The novel coronavirus disease 2019, caused by severe acute respiratory syndrome coronavirus 2, has created a global pandemic, with many cases affecting the elderly. However, children have been affected as well, with ∼2.4% to 3.7% of cases reported. This case is the first published case of an adolescent presenting with rhabdomyolysis as the first sign of novel coronavirus disease 2019, with extremely elevated creatinine kinase levels, approaching almost 400 000 U/L. This case adds to the growing body of literature of a variety of life-threatening manifestations associated with severe acute respiratory syndrome coronavirus 2 infection and highlights the importance of how prompt recognition of these unique presentations of the disease is important to mitigate complications.
The novel coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has created a global pandemic unlike any seen in modern history. Originating from Wuhan, China in December 2019, there have now been 21 294 845 confirmed cases, 761 779 deaths, and 216 countries, areas, and territories reporting cases according to the World Health Organization as of August 16th, 2020.1 Many reported cases have affected the elderly; however, children have been affected as well, with ∼2.4% of cases occurring in patients <18 years of age worldwide, with a higher incidence in the United States of up to 3.7% in ages 10 to 19.2,3 Some children remain asymptomatic during infection with the virus; nevertheless, the most-common symptoms reported are fever, cough, chills, dyspnea, myalgias, sore throat, anosmia, ageusia, nausea, vomiting, and diarrhea.4–6 There have been no published cases of rhabdomyolysis as the primary sign of COVID-19 in children and adolescents. In this article, we discuss a case of COVID-19 presenting as rhabdomyolysis in an adolescent boy.
Clinical Presentation
A 16-year-old boy with a history of asthma presented to the emergency department (ED) with 1 day of dark, black-colored urine and bilateral pain in his shoulders and thighs. He denied any inciting factors such as strenuous exercise, recent injuries, new medications, illicit drug use, or known metabolic syndromes. He denied sick contacts and had been at home in quarantine per community stay-at-home orders. On presentation to the ED, his temperature was 37.7°C, he was hypertensive with a blood pressure measurement of 136/97 mm Hg, tachycardic with a pulse of 136 beats per minute and normoxic with an oxygen saturation of 98% via pulse oximetry. His weight was 86 kg and his BMI was 29.4 kg/m2 (97th percentile). On physical examination, he had bilateral tenderness to palpation in his anterior shoulders and thighs. His physical examination was otherwise unremarkable. A chest radiograph revealed no evidence of pneumonia or other acute cardiopulmonary process.
Laboratory tests in the ED included a urinalysis, which revealed an amber and cloudy appearance, pH of 6.0, proteinuria measured at 100 mg/dL, and a large amount of blood, measuring >4+ on urine dipstick but <1 intact red blood cell on urine microscopy. A creatinine kinase (CK) level was elevated at 116 640 U/L. A complete metabolic panel revealed an elevated lactate dehydrogenase (LDH) of 7389 U/L and elevated hepatic enzymes, with an aspartate aminotransferase (AST) of 662 U/L and an alanine aminotransferase (ALT) of 131 U/L. The patient’s serum urea nitrogen and creatinine were within normal range at 12 and 0.8 mg/dL, respectively, on presentation. A nasopharyngeal SARS-CoV-2 real-time reverse transcription polymerase chain reaction test was sent from the ED, which detected the presence of the virus on day 2 of admission. A respiratory viral panel testing for additional viruses was not completed due to hospital protocol to preserve nasopharyngeal viral swabs. The patient was admitted to the PICU, because of COVID-19–positive status per hospital protocol, for management of rhabdomyolysis.
Hospital Course
In the PICU, the patient had low-grade fevers on hospital days (HDs) 1 and 2, with a peak temperature of 39.4°C, and remained afebrile for the remainder of his hospitalization, without antipyretic therapy. Intravenous fluids were initiated on HD 1 by using 0.9% normal saline at 2 times the maintenance rate. Over the course of his hospital stay, intravenous fluids included a combination 0.9% normal saline and 0.45% normal saline with sodium bicarbonate. Fluids were titrated to achieve alkalinization of the urine, with a goal urine pH of 8.0. The patient’s CK levels continued to uptrend, with a maximum of 392 488 U/L on HD 3, and then began to downtrend with a nadir of 13 912 U/L before discharge. Additionally, his AST, ALT, and LDH began to uptrend until HD 2 to 3, and then steadily decreased until discharge (see Table 1). Because of concern over worsening rhabdomyolysis, leading to the potential for life-threatening electrolyte abnormalities and renal injury, consideration was also given to the administration of remdesivir, which the hospital possessed exclusively for experimental use. After consultation with the infectious disease service, it was determined that the patient could only receive the medication in a compassionate use capacity. He did not qualify on the basis of his age and clinical status. Administration of glucocorticoids was also entertained, to suppress the inflammatory process. However, at that time, the general consensus among medical professionals was that this therapeutic modality was not recommended for infection with this virus. He exhibited myoglobinuria and proteinuria each day until HD 6, with daily improvement in urine color. The pain in his upper and lower extremities also improved, resolving completely on HD 7. His kidney function and electrolyte levels remained stable in normal range over the course of the hospitalization (see Table 1). The patient denied symptoms of shortness of breath, cough, sore throat, and chills throughout his hospital course. The patient was discharged on HD 9, with follow-up 8 days after discharge, at which point he remained asymptomatic. No additional laboratories were completed at this time.
CK, AST, ALT, LDH, Potassium, Phosphate, and Calcium by HD
| HD . | CK (U/L) . | AST (U/L) . | ALT (U/L) . | LDH (U/L) . | Potassium, mEq/L . | Phosphate, mg/dL . | Calcium, mg/dL . |
|---|---|---|---|---|---|---|---|
| 0 | 116 640 | 662 | 131 | 7389 | 4.0 | 4.8 | 9.1 |
| 1 | 196 341 | 991 | 185 | 10 728 | 4.0 | 4.2 | 8.7 |
| 2 | 268 326 | 1291 | 261 | 10 774 | 4.4 | 4.3 | 8.4 |
| 3 | 392 488 | 2055 | 385 | 13 942 | 4.7 | 4.2 | 8.5 |
| 4 | 160 975 | 1639 | 426 | 6059 | 4.4 | 3.9 | 8.4 |
| 5 | — | 1053 | 381 | 2214 | 4.2 | 3.9 | 8.4 |
| 6 | 28 965 | 556 | 342 | 583 | 4.1 | 3.9 | 8.6 |
| 7 | 13 912 | 230 | 263 | — | 4.2 | 4.4 | 9.2 |
| HD . | CK (U/L) . | AST (U/L) . | ALT (U/L) . | LDH (U/L) . | Potassium, mEq/L . | Phosphate, mg/dL . | Calcium, mg/dL . |
|---|---|---|---|---|---|---|---|
| 0 | 116 640 | 662 | 131 | 7389 | 4.0 | 4.8 | 9.1 |
| 1 | 196 341 | 991 | 185 | 10 728 | 4.0 | 4.2 | 8.7 |
| 2 | 268 326 | 1291 | 261 | 10 774 | 4.4 | 4.3 | 8.4 |
| 3 | 392 488 | 2055 | 385 | 13 942 | 4.7 | 4.2 | 8.5 |
| 4 | 160 975 | 1639 | 426 | 6059 | 4.4 | 3.9 | 8.4 |
| 5 | — | 1053 | 381 | 2214 | 4.2 | 3.9 | 8.4 |
| 6 | 28 965 | 556 | 342 | 583 | 4.1 | 3.9 | 8.6 |
| 7 | 13 912 | 230 | 263 | — | 4.2 | 4.4 | 9.2 |
—, laboratory value not obtained on this day.
Discussion
Rhabdomyolysis is “the dissolution of striated muscle,” resulting in the release of muscle cell contents, including electrolytes (potassium and phosphates), enzymes (CK, LDH, and AST), and proteins (myoglobin), as demonstrated in the laboratory abnormalities of our patient.7,8 The underlying pathophysiology resulting in the lysis of myocytes involves increased intracellular calcium levels that increase calcium-dependent enzyme activity that subsequently destroys cell membrane proteins.8 Rhabdomyolysis is commonly the result of congenital disorders or infections in children, with viral infections accounting for the majority of the pathogens.7,9,10
Influenza A and B, enteroviruses, and HIV have been most implicated in precipitating rhabdomyolysis. Less commonly, it can be triggered by herpesviruses, Chinkungunya, and norovirus.8–12 Infection with another coronavirus, severe acute respiratory syndrome coronavirus, has also been associated with rhabdomyolysis, during the 2002 to 2004 outbreak, but few cases were reported in the literature.13 Jin and Tong14 presented a case of rhabdomyolysis as a late onset of COVID-19 infection in a 60-year-old man in Wuhan, China; Suwanwongse and Shabarek15 presented a case of an 88-year-old man with rhabdomyolysis as an initial presentation of COVID-19; and Valente-Acosta et al16 also presented a case of a 71-year-old man with rhabdomyolysis as an initial presentation of COVID-19. In each case, the primary signs and symptoms were cough and fever. Rhabdomyolysis was an incidental finding and the peak CK of <14 000, hardly life-threatening. In addition, a recent publication from the Critical Coronavirus and Kids Epidemiology Study collected data on 17 children <19 years old with critical COVID-19 requiring PICU management; findings also reveal that rhabdomyolysis is rare.17 The exact pathogenesis that causes muscle destruction from a viral etiology remains unclear because the presence of a virus in muscle is difficult to demonstrate. However, current working theories include direct invasion into muscle tissue by a viral agent and myotoxic cytokines released in response to a virus.17 With our case, we report the first pediatric patient with COVID-19, or other coronaviruses, whose presenting symptom was severe rhabdomyolysis with an extremely elevated CK, which peaked at almost 400 000. This case adds to the growing body of literature of a variety of life-threatening manifestations associated with SARS-CoV-2 infection. One limitation of this report is that there was no way to definitively rule out other viruses as a cause of this patient’s disease; however, other viruses are less likely given the time of presentation in May, which is after the typical respiratory season. Pediatric patients with COVID-19 have increasingly started having unique presentations of this disease, including immune thrombocytopenia, respiratory failure, severe thrombocytopenia, multisystem inflammatory syndrome, and myocarditis, especially with those patients presenting with predominantly gastrointestinal symptoms.17–20 Prompt recognition of these associations are important for proper testing, triage, and isolation precautions. Furthermore, continuous monitoring and publications of novel presentations will be important for clinicians as this disease continues to manifest itself in various ways.
Conclusions
Rhabdomyolysis can be a presenting finding of COVID-19 in pediatric patients, and high clinical suspicion must be held for any patient demonstrating signs or symptoms of rhabdomyolysis.
Acknowledgments
Thank you to the patient and his family for their willingness to share this case. Thank you to all the members of the health care team who contributed to the care of this patient. Thank you to Dr Letitia Hillsman (pediatric resident), Dr Norman Jacobs (Pediatric Infectious Disease), Dr Kenneth Soyemi (Pediatric Emergency Medicine), and Dr Paul Severin (Pediatric Critical Care) for their review and feedback on this article.
Drs Gilpin, Byers, Byrd, Cull, Peterson, Thomas, and Jacobson gave substantial contribution to conception and design, drafted the article, and reviewed and revised the manuscript; and all authors approved the final version of the manuscript as submitted and agree to be accountable for all aspects of the work.
FUNDING: No external funding.
References
Competing Interests
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
Comments
RE: Rhabdomyolysis as the Initial Presentation of SARS-CoV-2 in an Adolescent
We read with interest this report,1 but thought it prudent to comment on further potential causes of this patient’s rhabdomyolysis. In addition to viral, environmental, and drug toxicity causes, it is necessary to also look for genetic factors that predispose to rhabdomyolysis, that may not be phenotypically noticeable. They include metabolic muscle disorders,2 mitochondrial disorders,3 ryanodine receptor gene (RYR1) related myopathies,4 and subclinical muscular dystrophies.5
Metabolic muscle disorders encompass disorders of both fatty acid and glycogen metabolism. These myopathies typically present after skeletal muscle exertion. Glycogenolysis and glycolysis disorders occur almost immediately after maximal exercise or muscle contraction, most commonly during strenuous activity, whereas fatty acid metabolism disorders manifest over a more prolonged period of time after activity. While the described patient was inquired about any exercise surrounding this event, fever, fasting, and stress can also induce an episode of rhabdomyolysis. Enzymatic and genetic testing can aid in diagnosis, along with a detailed family history, as most of these disorders are passed in an autosomal recessive fashion.
Mitochondrial disorders are the most common neurometabolic disease of childhood and are characterized by impaired energy production due to genetically altered oxidative phosphorylation. Organ systems that are most in need of energy are affected, including skeletal and cardiac muscle. Therefore, history taking focuses on muscular and cardiac issues. These myopathies can present as muscle pain or rhabdomyolysis and diagnosis consists of a muscle biopsy along with genetic testing.
Published reports describe cases of virally induced rhabdomyolysis occurring with RYR1 pathogenic variants. These receptors regulate calcium release into the sarcoplasmic reticulum, leading to muscle contraction. An RYR1 pathogenic variant can be associated with malignant hyperthermia susceptibility, however, there exists a broad range of additional myopathies that can occur. Histologically, these subtypes include central core disease, multiminicore disease, core-rod myopathy, and congenital fiber-type disproportion. Clinical presentations of this disease vary between malignant hyperthermia susceptibility, exertional heart stroke, rhabdomyolysis-myalgia, King Denborough syndrome and atypical periodic paralysis. If suspected, genetic sequencing of the entire RYR1-gene is completed to assess for presence of mutations. A pathologic RYR1 variant can lead to life threatening rhabdomyolysis.
1. Gilpin S, et al. Rhabdomyolysis as the Initial Presentation of SARS-CoV-2 in an Adolescent. Pediatrics. 2021 Mar;147(3):e2020019273.
2. Scalco RS, et al. Rhabdomyolysis: a genetic perspective. Orphanet J Rare Dis. 2015 May 2;10:51.
3. Haas RH, et al. Mitochondrial disease: a practical approach for primary care physicians. Pediatrics. 2007 Dec;120(6):1326-33.
4. Lawal TA, Todd JJ, Meilleur KG. Ryanodine Receptor 1-Related Myopathies: Diagnostic and Therapeutic Approaches. Neurotherapeutics. 2018 Oct;15(4):885-899.
5. Shieh PB. Muscular dystrophies and other genetic myopathies. Neurol Clin. 2013 Nov;31(4):1009-29.
RE: Rhabdomyolysis as the Initial Presentation of SARS-CoV-2 in an Adolescent
Metabolic muscle disorders encompass disorders of both fatty acid and glycogen metabolism. These myopathies typically present after skeletal muscle exertion. Glycogenolysis and glycolysis disorders occur almost immediately after maximal exercise or muscle contraction, most commonly during strenuous activity, whereas fatty acid metabolism disorders manifest over a more prolonged period of time after activity. While the described patient was inquired about any exercise surrounding this event, fever, fasting, and stress can also induce an episode of rhabdomyolysis. Enzymatic and genetic testing can aid in diagnosis, along with a detailed family history, as most of these disorders are passed in an autosomal recessive fashion.
Mitochondrial disorders are the most common neurometabolic disease of childhood and are characterized by impaired energy production due to genetically altered oxidative phosphorylation. Organ systems that are most in need of energy are affected, including skeletal and cardiac muscle. Therefore, history taking focuses on muscular and cardiac issues. These myopathies can present as muscle pain or rhabdomyolysis and diagnosis consists of a muscle biopsy along with genetic testing.
Published reports describe cases of virally induced rhabdomyolysis occurring with RYR1 pathogenic variants. These receptors regulate calcium release into the sarcoplasmic reticulum, leading to muscle contraction. An RYR1 pathogenic variant can be associated with malignant hyperthermia susceptibility, however, there exists a broad range of additional myopathies that can occur. Histologically, these subtypes include central core disease, multiminicore disease, core-rod myopathy, and congenital fiber-type disproportion. Clinical presentations of this disease vary between malignant hyperthermia susceptibility, exertional heart stroke, rhabdomyolysis-myalgia, King Denborough syndrome and atypical periodic paralysis. If suspected, genetic sequencing of the entire RYR1-gene is completed to assess for presence of mutations. A pathologic RYR1 variant can lead to life threatening rhabdomyolysis.
1. Gilpin S, et al. Rhabdomyolysis as the Initial Presentation of SARS-CoV-2 in an Adolescent. Pediatrics. 2021 Mar;147(3):e2020019273.
2. Scalco RS, et al. Rhabdomyolysis: a genetic perspective. Orphanet J Rare Dis. 2015 May 2;10:51.
3. Haas RH, et al. Mitochondrial disease: a practical approach for primary care physicians. Pediatrics. 2007 Dec;120(6):1326-33.
4. Lawal TA, Todd JJ, Meilleur KG. Ryanodine Receptor 1-Related Myopathies: Diagnostic and Therapeutic Approaches. Neurotherapeutics. 2018 Oct;15(4):885-899.
5. Shieh PB. Muscular dystrophies and other genetic myopathies. Neurol Clin. 2013 Nov;31(4):1009-29.
RE: Exclude all differentials of rhabdomyolysis before attributing it to SARS-CoV-2.
With interest we read the article by Gilpin et al. about a 16 years old SARS-CoV-2 positive male with massive rhabdomyolysis as the initial manifestation of the viral infection COVID-19 [1]. It was concluded that rhabdomyolysis can be the presenting manifestation of COVID-19 in pediatric patients and that high clinical suspicion must be held for any patient demonstrating signs or symptoms of rhabdomyolysis [1]. We have the following comments and concerns.
The main shortcoming of the study is that the individual history is insufficient. We should know the medication the patient was regularly taking, we should know if creatine-kinase was elevated previously, we should know the family history, and we should know since when the patient had elevated body temperature and tachycardia. His previous history was positive for asthma, why it is conceivable that he was either using sprays or drugs with myotoxic components, such as steroids or beta-2 mimetics. From both drugs it is well known that they can be myotoxic and may even induce the development of myopathy [2]. If elevated body temperature and tachycardia occurred already prior to myoglobinurea and myalgia, it is conceivable that COVID-19 manifested with only mild manifestations prior to the onset of rhabdomyolysis. However, we do not want to neglect that the three cardinal manifestations of rhabdomyolysis are dark urine, myalgia, and fever [3]. All previous results of blood samples should be reviewed for elevated creatine-kinase or even renal insufficiency. We should know if the patient reported hypogeusia or hyposmia, frequent initial clinical manifestations of a SARS-CoV-2 infection, prior to onset of rhabdomyolysis one day before hospitalisation. It is also crucial to know the family history, particularly for neuromuscular disease. It should be mentioned if any of the first-degree relatives of the index case had myopathy
Since rhabdomyolysis may be the initial manifestation of hypothyroidism [4] and since the patient was obese, we should know if this was due to predisposition, diet, a Cushing syndrome from long-term application of steroids, or due to hypothyroidism. Hypothyroidism could simply explain rhabdomyolysis triggered by the viral infection.
A further shortcoming of the study is that no work-up for differentials of rhabdomyolysis was initiated after recovery. Patients with rhabdomyolysis should undergo investigations for hereditary and acquired muscle disease to discover the cause of rhabdomyolysis [5].
Overall, we do not agree that rhabdomyolysis was directly due to the virus infection in the sense of a viral myositis but rather suspect that a muscle previously damaged by chronic myotoxic drugs or subclinical hereditary muscle disease reacted with acute muscle necrosis to the viral infection. If rhabdomyolysis was truly the initial manifestation of the viral infection remains speculative but is rather unlikely.
References
1 Gilpin S, Byers M, Byrd A, Cull J, Peterson D, Thomas B, Jacobson P. Rhabdomyolysis as the Initial Presentation of SARS-CoV-2 in an Adolescent. Pediatrics 2020 Oct 9:e2020019273. doi: 10.1542/peds.2020-019273.
2 Vogel F, Braun LT, Rubinstein G, Zopp S, Künzel H, Strasding F, Albani A, Riester A, Schmidmaier R, Bidlingmaier M, Quinkler M, Deutschbein T, Beuschlein F, Reincke M. Persisting Muscle Dysfunction in Cushing's Syndrome Despite Biochemical Remission. J Clin Endocrinol Metab 2020 Dec 1;105(12):dgaa625. doi: 10.1210/clinem/dgaa625.
3 Yao Z, Yuan P, Hong S, Li M, Jiang L. Clinical Features of Acute Rhabdomyolysis in 55 Pediatric Patients. Front Pediatr 2020 Sep 4;8:539. doi: 10.3389/fped.2020.00539.
4 Salehi N, Agoston E, Munir I, Thompson GJ. Rhabdomyolysis in a Patient with Severe Hypothyroidism. Am J Case Rep 2017 Aug 22;18:912-918. doi: 10.12659/ajcr.904691.
5 Heytens K, De Ridder W, De Bleecker J, Heytens L, Baets J. Exertional rhabdomyolysis: Relevance of clinical and laboratory findings, and clues for investigation. Anaesth Intensive Care 2019;47:128-133. doi: 10.1177/0310057X19835830.