Primary Human Immunodeficiency Virus Infection and Rhabdomyolysis

Rhabdomyolysis is a syndrome characterized by skeletal muscle breakdown, myoglobinuria, and creatine phosphokinase (CPK) elevation and can frequently lead to renal dysfunction. Numerous precipitating factors have been linked to rhabdomyolysis including trauma, seizures, drugs, toxins, metabolic derangements, severe exercise, and infections [1,2]. Human immunodeficiency virus (HIV) infection has been associated with rhabdomyolysis [1,3,4]. Whether HIV itself or a different agent such as another infection or a drug is the direct cause of rhabdomyolysis is not clearly understood. We present 3 cases of Primary HIV infection (PHI) and rhabdomyolysis from our institution. In addition, we include a review of the English-language literature of reported cases of PHI and rhabdomyolysis and discuss the importance of recognizing rhabdomyolysis as a presenting illness in patients with PHI.

chlamydial urethritis. Over the preceding month he had unprotected sexual intercourse with two different male partners. He denied recent foreign travel, tobacco and recreational drug use but he drank 4-5 glasses of wine per week. His only medication was occasional Tylenol. On physical exam, he was febrile to 38.2 o C and the rest of his exam was otherwise unremarkable. Laboratory data revealed a creatinine and a CPK of 1.4 mg/dl and 1176 IU/L respectively. CPK was not checked until 5 days after admission, during which period the patient had received intravenous hydration. Hepatitis A, B, C and EBV serologies were negative and an RPR was non-reactive. An HIV antibody ELISA test was negative but an HIV-1 RNA viral load and a CD4 T cell count were >750,000 copies/ml and 189 respectively. Patient was lost to follow up after discharge from the hospital.

Discussion and Literature Review
A number of infections have been associated with rhabdomyolysis, but viruses, especially influenza A and B, are by far the most common causes [2,3]. Other viruses include HIV, enteroviruses, EBV, CMV, adenovirus, herpes simplex virus, Varicella-zoster virus, and parainfluenza virus [3]. Among bacterial agents causing rhabdomyolysis, Legionella sp. is reported as the most common cause [2,3] . Other bacteria that may cause rhabdomyolysis include but are not limited to Francisella sp, Streptococcus pneumoniae, Salmonella sp, and Staphylococcus aureus [2,3] .
HIV-infected patients may develop a variety of muscular disorders such as polymyositis, inclusion-body myositis, myopathy secondary to HIV therapy, HIV wasting syndrome, and rhabdomyolysis [5]. Rhabdomyolysis can occur at any stage of HIV infection [1] and is usually multifactorial [4]. Substance abuse, alcohol, infection, and drugs are among the most common precipitating factors in HIV-infected patients [4]. Raltegravir, an integrase inhibitor approved for treatment of HIV infection and used in combination with other antiretroviral drugs has been associated with rhabdomyolysis [6][7][8]. The exact pathogenic role of HIV itself in causing rhabdomyolysis has not been elucidated. Chariot et al speculated that skeletal muscle involvement in HIV patients could be due to immune-mediated mechanisms activated by HIV itself which lead to infiltration of the muscle by inflammatory cells leading to muscle injury and breakdown [1]. Another possible explanation is the direct invasion of the muscle by HIV itself but HIV particles have not been found in muscle fibers in most of the studies done [9]. One study using in situ hybridization and PCR methods on muscle biopsies of HIV-infected patients who had polymyositis found HIV RNA in the lymphoid cells surrounding the muscle fibers but not in the muscle itself [10].
Patients with PHI can be asymptomatic or can present with a fever, sore throat, fatigue, and weight loss [11]. Myalgias are common [11,12] but rhabdomyolysis is not a typical presentation. Other presenting signs and symptoms may include pharyngitis, lymphadenopathy, oral or genital ulcers, and aseptic meningitis [11]. Laboratory abnormalities can include lymphopenia, thrombocytopenia, and elevated hepatic transaminases [13].
We searched medline through PubMed using the words rhabdomyolysis, primary HIV infection and acute HIV infection to look for cases of rhabdomyolysis and PHI in the English-language literature. Several case reports presented cases of patients with PHI and rhabdomyolysis [9,12,[14][15][16][17][18][19][20][21][22]. A summary of these case reports in addition to our three cases is found in (Table 1) Most of the patients complained of myalgias and had a history of elevated temperatures or a fever on presentation. Nearly half of the patients reported sore throat on presentation but only a few had lymphadenopathy on physical exam. Some patients had mainly gastrointestinal symptoms such as nausea, vomiting, and diarrhea. All patients had elevated CPK on presentation and most of them had elevated AST and ALT levels when performed. Most patients had an elevated serum creatinine and few patients developed severe acute renal failure [12] including our second case. However, most patients recovered their kidney function with intravenous hydration. Most patients in these case reports had serological testing for viral infections that could contribute to their presentation with rhabdomyolysis but some were not tested for CMV. One of the case reports described a patient with simultaneous primary HIV and CMV coinfection presenting with rhabdomyolysis [16]. In addition, a number of these reports did not mention if a drug screen was done and an alcohol history was not clear or an alcohol blood level was not obtained. It is noteworthy that few patients presented with rhabdomyolysis in the setting of multi-organ involvement such as liver failure [20] or myocarditis [15,20,21] in the setting of PHI. All patients including the ones from the present study survived the acute presentation of rhabdomyolysis and none was started on antiretroviral therapy immediately.
Whether HIV itself is the direct cause of rhabdomyolysis in these patients is not clear. A major limitation of the cases reported in this article or in the reports found during literature review is that not all patients had viral serologies and drug screens done to exclude a viral or a drug related rhabdomyolysis.However, we believe that it is important to include acute HIV seroconversion in the differential diagnosis when patients present with rhabdomyolysis. This is especially important since many of these patients presented with rhabdomyolysis without other symptoms that are suggestive of PHI. [Reference] Age/sex Symptoms CPK peak, U/L AST Remarks Outcome  In summary, HIV infection has been associated with rhabdomyolysis. Other precipitating factors include other infections, substance abuse, or medications. Clinicians need to be aware of the possibility of acute HIV seroconversion in the setting of rhabdomyolysis especially if patients have no other risk factors for rhabdomyolysis. The exact role of HIV itself in the pathogenesis of rhabdomyolysis is still unclear. Treatment of rhabdomyolysis in the setting of PHI remains supportive.