Exercise-induced rhabdomyolysis refers to the breakdown of striated muscle, which releases intracellular elements into the bloodstream due to heavy physical activity. In rare instances, this condition may be the first clinical manifestation of sickle cell trait (SCT). We report on a 31-year-old woman with post-infectious fatigue who, after suffering mild COVID-19 symptoms 3 weeks prior, presented with intense muscle pain in the ankles, dyspnea, and choluria hours after strenuous physical exercise during a practical test. She sought emergent care the next day, where serum creatinine was measured at 2.4 mg/dL (baseline 1.0 mg/dL) and creatine phosphokinase at 118,000 U/L. She was previously healthy, without regular use of any medication, and habitually sedentary except in training, with no personal or family history of blood or muscle diseases. She was admitted without hemodialysis and discharged after 2 weeks. At 3 months, she had normalization of creatine phosphokinase and creatinine. As an outpatient, other tests were requested. Hemoglobin (Hb) electrophoresis revealed HbA1 of 57.8%, HbA2 of 3.1%, HbF of 0.3%, and HbS of 38.8%, which were compatible with SCT. Evaluation for SCT should be considered in cases of exercise-induced rhabdomyolysis, especially in young, healthy patients.

© 2022 The Author(s). Published by S. Karger AG, Basel

Rhabdomyolysis refers to the breakdown of striated muscle, which releases intracellular elements into the bloodstream and leads to kidney and acute muscular damage [1]. This syndromic diagnosis is typically associated with high levels of creatine phosphokinase (CPK) and is an important cause of acute kidney injury (AKI) due to a direct toxic effect of myoglobin, leading to renal ischemia caused by a predominance of vasoconstrictor factors and tubular obstruction by myoglobin cylinders [1]. CPK accounts for about 7–10% of all cases of AKI in the USA, with a reported incidence of 13% to approximately 50% [2].

Sickle cell trait (SCT) is part of the spectrum of sickle cell disease and is characterized by the heterozygous presence of hemoglobin (Hb) S and the absence of anemia [3]. In most cases, it is an asymptomatic condition without major clinical implications [3, 4]. However, severe rhabdomyolysis associated with SCT has notably been described following exposure to triggering factors such as trauma or strenuous exercise and should be considered as a differential diagnosis [4-7]. We report on a previously healthy young patient with a recent history of mild SARS-CoV-2 infection, who presented with severe rhabdomyolysis after strenuous physical activity.

We present a case of a 31-year-old woman who was admitted complaining of ankle pain, mild edema, choluria, and dyspnea that started immediately after performing strenuous physical exercise the day before (she performed in up to 20 min a 2.4 km run, 14 push-ups, and 30 sit-ups). Her medical history included only a history of SARS-CoV-2 infection (COVID-19) 20 days prior to the current symptoms. At the time of presentation, she had normal verbal response, body temperature of 36.2°C and peripheral oxygen saturation of 95% on room air, no edema, was anicteric, blood pressure was 130 × 80 mm Hg, heart rate of 94 bpm, and respiratory rate of 22 breaths/min. Laboratory tests showed serum creatinine, 2.4 mg/dL (baseline creatinine 1.0 mg/dL); D-dimer, 7,000 ng/mL; CPK, 118,000 U/L; pH, 7.28, pO2, 115 mm Hg; pCO2, 27.8 mm Hg; HCO3, 13.5 mEq/L; lactate, 1.2 mmol/L; Hb, 15.1 g/dL; mean corpuscular volume, mean corpuscular Hb concentration, and red cell distribution width within normal limits; and leukocytes, 23,180 mm3, with 88% neutrophils and platelets, 215,000 mm3. Urinalysis showed no albumin, but hematuria of 2+/4+ was found, with 5–10 red blood cells per field, using a urinary catheter. Based on initial findings, she was admitted to intensive care unit for better monitoring and immediate initiation of hemodialysis if needed.

Two days after admission, while on intravenous fluids with sodium bicarbonate, the patient had improvement in her symptoms, was afebrile, and had 24-h diuresis of 4 L. In addition, creatinine peaked at 7.2 mg/dL, with normal electrolytes. The evolution of day-to-day laboratory tests can be found in Table 1. On the fourth day of hospitalization, she developed mild edema of the lower limbs, and intravenous furosemide was initiated. On that day, the patient had a creatinine of 8.5 mg/dL, urea of 124 mg/dL, and normal sodium and potassium levels. The patient became stable, with normal urinary output, and on the seventh day of hospitalization, Doppler echocardiogram showed normal cardiac chambers, with preserved systolic and diastolic function.

Evolution of laboratory tests

On the 10th day after admission, repeat liver function tests showed decreases to aspartate transaminase (AST), 69 U/L, and alanine transaminase (ALT), 387 U/L. From the 11th day onward, creatinine began to decrease. After 13 days of hospitalization, the patient was discharged with a serum creatinine, 6.0 mg/dL; AST, 48 U/L; ALT, 181 U/L; Hb, 10.1 g/dL; leukocytes, 8,800/mm3; electrolytes – within normal limits; and diuresis of 2,450 mL/24 h.

The patient returned for follow-up without complaints. Physical examination was unremarkable, and laboratory tests had returned to normal baseline values. At that time, other examinations were performed as the patient had AKI and rhabdomyolysis too severe to be attributed only to physical exercise and a history of COVID-19 infection. Thyroid function was normal, and human immunodeficiency virus serology was negative. Hb electrophoresis was requested, in which a distribution of 38.8% of HbS was found, compatible with the presence of SCT.

We report a case of severe exercise-induced rhabdomyolysis in a patient unaware of having SCT, which was attributed to her severe kidney and muscle damage due to a previous COVID-19 infection potentiating the damage of physical activity. Most people who get COVID-19 recover within a few weeks, but some, even those who had mild disease, might have symptoms that last a long time afterward. Prolonged inflammation has a key role in the pathogenesis of most post-COVID manifestations, with some patients having mild but asymptomatic pulmonary function abnormalities at 3 months after discharge [8].

In the present case, physical exercise as a trigger for severe rhabdomyolysis in a young woman did not further strengthen the clinical investigation of the main causes of rhabdomyolysis (Table 2). The initial laboratory tests established a diagnosis of rhabdomyolysis, liver damage, and KDIGO (Kidney Disease: Improving Global Outcomes) grade 3 AKI. The incidence of AKI in patients with exercise-induced rhabdomyolysis is estimated to be between 10% and 30% and mortality can be as high as 59%, even in an ICU setting [2]. The primary causes of AKI are renal vasoconstriction secondary to myoglobin, hypovolemia, elevated circulating cytokines, and enhanced renin-angiotensin-aldosterone system activation. Myoglobin can also contribute to kidney damage by cast formation.

However, only during outpatient follow-up was the association with SCT hypothesized as a possible etiopathogenic triggering substrate for the exercise-induced muscle damage in this young patient. This correlation is infrequent and commonly goes unnoticed by physicians, which contributes to its rare reporting [7, 9]. In general, most reported cases have occurred in the context of strenuous exercise or in patients who had climbed to high altitudes.

Nonhematological manifestations of hemoglobinopathies are extremely common and within the natural history expected for these conditions. This is also evident to a lesser degree in quantity and intensity in carriers of SCT [9]. Myopathic syndromes associated with SCT generate conditions that can range from virtually asymptomatic to rhabdomyolysis associated with acute liver and kidney damage [5-7, 9]. Mild to moderate cases of acute exertional rhabdomyolysis can cause metabolic disorders, including hypernatremia, hyperkalemia, hyperphosphatemia, hypocalcemia, and lactic acidosis. Severe cases may result in renal failure and even death.

Sickle cell disorder is a term used for all diseases that have an HbS mutation present on at least one beta chain. If the mutation affects only one β-globin chain, it is called an SCT, which usually has a relatively benign course. HbS formation is possible due to a point mutation on the beta chain that substitutes valine for glutamic acid. This substitution allows the HbS to bind with another HbS in the deoxygenated state, which results in distortion of erythrocytes. This modified form causes the sickling and increases the risk of hemolysis. However, that modification occurs only during the deoxygenated state of the Hb, so if it kept well oxygenated, the sickling can be prevented even with a high concentration of HbS [3, 10, 11]. Sickle cell disease remains one of the most prevalent genetic disorders in the world, with approximately 5% of the global population having the gene, and, therefore, it constitutes a serious but unrecognized public health problem [12].

A recent history of COVID-19 infection (20 days prior) and possible residual lung damage may have acted as confounding factors during the efforts to determine the etiopathogenesis of the case. Pulmonary and extrapulmonary complications of COVID-19 have been reported in the literature since the early 2020s [13]. Although the patient had dyspnea at the onset, she did not meet criteria for influenza syndrome or lower airway infection. She presented with classic findings of rhabdomyolysis, which could explain the respiratory distress due to direct skeletal muscle injury, in addition to acute metabolic acidosis. However, if a post-COVID-19 syndrome can result in such significant muscular, hepatic, and renal damage, other possibilities regarding the differential range of rhabdomyolysis need to be investigated, such as paroxysmal nocturnal hemoglobinuria, intermittent porphyria, hepatocellular diseases, or infections with myopathic sequelae [1, 14, 15]. This was not the case in this patient.

There have been case reports describing fatal or serious musculoskeletal complications following strenuous exercise in carriers of SCT, notedly in young people [3-7, 9, 16-18]. It has been suggested that this association is elicited by dehydration, increased blood viscosity, hyperthermia, hyperosmolality, and acidosis resulting from the vigorous physical activity. This intricate set of mechanisms induces polymerization of HbS, leading to vascular occlusion and endothelial damage, which activates a cascade of events including rhabdomyolysis, myoglobinuria, acute renal failure, release of different vasoactive substances, disseminated intravascular coagulation, and coronary vasoconstriction [2, 3, 17, 18]. Although at increased risk, patients with SCT should be encouraged to engage in guided physical exercise, seeking an optimal balance between the risks and benefits [19].

In summary, we recommend broad complementary laboratory investigation for exercise-induced rhabdomyolysis in young patients. Hb electrophoresis is one such test that allows quantitative measurement of erythrocytes and is able to accurately and definitively diagnose the presence of a hematological disorder such as SCT, which is usually neglected in clinical practice.

Written informed consent was obtained from the patient for publication of the details of their medical case. This case report was approved by the Research Ethics Committee – Certificado de Apresentação de Apreciação Ética (CAAE): 57121522.3.0000.8807.

The authors have no conflicts of interest to declare.

The authors have no conflicts of interest to declare.

Luiz Henrique Lélis Miranda and Débora Nóbrega de Lima were responsible for analyzing and writing the manuscript. Marclébio Manuel Coêlho Dourado were responsible for recruitment and analyzing and writing the manuscript.

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.

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