Pathways Case Record: Legionella-induced Rhabdomyolysis With Acute Renal Failure

A 47-year-old male presented to the hospital with garbled, unintelligible speech and confusion after experiencing fatigue and myalgias throughout the week preceding his hospitalization. He would later report regular use of alcohol, tobacco, marijuana and herbal supplements. Notable family history includes nemaline myopathy type 2 (sister), which is likely autosomal recessive. He was diagnosed with acute renal failure, rhabdomyolysis (a breakdown of muscle tissue that causes the release of harmful proteins into the blood), stress cardiomyopathy and a lobar infiltrate from severe Legionnaires' disease.

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The Pathways Consult Service in the Department of Medicine at Massachusetts General Hospital was consulted and focused on two key questions:

1. What host factors made our patient susceptible to Legionella?
2. How does Legionella infection lead to rhabdomyolysis?

Diagnostic Approach

Legionnaires' disease is a severe form of pneumonia caused by the bacterial pathogen Legionella. Clinical presentation of Legionnaire's disease typically includes fever, cough and labored breathing. Less common symptoms include neurological abnormalities (including confusion), muscle aches, chest pain, headaches and nausea (Annu Rev Pathol). Furthermore, Legionnaires' disease can present with extra-pulmonary manifestations including rhabdomyolysis-induced renal failure and gastrointestinal disease. Risk factors contributing to Legionnaires' disease include smoking, chronic lung disease, age, malignancy and immune suppression. Relevant to our patient, tobacco and marijuana use increases the number of alveolar macrophages, the primary host for Legionella in humans, impairs pathogen clearance from lungs and suppresses secondary immunity to Legionella (Am Rev Respir Dis, Infect Immun).

An association between Legionella and rhabdomyolysis has been well documented. Rhabdomyolysis is characterized by amplified levels of creatinine phosphokinase (CPK) in serum and myoglobin in the urine, resulting in renal dysfunction. Legionella is the most cited bacterial etiology of rhabdomyolysis and together, carries a high mortality rate (Respir Med Case Rep). Besides Legionella infection, our patient presented with no other known causes of muscle cell breakdown.

Current literature provides three primary hypotheses of Legionella-induced skeletal muscle injury: (1) direct tissue invasion, (2) toxin-mediated and (3) inflammation-mediated. Direct tissue invasion has been reported in one case report but has not been reported since (Neurology). Additionally, alveolar macrophages are not known to be able to enter skeletal muscle, and legionella requires these cells for survival in the body. The indirect effect on sites outside the lungs may be caused by circulating Legionella-derived endotoxin leading to vasoconstriction or occlusion of vasculature in other organs, such as kidneys (J Med Case Rep). While possible, this explanation seems unlikely as muscle-targeting endotoxin has not been observed in this well-studied organism. Invasion by an external organism elicits local immune responses that send signals (e.g., cytokines and chemokines) that can recruit immune cells to the site of infection (Cell Microbiol). In the absence of direct invasion or Legionella endotoxin, the immune response to infection may trigger a reaction in skeletal muscle and subsequent dysfunction.

In addition to Legionella-mediated pathways, underlying genetic susceptibilities may contribute to skeletal muscle injury. Importantly, the patient has a sister with nemaline myopathy and a brother and mother who experience intermittent paralysis and muscle weakness. Nemaline myopathy is characterized by rod-like structures named nemaline bodies in muscles resulting in muscle weakness. Our patient's sister has nemaline myopathy type 2 and is thought to be autosomal recessive, suggesting he could be a carrier for nemaline myopathy. Silent carriers of these and other metabolic disorders or myopathies such as RyR-1 defects, glycogen storage diseases and carnitine deficiencies, may explain why other young, previously healthy people experience Legionella-mediated rhabdomyolysis. Thus, the Pathways service hypothesized that the genetic risk posed by being a carrier for nemaline myopathy coupled with the Legionella-induced hit on the immune system led to diffuse muscle injury and cell death.

Summary and Future Steps

Legionnaires' disease complications contributing to rhabdomyolysis and acute kidney failure are well recognized, but the underlying mechanisms remain understudied. Legionella may contribute to skeletal muscle injury through direct interaction, toxins, inflammatory factors or some combination of these. Understanding the critical components of skeletal muscle damage can be readily addressed using cell culture techniques with Legionella and primary skeletal myocytes. In addition, further investigation is needed to understand genetic contributions to the development of rhabdomyolysis. Genetic examination of patients with rhabdomyolysis induced by Legionnaires' disease is important to characterize risk and provide new therapeutic strategies to treat and prevent this complication in the future.

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