Malaria is a vector borne parasitic disease that affects millions of people every year and can cause significant morbidity and mortality if not recognized and treated. There were 216 million cases of malaria and 445,000 deaths worldwide according to the latest World Health Organization’s World Malaria Report (1). Exertional rhabdomyolysis is a well-known complication of intense physical training. The following case describes a college football player who developed postworkout rhabdomyolysis in the setting of an undiagnosed malaria infection.
An 18-year-old male African American NCAA Division I football athlete presented to the emergency department with a chief complaint of 3 d of back and groin pain, muscle aches, dark urine, and headache. This was followed by subjective fever and chills on the day before admission. His symptoms started the day after a vigorous exercise routine in preparation for the start of football camp. The patient reported this routine to be like previous workouts he had completed, consisting of low-intensity weight training of the biceps, abdomen, quadriceps, and hamstrings. The workout finished with multiple sets of abdominal crunches with a 45-pound (20 kg) plate held across the chest. At the top of the crunch, there was a twist from side to side before returning to the supine position. He did not consider it extreme. The day after the workout, he developed significant muscle pain in his anterior abdominal wall and hip flexors. Three days after the workout, as his muscle pains were improving, he began to feel feverish. He had been taking ibuprofen without relief. Review of systems was otherwise negative. He recently spent a week in Nigeria, having returned 2 wk before presentation. He reported being noncompliant with his malaria prophylaxis. He had no known allergies, no medical or surgical history, no alcohol, tobacco, or illicit drug use. Family history was noncontributory. On initial evaluation, his vital signs were significant for a temperature of 103.1° F, pulse of 95, blood pressure of 140/42, respiratory rate of 25, and an oxygen saturation of 98%. He was alert, oriented, in no acute distress, with normal affect and mood. The rest of his examination was unremarkable. There was no musculoskeletal examination recorded on admission. Laboratory evaluation included a complete blood count (CBC), a comprehensive metabolic panel (CMP), creatine kinase (CK), blood cultures, activated partial thromboplastin time (APTT), prothrombin time with INR (PT), urinalysis with microscopy (UA), lactate, and influenza screen. The CBC was notable for a finding of undefined parasitemia and mild thrombocytopenia. It included a white blood count (WBC) of 4.8 K·µL−1, hemoglobin of 14.9 g·dL−1, hematocrit of 45.6%, and a platelet count of 103 K·µL−1. As a result of the finding of parasitemia on the CBC, a formal peripheral smear and parasite stain was ordered. Later that day, it was reported that the patient was positive for Plasmodium falciparum, 0.1%. The CMP was notable for findings of an elevated creatinine at 1.76 mg·dL−1, a significantly elevated aspartate aminotransferase (AST) at 1063 U·L−1, and a mildly elevated alanine aminotransferase (ALT) at 196 U·L−1. The remainder of the CMP included the following; a glucose of 104 mg·dL−1, sodium of 136 meq·L−1, potassium of 4.2 meq·L−1, chloride of 100 meq·L−1, CO2 of 26 meq·L−1, blood urea nitrogen of 11 mg·dL−1, alkaline phosphatase of 76 U·L−1, and a total bilirubin of 0.6 mg·dL−1. UA showed a specific gravity of 1.023, pH of 6.0, and the following positive findings: 2+ protein, 1+ glucose, 3+ blood, along with no RBC, 0–5 WBC, no bacteria, and no renal cells on microscopy. The CK was well above five times the normal limit (upper limit of normal defined by the testing laboratory is 308 U·L−1) at 43,102 U·L−1. Influenza swab, APTT, and PT were normal. Blood cultures were negative after 5 d. A chest X-ray and renal ultrasound were normal. In the emergency department, the patient was given an empiric dose of vancomycin and piperacillin/tazobactam out of concern over sepsis, fluid resuscitated, and admitted to the hospital. After the diagnosis of malaria, he was started on atovaquone-proguanil. Over the next 3 d, his serum creatinine, CK, and AST all began to recover, and his symptoms resolved. On discharge, he had a serum creatinine of 1.01 mg·dL−1, CK of 9,675 U·L−1, and an AST of 435 U·L−1. On follow-up, 4 d after discharge, he had a serum creatinine of 1.07 mg·dL−1, CK of 1,193 U·L−1, AST of 200 U·L−1, and a normal urinalysis. After 3 wk of rest, he started football camp. The sports medicine team (physician, athletic trainer, and strength and conditioning coach) developed and implemented a gradual acclimatization and return to play program. The protocol started with conditioning for the first week, individual drills and conditioning in the second week, and progressed to full practices in the third week. The patient had no recurrence of symptoms over the course of the season, and was successful in earning a starting position.
This is the first report of exertional rhabdomyolysis associated with a concomitant subclinical infection with falciparum malaria. Nonexertional rhabdomyolysis has been reported in the literature as a complication of falciparum malaria and is associated with lower levels of myoglobin and CK than are seen with exercise induced rhabdomyolysis. The proposed mechanism in these cases is microcirculatory obstruction and vascular sequestration of parasitized red blood cells in skeletal muscle. This mechanism was initially proposed in a 1989 study that reported evidence of rhabdomyolysis in 58 Gambian children with malaria. In this study, clinical severity and percent parasitemia correlated with increased myoglobin and CK levels and none of the patients developed acute kidney injury or renal failure. The peak CK level reported was 3,903 U·L−1 in a patient with 9.3% parasitemia (2). A 1999 biochemical study of 36 patients with falciparum malaria revealed that in those patients with cerebral malaria, there was a significant increase in the percentage of parasitized intravascular erythrocytes in muscle tissue. Despite this finding, all 36 patients had relatively low levels of serum myoglobin and serum CK levels, and muscle biopsies did not reveal any evidence of muscle necrosis (3). A 2010 case series of 12 patients diagnosed with malaria-induced rhabdomyolysis, only 7 of the 12 patients had CK levels meeting the commonly accepted diagnostic threshold of 1,000 U·L−1, and none had a level greater than 6,100 U·L−1 (4).
Rhabdomyolysis can lead to acute renal and multi-organ failure. There are three reported cases of acute renal failure in falciparum malaria associated with nonexertional rhabdomyolysis. One of these cases only had a peak CK of 9,170 U·L−1, in combination with acute tubular necrosis and required hemodialysis (5). Given the low peak CK level and the presence of acute tubular necrosis, it is unclear whether rhabdomyolysis was the sole etiology of this patient’s renal failure. The other two cases had CK of 71,940 and 73,000 U·L−1. One of the patients was treated with peritoneal dialysis and the other with IV fluids (6,7). Though our patient had a significantly elevated CK level, he only met the criteria for stage I acute kidney injury, not acute renal failure (8). His kidney function rapidly returned to normal with intravenous fluids and dialysis was not required. In this case, liver injury also was a concern, due to elevations in his AST and ALT. Though liver injury is certainly a consideration in rhabdomyolysis, a retrospective chart review of 215 patients admitted for acute exertional rhabdomyolysis revealed that AST and ALT elevations did not represent acute liver injury and normalized in concert with the CK. The conclusion was that muscle damage can be responsible for elevated AST and ALT levels in exertional rhabdomyolysis (9).
It is our opinion that the patient developed exertional rhabdomyolysis and acute kidney injury in the setting of a subclinical infection with plasmodium falciparum. We suspect that the mechanism of his injury was from microvascular obstruction by parasitized red blood cells in skeletal muscle under exertional demand causing myonecrosis, muscle damage, and rhabdomyolysis. This mechanism is consistent with the proposed cause of nonexertional rhabdomyolysis in falciparum malaria, which is microcirculatory obstruction and vascular sequestration of parasitized red blood cells in skeletal muscle (2). The argument can be made that the patient’s rhabdomyolysis and acute kidney injury was nonexertional and a direct result of his malaria infection; however, the complete clinical picture of postworkout abdominal wall and hip flexor pain in combination with a CK of 43,102 U·L−1 leads us to conclude that rhabdomyolysis was exertional and responsible for the kidney injury. The rise and fall of his CPK, AST, and ALT, and the urinalysis testing positive for hemoglobin (without any RBC on microscopy) are all consistent with muscle damage. The lack of RBC, WBC, and renal cells on microscopic analysis of the urine makes acute tubular necrosis, the common mechanism of renal failure in falciparum malaria less likely (10). Renal failure in the setting of infection with falciparum malaria has a reported prevalence of 1% and is characterized by an onset 4 d to 7 d following the development of fever, hyperkalemia, elevations in alkaline phosphatase out of proportion to elevations of the transaminases, and cholestatic jaundice. The patient’s history and laboratory results were not consistent with those characteristics, and his mild acute kidney injury is most consistent with exertional rhabdomyolysis. Renal failure-associated rhabdomyolysis from all causes (inherited diseases, overdoses, muscle compression, and overexertion) has been reported in 15% to 33% of patients (11) but is much less common in exertional rhabdomyolysis (12). Our conclusion that exertional rhabdomyolysis developed as a result of a subclinical infection is supported by the following facts: first, he had previously performed this workout without complications; second, that his initial symptoms were muscle pain and dark urine; and third, that he was afebrile until postworkout day 3. Infection with falciparum malaria is a severe disease with significant complications. It is highly likely he would have developed clinical disease without performing the workout; however, we do not believe he would have developed clinically significant rhabdomyolysis and acute kidney injury in that scenario.
We present a case of exertional rhabdomyolysis and stage I acute kidney injury, responsive to fluid resuscitation and antimalarial medications, in a previously asymptomatic patient with undiagnosed plasmodium falciparum parasitemia. After a period of acclimatization and athletic conditioning, he successfully returned to NCAA competition. The diagnosis of malaria should be included on the differential diagnosis of athletes who reside in, compete in, or travel to malaria-endemic areas and present with signs and symptoms of exertional rhabdomyolysis.
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