no consent was given.
Our patient’s respiratory status improved. He was eventually weaned off from mechanical ventilation. Creatinine was stable at a range of 400-500 umol/L. A repeat SARS-COV2 RNA test and SARS-COV 2 IgG were done on the 14th hospital day revealing a positive result with low viral load and positive antibody (86.6 AU/ml), respectively. Hence, he was tagged as a COVID-19 recovered case and was transferred to a non-COVID intensive care unit.
On the 15th hospital day, the patient presented with bilateral lower extremity pain, dark colored to bloody urine with associated decreasing urine output. Diagnostic tests requested showed total creatine kinase more than 800 times elevated from the reference range, transaminitis, hyperkalemia, metabolic acidosis, and increasing creatinine trends. The urgent need for renal replacement therapy was explained and his wife eventually consented to the procedure. Initiation hemodialysis was done.
On the 16th hospital day, our patient presented with persistent abdominal pain, hematomas, hematuria and coffee ground output per nasogastric tube. The patient was seen by Surgery service to rule out possible partial gut obstruction for which immediate surgical intervention was assessed to be not indicated. Coagulation studies, 12 L ECG, urinalysis with RBC morphology, flat plate abdominal supine and upright xray and blood chemistry tests were requested. Enoxaparin, Clopidogrel and Amlodipine were discontinued. Repeat diagnostic tests at this time showed elevating trends of coagulation tests as shown in Table 1. Patient was managed as a case of rhabdomyolysis with secondary disseminated intravascular coagulation. Resuscitative efforts led to improvement in the muscle pain, resolution of bloody urine and decreasing trends in the creatinine kinase. Patient was later diagnosed to have Hospital-acquired pneumonia with Carbapenem resistant Acinetobacter baumannii for which Polymyxin was given. Patient suffered from septic shock which caused his eventual demise.
SARS-CoV-2 has shown a wide variability of systemic presentations. This report focuses on its muscular involvement. Creatine kinase (CK) is the most widely used marker for muscle damage. The serum CK begins to rise within 2 to 12 hours following the onset of muscle injury and reaches its peak within 24 to 72 hours. [5,6,7]
Rhabdomyolysis has been described anecdotally with just a few cases reported so far. Table 2 below, summarizes the cases of COVID-19 and rhabdomyolysis that were reported. In the cases presented, all were male and most were more than 60 years old. Six out of eight cases had hypertension and were on statins for dyslipidemia. Four of these patients have elevated creatinine at presentation. Presentation of these patients were varied, and the onset of rhabdomyolysis occurred at different times during their illness. In four patients, significant muscle injury was noted at time of admission as evidenced by elevated creatine kinase alongside with symptoms of diffuse myalgia or acute renal failure, while the rest developed rhabdomyolysis during their hospital course, which mostly presented at the 2nd to 3rd week of illness. Most patients suffered significant kidney injury and only one patient presented with normal creatinine up until discharge. Four of the cases were treated with renal replacement therapy in conjunction with supportive management. Three patients died from complications and five were sent home, two of which had continuation hemodialysis after recovery. [2,3,4,8]
Concomitant bacterial infection in COVID-19, generally, has been associated with worse disease severity and poorer outcomes.  However, the relationship between rhabdomyolysis and concomitant bacterial infection has yet to be established.
In the case presented, a 74-year-old man who is a known diabetic and hypertensive presented with dark-colored urine and worsening muscle pain on the 16th hospital day and is in the recovery phase of COVID-19. Patient was managed as a case of rhabdomyolysis with secondary disseminated intravascular coagulation. In some cases, severe rhabdomyolysis may be associated with the presentation of disseminated intravascular coagulation due to the liberation of thromboplastin and other prothrombotic substances from the damaged muscles. [5,6,7] The patient was given careful hydration due to his oliguria and elevated creatinine levels that may progress to volume overload. Hemodialysis was then assessed to be the better option for the management of the patient as this will address symptoms of acute renal failure and will prevent further pulmonary congestion.
The cases presented showed preponderance of rhabdomyolysis in male patients with COVID-19. This may be related to a study that demonstrated the positive correlation of ACE2 expression and the infection of SARS-CoV.  This means that an organism whose expression of ACE 2 protein is high has a facilitated environment for pathogenesis of coronavirus. In one study, it has been stated that male patients may had higher expression of angiotensin-converting enzyme 2 (ACE2), which may be regulated by male sex hormones rendering them to more risk for SARS-CoV-2 infection and poor clinical outcomes. RNA sequencing showed highest expression of ACE 2 receptors in various organ systems including the small intestine, testis, kidneys, heart, thyroid, and adipose tissue, while blood, spleen, bone marrow, brain, blood vessels, and muscle had the lowest ACE2 expression levels. In the lungs, colon, liver, bladder, and adrenal gland, ACE2 showed medium expression levels.  The widespread distribution of these receptors may explain the variability of COVID-19 presentation.
The pathophysiology in viral myositis is not well known, and the mechanism by which SARS-CoV-2 cause rhabdomyolysis has not been studied.  The proposed mechanisms include direct viral invasion of muscle tissue and toxicity mediated by cytokines or immunological cross-reactivity. 
As we discover more about the various presentation of COVID-19 virus, clinicians are challenged to heighten their clinical eye as this virus reveals itself in innumerable ways. A high index of suspicion is key to diagnose rhabdomyolysis in patients with prominent myalgia and fatigue to prevent complications such as acute kidney injury, arrhythmia, DIC and death. The authors are recommending inclusion of muscle injury markers such as total creatine kinase and creatine kinase MM in patients presenting with prominent myalgia, weakness and dark urine. Prompt initiation of hemodialysis in patients who are oliguric and presenting with rhabdomyolysis showed good response in some cases presented. Referral to Nephrology should never be delayed when suspecting rhabdomyolysis in a patient. Follow up investigation is recommended to identify the prevalence of rhabdomyolysis in COVID-19 patients.