Legionella pneumonia complicated by rhabdomyolysis

Abstract

Legionnaires’ disease is a recognised but rare cause of rhabdomyolysis. It can be further complicated with renal impairment. In this case report, we describe a previously healthy, semiactive 50-year-old man who within days was reduced to having periods of dyspnea after minutes of walking in addition to near fatal acute renal failure. He was found to have the rare triad of Legionella pneumonia, renal failure and rhabdomyolysis, which is associated with high morbidity and mortality. He was treated according to guidelines with azithromycin monotherapy and aggressive fluid hydration. 20 days after admission, the patient was walking independently and discharged home.

Background

Undiscovered until the mid 1970s, Legionnaires’ disease is a severe form of pneumonia, that is, caused by the Legionella genus of bacteria, most commonly by the species Legionella pneumophila. Spread through inhalation or aspiration of droplets, the pathogen is found mostly in bodies of freshwater such as lakes and rivers, although it can proliferate in human-made water systems that include cooling towers, hot and cold water systems and whirlpool spas.¹ Symptoms associated with the illness include productive, or sometimes dry, cough, dyspnea, nausea, vomiting, diarrhoea, as well as fever, general muscle aches, fatigue and confusion.²

Legionnaires’ disease is a recognised but rare cause of rhabdomyolysis.³ It can be further complicated with renal impairment. In this case report, we describe a fascinating encounter of an immunocompetent patient with Legionella pneumonia, renal failure and rhabdomyolysis. Although this triad occurs rarely, it is associated with high morbidity and mortality causing death in 38% of cases.⁴

Case presentation

A 50-year-old man with no medical history presented with a 3-day history of shortness of breath. There was associated tactile fevers, sweating and mild cough with no sputum production or rhinorrhea. He also reported watery diarrhoea for 5 days and subsequently feeling weak. He denied chest pains, abdominal pain or urinary symptoms. Taking an over-the-counter cold and influenza treatment product did not alleviate his symptoms. He lived in an apartment where opossums have been seen in the backyard, although he has not been in contact with them. He worked for a company that maintained boilers and stated that several people at his job reported being ill recently. He denied recent travels outside of the city and remained within an urban setting. He smoked two cigarettes per day since he was 20-years-old.

Investigations

On admission, the patient appeared to be shivering with diaphoresis and fatigue. He was febrile (38.8°C) with tachycardia (resting heart rate of 140bpm) and tachypnea (respiratory rate of 38 rpm). He was hypoxic on room air and required 6 L of oxygen via nasal cannula (peripheral capillary oxygen saturation (SpO₂) of 93%). His eyes were icteric. Cardiac auscultation was uneventful without any pathological murmurs. Auscultation of the lungs revealed decreased breath sounds and scattered wheezes with fine crepitations bilaterally. No jugular venous distention and no lower limb swelling were appreciated.

Laboratory tests revealed white cell count of 30.8×10⁹/L with neutrophil predominance, haemoglobin concentration of 14.9 g/dL with a mean cell volume of 98.7fL, sodium of 130 mmol/L, potassium of 4.9 mmol/L, calcium of 8.2 mmol/L, glucose of 288 mg/dL, blood urea nitrogen (BUN) of 34 mg/dL, creatinine of 2.6 mg/dL, alanine aminotransferase (ALT) of 202 U/L and aspartate aminotransferase (AST) of 922 U/L. Creatine kinase was >160 000 U/L, while lactate dehydrogenase was 4300IU/L. Urine analysis showed microscopic hematuria (15–20 red blood cells per high-power field). Arterial blood gas showed a pH of 7.46, pCO₂ of 26.6, pO₂ of 69.3 and HCO₃ ^– of 18.5. Erythrocyte sedimentation rate and ferritin were elevated at 39 mm/hour and 1080 ng/mL. Chest X-ray showed left lower lobe pulmonary infiltrates. Electrocardiogram (EKG) showed sinus tachycardia.

Differential diagnosis

In our repertoire of differentials, we considered common causes of community-acquired pneumonia, as well as atypical causes brought about by exposure. High on our list was Streptococcus pneumoniae as it is the main pathogen that causes community-acquired pneumonia worldwide independent of age. It is responsible for 27.3% of cases followed by Haemophilus influenzae at 12%.⁵ Viruses, particularly influenza virus and human rhinovirus, were the most common pathogens found in community-acquired pneumonia requiring hospitalisation among US adults.⁶ In an immunocompetent patient with no history HIV/AIDS, haematological malignancy or solid-organ transplant, the likelihood of infection by Pneumocystis jirovecii was very low. The presence of opossums living near the patient’s home lead to the possibility of infection by Francisella tularensis. Pneumonic tularemia can be seen with typhoidal disease, often presenting with high fevers, myalgia, vomiting and diarrhoea.⁷ However, the likelihood of infection by this pathogen was low since no contact was confirmed. Finally, infection by L. pneumophila was strongest among our differentials due to the patient’s history of smoking, age and exposure to boilers. Manifestations would include fever, cough, chills, dyspnea, myalgia, diarrhoea, nausea and vomiting.²

Treatment

Despite treatment with broad-spectrum antibiotics (vancomycin and cefepime) and intravenous fluids, the patient’s condition deteriorated on day 2 of hospital admission. The patient was transferred to the intensive care unit (ICU) for invasive monitoring and management of hypoxemic respiratory failure secondary to multilobar pneumonia and transaminitis. ALT increased to 432 U/L and AST elevated to 1173 U/L. CT of the chest revealed left lower lobe infiltrate and consolidation with patchy infiltrates in the left upper lobe. Transthoracic echocardiogram revealed mildly dilated right atrium, dilated right ventricle, paradoxical motion of the ventricular septum and an ejection fraction of 40%–50%.

Viral studies were negative for influenza A and B, respiratory syncytial virus and adenovirus by PCR. Induced sputum was negative for P. jirovecii under microscopy, with negative Gram stain, acid fast stains and bacterial cultures. Serological testing for F. tularensis antibody proved negative (<1:20). However, the urinary antigen test detected Legionella bacterium. Antibiotic therapy was switched to intravenous azithromycin.

Outcome and follow-up

After multiple days of improvement with the absence of respiratory distress, the patient began to experience difficulty breathing with leg swelling and trouble urinating on day 6 of hospital admission. He continued to have leucocytosis (white blood cells (WBC) of 27.8×10⁹/L) but now developed thrombocytosis (757×10⁹/L) and hypoalbuminemia (2.3 g/dL). He had hyperkalemia (5.0 mmol/L) and hypocalcemia (6.1 mmol/L). BUN rose to 102 mg/dL and creatine increased to 9.7 mg/dL, with sufficient urine production at a rate of 100 mL/hour. Urine analysis continued to reveal large presence of blood (15–20 red blood cells per high-power field). Repeat chest X-ray showed mild congestive changes. He was now being managed for nonoliguric acute kidney injury secondary to acute tubular necrosis associated with rhabdomyolysis.

After 20 days postadmission, the patient made a complete recovery. He never required invasive ventilation, inotropes or haemodialysis at any point during the course of his stay in the ICU. Repeat transthoracic echocardiogram revealed the return to normal size of the right atrium and right ventricle, and an improvement of the left ventricle systolic function with an ejection fraction of 62.59%. Oedema of his lower extremities resolved. He was in good spirit and walking on his own when he was discharged from the hospital.

Discussion

Rhabdomyolysis is characterised by the dissolution of skeletal muscle. Common causes include trauma, excessive exercise, medications, metabolic myopathies, electrolyte disturbances, connective tissue diseases, toxins and infections. As muscle cells break down, electrolytes, creatine kinase, myoglobins, aldolase, lactase dehydrogenase, and ALT and AST are released into the bloodstream.⁸ Hypocalcemia is a common complication of rhabdomyolysis and usually results from calcium entering the ischaemic and damaged muscle cells and from the precipitation of calcium phosphate with calcification in necrotic muscle.⁹ Other electrolyte abnormalities include hyperkalemia, which is an early manifestation of rhabdomyolysis, hyperphosphatemia, hyperuricemia, high anion-gap metabolic acidosis and hypermagnesemia mainly when renal failure is present.⁸ It was unusual for our patient to have hypocalcemia and normal phosphorus in the context of rhabdomyolysis.

Acute kidney injury associated with myoglobinuria is a serious complication of non-traumatic rhabdomyolysis. After being admitted into the ICU, our patient suffered from acute renal failure due to rhabdomyolysis. While over the last 10 years, there have been few reports of rhabdomyolysis occurring as a result of having Legionnaires’ disease,^10–16 the mechanism of action is still unclear. There are theories that include the direct invasion of the bacteria into the muscle,¹⁷ much like the influenza virus. It has been shown that the mechanism of rhabdomyolysis during influenza infection appears to be due to direct viral invasion of myocytes.¹⁸ Another theory is the release of the bacteria’s endotoxin into the bloodstream leading to muscle damage,¹⁷ similar to Clostridium perfringens. Studies have shown that C. perfringens enterotoxin affects neuromuscular transmission and the autonomic nervous system, causing arterial constriction, thereby contributing to rhabdomyolysis.¹⁹ Additionally, while the resulting acute renal failure was expected due to the increased work the kidneys had to do to filter out the muscle break down, it is more common for the acute renal failure to occur due to shock and hypotension.¹⁷

The management of rhabdomyolysis, that is, associated with acute kidney injury is early, aggressive repletion of fluids, as there is normally sequestration of water in injured muscles.⁸ There was discussion during the early phase of rhabdomyolysis whether to alkalinise the urine by administering sodium bicarbonate as the patient’s urine pH was 6. Alkalinisation reduces the precipitation of Tamm-Horsfall protein–myoglobin complex, inhibits reduction–oxidation cycling of myoglobin and lipid peroxidation thereby improving tubule injury, and prevents vasoconstriction caused by metmyoglobin. The disadvantage is that it can exacerbate hypocalcemia.⁸ Fortunately, alkalinisation was never performed as his renal output improved on the resolution of Legionnaires’ disease.

Urinary detection of the L. pneumophila antigen is still widely used as first-line test due to its speed in diagnosis.² However, it has limitations, including poor sensitivity of non-L. pneumophila serogroup 1 strains²⁰ and false-positive results of patients with Pontiac fever.²¹ Real-time PCR of respiratory specimens is now regarded as the molecular method of choice for detection of Legionella spp. A systematic literature review conducted by Avni et al ²² found that PCR identified 18%–30% more Legionella infections than did the urine antigen.

The recommended treatment for Legionnaires’ disease is empiric therapy with azithromycin or quinolones as monotherapy, or in combination with a beta-lactam while cultures or Legionella-specific tests are pending. Other less effective antibiotics include tetracyclines, trimethoprim/sulfamethoxazole, clindamycin and imipenem.²³ Our take away message therefore highlights the importance of collecting the patient’s history, especially when the clinical presentation is complicated and the patient is not responding to empiric antimicrobial therapy.

Despite the patient’s vocational risks of contracting Legionnaires’ disease, as well as the claim that multiple coworkers reported being similarly ill, no follow-up epidemiological study or environmental investigations to find the source of infection was triggered. Outbreak of Legionnaires’ disease has been associated with adverse disturbance in water distribution system condition,²⁴ contaminated cooling towers²⁵ and poor monitoring in healthcare water network,²⁶ affecting many lives. The control and eventual eradication of Legionnaires’ disease depends on the ability to measure risk in different environmental settings.¹ It is therefore important that surveillance systems are strengthened and physicians include Legionnaires’ disease in the differential diagnosis of patients with pneumonia in endemic areas.

Our patient was a previously healthy, semiactive 50-year-old man who within days was reduced to having periods of dyspnea after minutes of walking in addition to near fatal acute renal failure. The complications that arose during the course of care for our patient were perplexing and intriguing. It is our hope that publishing the events can help other clinicians become more aware of the events that have the potential to take place due to a Legionella infection.

Learning points.

• It is very important to collect a detailed patient’s history in order to include Legionnaires’ disease as part of the list of differentials, especially in those who do not respond to empiric antimicrobial therapy.

• The triad of Legionella pneumonia, renal failure and rhabdomyolysis is rare, but is associated with high morbidity and mortality.

• The recommended treatment for Legionnaires’ disease is empiric therapy with azithromycin or quinolones as monotherapy, or in combination with a beta-lactam is recommended while cultures or Legionella-specific tests are pending.

• The management of rhabdomyolysis, that is, associated with acute kidney injury is early, aggressive repletion of fluids.

• Beware of managing acidic urine as urine alkalinisation will exacerbate hypocalemia, which is a common complication found with rhabdomyolysis.