Atypical Presentation of Legionnaire’s Disease A Case Report and Review

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Abstract

A case of a 62-year-old man with Legionella pneumonia complicated with multisystem organ failure is presented, and English-language literature on Legionnaire’s disease is reviewed. Clinical spectrums of this patient include not only respiratory involvement, but also abdominal complaints, encephalopathy, rhabdomyolysis with renal failure, hepatic dysfunction and myocarditis. Our patient experienced severe mutilobar pneumonia and respiratory failure requiring mechanical ventilation in the intensive care unit and underwent hemodialysis for acute renal failure. Even though Legionnaire’s disease is implicated in systemic manifestations with multiple organ involvement, nonspecific signs and symptoms of the disease and difficulties in isolating Legionella pneumophila from specimens make the diagnosis of this disease very difficult. Despite a delay in diagnosing with positive serology, this patient was successfully treated with erythromycin and levofloxacin. Review of published articles showed that delay in starting adequate therapy is shown to be a key factor associated with poor outcome in many cases. Thus, Legionellosis should be considered in the differential diagnosis of patients presenting with neurologic, cardiac and gastrointestinal symptoms in the setting of pneumonia in immunocompromised or critically ill patients, and treatment for Legionnaire’s disease should be initiated as soon as possible.

Introduction

Legionnaire’s disease (LD) was first coined as a pneumonia causing an epidemic among delegates to the 1976 American Legion convention in Philadelphia. Legionella was later identified as a causative agent. To date there are at least 48 species and 70 serogroups of legionella species were found in environment. 1   They exist in freshwater ponds and creeks, cooling towers, central air conditioning systems, hot water systems and water fountains. 2  Legionella are facultative gram negative bacteria that live within amoeba as parasites in nature. Disease transmission is via inhalation of aerosol droplets or aspiration of water containing bacteria, and infection is through respiratory tract mainly. 1  Risk factors for the disease include old age, male sex, smoking, alcoholism, diabetes, chronic lung disease, malignancy, end-stage renal disease, immunosuppression and HIV/AIDS. 3  Later study included previously healthy middle-aged male as predominant group. 2  In the United States, the disease occurs sporadically in hospitals, nursing homes, spas and hotels, etc., all via contaminated water, affecting 8,000 to 18,000 individuals a year. 4 5

Among all the different species, Legionella pneumophila serogroup1 (LP1) is the most pathogenic strain, causing 71% to 90% of legionnaire’s disease, followed by L.micdadei. 2 4  LD accounts for the top three most common cause of community-acquired pneumonia (CAP) and second highest cause of severe pneumonia requiring admission to intensive care unit (ICU). 3 6  There are also reports of extrapulmonary involvement of Legionnaire’s disease including gastrointestinal, renal, cardiac and central nervous systems. Literature review reported a very high mortality rate from LD when multiple organ dysfunctions developed. We report a case of Legionnaire’s disease where various organ systems were afflicted by the bacteria and where the patient had a favorable outcome.

Methods

A computer-based search of MEDLINE (National Library of Medicine, Bethesda, MD) literature published in English language was performed. Key words used in the search were Legionella, Legionellosis, Legionnaire’s disease, age 19 to 80, years 1976-2007, case reports, rhabdomyolysis, renal failure, myocarditis, myocardial infraction, neurologic dysfunctions, Neurology, intensive care treatment, infectious diseases and epidemiology. The citations in all identified articles were also reviewed.

Case Report

A 62-year-old man presented to our emergency department with 5 days history of altered mental status. As per family, the patient had been drinking alcohol heavily, not eating well for several days and confused. At triage, patient was complaining of light headedness and epigastric pain. Patient then vomited coffee ground material. Family denied recent travel, previous hospitalization or sick contact. His past medical history was remarkable for peptic ulcer disease, chronic low back pain and cataract of left eye. Social history was significant for alcoholic abuse and cigarette smoking with 45 pack years. The only home medicines were cimetidine, multivitamin and motrin for low back pain as needed. Patient received 1 ampule of dextrose 50 and thiamine 100mg on the ambulance with slight improvement in mental status. In the emergency department he looked obtunded, pale and confused, but not in acute distress. His initial vitals were as follows: temperature 37.0ºC, pulse rate 130 beats per minute, respiratory rate 26 breaths per minute, blood pressure 119/86 and oxygen saturation of 95% on room air. His physical examination revealed pale conjunctiva without icterus, hepatomegaly, epigastric tenderness, severe clubbing of his finger and toe nails, and positive stool guaiac. Chest x-ray was normal without infiltrate (Fig.1A). Electrocardiogram revealed sinus tachycardia with non-specific ST depression and T wave inversion in inferolateral leads (Fig. 3A). Laboratory data were as follows: white blood cell count 17,400 /µL with 94% neutrophils, sodium 131 mEq/L, potassium 3.2 mEq/L, creatinine 3.6 mg/dl, alanine transaminase 46 IU/l, ammonia 38µmol/L, coagulation profile, amylase, lipase all within normal limit, urine toxicology and blood alcohol level were both negative (Table 1).

Table 1. Admission Laboratory Data.
WBC count (per mm3) 17,400 (H) Sodium (mEq/L) 131 (L)
Hemoglobin (g/dL) 14.4 Potassium (mEq/L) 3.2 (L)
Hematocrit (%) 40.2 Chloride (mEq/L) 96
Platlets (per mm3) 171 Bicarbonate (mEq/L) 21
Neutrophils (%) 94.4 Urea nitrogen (mg/dL) 46 (H)
PT (seconds) 10.9 Creatinine, serum (mg/dL) 3.6 (H)
INR 1.1 Glucose (mg/dL) 200 (H)
PTT (seconds) 30.3 Ammonia (mg/dL) 38
Albumin (g/dL) 3.4 Total Protein (g/dL) 7.6
Total bilirubin (mg/dL) 0.9 (H) Lactic Acid (mg/dL) 1.2
Alkaline phosphatase (IU/L) 36 (H) CSF WBC (per mm3) 0
AST (IU/L) 27 CSF RBC (per mm3) 2
ALT (IU/L) 46 (H) CSF Glucose (mg/dL) 133
Amylase (IU/L) 75 CSF Protein (mg/dL) 37
Lipase (IU/L) 16 Alcohol, serum (mg/dL) None detected
CPK (IU/L) 1991 (H) Urine Toxicology Negative

*Note: (H) indicates high and (L) indicates low.

The patient was admitted to the intensive care unit (ICU) with presumptive diagnosis of upper gastrointestinal bleeding. Over the next 6 hours, patient’s condition worsened. In ICU patient was unable to stand up without assistance, and developed visual hallucination, respiratory insufficiency and diarrhea with fever of 39.5ºC. Neurologic examination was non-focal aside from confusion. Computed tomography (CT) of the head was interpreted as normal. A lumbar puncture revealed white blood cell count 0, red blood cell count 3, normal glucose level of 133 mg/dL and normal protein level of 37 mg/dL. Chest CT and chest x-ray now demonstrated a left lower lobe infiltrate (Fig.1B and 2). Patient developed culture negative sepsis and over the next few days developed multiple organ failure manifested by the following:  1) respiratory failure which required mechanical ventilation and high inspiratory oxygen concentration, 2) ventricular arrhythmias with positive troponin to 2.47 and globally reduced myocardial contractility with ejection fraction (EF) of 29% within 2 days (Fig.3B and C), 3) acute renal failure from rhabdomyolysis with creatine phosphokinase elevation to 176,500 IU/L which later required hemodialysis, 4) mild jaundice with elevated bilirubin to 1.7 mg/dl, alkaline phosphatase to 212 IU/L, aspartate transaminase 1205 IU/L and alanine transaminase 180 IU/L, 5) significant upper gastro-intestinal bleed with coffee ground emesis requiring blood transfusion with drop in hemoglobin/hematocrit ratio to 7.6 and 22.3, respectively. (Table 2).

Table 2.  Laboratory Data During Hospitalization.
WBC count (per mm3) 18.8 (H) Troponin (ng/ml) 2.47 (H)
Hemoglobin (g/dL) 7.6 (L) CK-MB (ng/mL) 38.3 (H)
Hematocrit (%) 22.3 (L) CPK (IU/L) 176,526 (H)
Platelets (per mm3) 87 (L) UA protein (mg/dL) 500 (H)
Total bilirubin (mg/dL) 1.7 (H) UA RBC (per HPF) 186 (H)
Alkaline phosphatase (IU/L) 212 (H) Urea nitrogen (mg/dL) 122 (H)
AST (IU/L) 1205 (H) Creatinine, serum (mg/dL) 13.6 (H)
ALT (IU/L) 180 (H) Phosphorus, inorganic (mg/dL) 9.0 (H)
Magnesium (mEq/L) 2.5 Calcium (mg/dL) 8.0
PT (seconds) 15.2 Ammonia (mg/dL) 60 (H)
INR 1.7 RPR Not reactive
PTT (seconds) 33.4 C. difficile toxin A and B, stool, EIA Negative
PaO2, Blood gas on Room Air 35.3 PaCO2, Blood gas on Room Air 31.6
Legionella antigen, urine, RIA positive Leptospira Antibody <1:50
Legionella antibody titer, IFA (day12) 1:64 Legionella antibody titer, IFA (day30) 1:1024
Hepatitis panel (B, C) Negative Acid Fast Bacillus Culture, sputum Negative
HIV-1 AB, EIA Negative PCP Culture, sputum Negative

*Note: (H) indicates high and (L) indicates low.

Electroencephalography (EEG) showed diffuse slowing of cerebral activity consistent with toxic encephalopathy. Urine legionella antigen to LP1 (detected by using radioimmunoassay, RIA, Quest Diagnostic, Inc.) sent on Day 2, came back positive on Day 6 of hospital admission. 1  Subsequent four fold rise in legionella antibodies (from acute phase titer of 1:64 to convalescent phase titer of 1:1024) was demonstrated with indirect immunofluorescence assay (IFA, Quest Diagnostic, Inc.) (Table 2). 1  All cultures from blood, urine, CSF, and sputum were negative initially. Initial broad spectrum antibiotics, for meningitis, possible GI pathology and pneumonia, including as ceftriaxone, doxycylclin, flagyl, and vancomycin, were started on Day2 of admission. Antibiotics were switched to zyvox, meropenem and azithromycin on Day 3 for worsening sepsis and renal failure. When urine legionella antigen became positive, Levaquin was added to his regimen; Zyvox and meropenem were discontinued. Patient received total of 11 days of azithromycin and 21 days of Levaquin. Patiet’s hospital stay was complicated by ventilation related pneumonia and superinfection with Pseudomonas aeruginosa, Acinetobacter baumanni and Klebsiella pneumonia a month later.

Confusion, pneumonia, renal failure, liver and cardiac functions abnormalities all resolved gradually.  However, the patient had persistent limb ataxia, severe polyneuropathy and left hemiparesis upon discharged from the hospital. CT of the brain without contrast showed non-specific hyperdense foci 1 month later then extensive bilateral infarction in basal ganglia and supraganglionic white matter 6 month later (Fig.4A and B). He required long-term rehabilitation for his persistent but improving left hemiparesis.

While in the nursing home, the patient continued to have intermittent hematemesis and anemia over 9 month period after legionella was successfully treated. Further gastrointestinal workup utilizing CT of the abdomen and pelvis with oral and intravenous contrast, upper endoscopy and colonoscopy found a large colonic mass at hepatic flexure. Biopsy of the mass and other colonic polyps turned out to be high grade tubulovillous adenocarcinoma.

Fig.1A Chest X-ray showing no acute infiltrate infiltrate at admission.
Fig.1A Chest X-ray showing no acute infiltrate infiltrate at admission.
Fig.1B Chest X-ray showing left pleural disease with infiltrate on Day2.
Fig.1B Chest X-ray showing left pleural disease with infiltrate on Day2.
Fig.2 Chest CT showing large left lower lobe pneumonia with bilateral pleural effusion.
Fig.2 Chest CT showing large left lower lobe pneumonia with bilateral pleural effusion.
Fig. 3A Electrocardiogram showing ST depression with T wave inversion in inferolateral leads at admission.
Fig. 3A Electrocardiogram showing ST depression with T wave inversion in inferolateral leads at admission.

Fig. 3B Electrocardiogram showing non-sustained ventricular tachycardia captured on cardiac monitor on Day 2 and 9.

Fig. 3C Electrocardiogram showing QT prolongation with QTc of 492 ms on Day 16.
Fig. 3C Electrocardiogram showing QT prolongation with QTc of 492 ms on Day 16.
Fig. 4A Head CT showing slight hyperdense foci conforming to the gyri in the right posterior parietal lobe one month later.
Fig. 4A Head CT showing slight hyperdense foci conforming to the gyri in the right posterior parietal lobe one month later.
Fig. 4B Head CT showing extensive bilateral infarctions in basal ganglia, supraganglionic white matter and centrum semiovale 6 months later.
Fig. 4B Head CT showing extensive bilateral infarctions in basal ganglia, supraganglionic white matter and centrum semiovale 6 months later.

Discussion

Legionnaire’s disease (LD) has been known to cause pneumonia with multiple organ system involvement. The classic presentations of LD include malaise, myalgia, anorexia, diarrhea, weakness, cough, confusion and headache. 2 6  Distinctive features of LD with statistical significance compared to other type of community-acquired pneumonia (CAP) included headache, diarrhea, arthralgias or myalgias, confusion, fever to 39°C, purulent sputum, hyponatremia, hepatic dysfunction, creatine phosphokinase (CPK) elevation, hypophosphatemia, proteinuria and hematuria. 6  Occasionally patients may present with predominantly gastrointestinal and neurological symptoms like upper gastrointestinal bleed, diarrhea, obtundation and confusion more so than pulmonary symptoms. However, pulmonary manifestation is the most common clinical presentation. 2  Extrapulmonary complications are uncommon but may involve any organ system. 2  LD manifests as pneumonia in 90% cases, 4 neurological involvement occurs in 43% of cases, 7 and rhabdomyolysis with acute renal failure occurs in 15% of patients, 8 and myocarditis is a rare complication in adult. 9  The mechanism of extrapulmonary disease is hypothesized as direct toxic effect from inflammatory factors or direct tissue invasion of the bacteria. 10  Overall mortality rate for LD is reported to be from 5% to 30% with an average of 24%. 4  Mortality from Legionella pneumonia requiring intensive care treatment is reported to be 27% with significant increased in rate with mutisystem dysfunction. 10

In our patient initial differential diagnoses were as varied as upper gastrointestinal bleed, alcohol withdrawal with delirium tremens, pneumococcal meningitis, ST elevation MI, status epilepticus and acute HIV syndrome. It was a mysterious infection until urine legionella antigen came back positive. Urine antigen testing only detects L. pneumophila serogroup 1 (RIA, Quest Diagnostic, Inc.) but it is the most commonly used diagnostic test. 1 5  This antigen can be detected in urine 1 to 3 days after infection, allowing early diagnosis of LD. 1 5  Cultures of L. pneumophila from this patient’s sputum, bronchial aspirate and blood were unsuccessful. L. pneumophila required special media (buffered Charcoal Yeat Extract, BCYE) to grow, which is considered the gold standard for diagnosis of LD. 1 5  Culture also allows for subtyping of the Legionella strain. 5  Unfortunately in the United States, cases of LD diagnosed by culture have declined; as many as two-thirds of clinical microbiology laboratories in the United States are unable to grow a pure culture of L. pneumophila. 1  Serologic diagnosis required four fold rise in titer (>1:256) of paired sera, 3-6 weeks apart. 1  Our patient had sixteen fold rise in titer to 1:1024 after 4 weeks of hospitalization. Quest Diagnostic’s serologic test for L. pneumophila detects serogroups 1 to 6. Elevated titer of ≥1:1024 likely suggests current disease. 1  Diagnosis of this patient with legionnaire’s disease neatly tied up the different organ systems involvement by one causative agent. He suffered a life-threatening legionella infection with mutiple organ system involvement.

The patient required ICU care for severe pneumonia with mechanical ventilation support and high inspiratory oxygen concentration. Initial chest radiograph at admission was read as no infiltrate, but subsequent radiographs were impressive with first unilobar then multilobar infiltrate with effusion (Fig. 1B and 2). Chest radiographic findings are shown to be nonspecific in diagnosis of LD. 6  In a few cases reported in literature with LD, fever and respiratory tract symptoms preceded chest radiograph finding. 2  In rare cases of nosocomial acquired LD and LD acquired post-op after chest tube or drainage tube insertion, there was no overt pneumonia. 2

Hemodialysis was instituted in this patient after anuric renal failure developed from rhabdomyolysis and severe sepsis. Rhabdomyolysis is likely to occur from direct invasion of L. pneumophila causing acute tuulointerstitial nephritis. 11  Severe breakdown of muscle cells and plugging of myoglobin and inflammatory factors in renal tubules is believed to precipitate acute renal failure in LD. Vancomycin was believed to have possibly contributed to renal function deterioration, and it therefore stopped within 2 days of initial administration. Although the patient suffered from severe sepsis, hypotension with an accompanied hypoperfusion state never developed. His blood pressure was always maintained above systolic BP of 90 with an MAP of at least 60 using isotonic fluid boluses.  Pressors were not employed. Many patients with rhabdomyolysis in LD suffer from in renal failure, although in some such patients renal failure may be prevented by generous fluid administration. 10  Our patient, however, developed renal failure despite continuous fluid infusion and use of sodium bicarbonate to help excrete myoglobin. In critically ill patients with severe sepsis, hemodialysis is the first choice of therapy to correct renal dysfunction, and it may also improve patient’s outcome by removal of inflammatory agents. 10

This patient’s cardiac involvement consisted of global hypocontractility without focal abnormality (ejection fraction of 29%), nonspecific ST changes and arrhythmia, consistent with a myocarditis (Fig. 3A and B). After Legionnaire’s disease was treated ST changes were normalized and ejection fraction improved to 45%, but with QT prolongation persisted (Fig. 3C). Legionella myocarditis was diagnosed on the basis of electrocardiogram and echocardiogram changes. Cardiac arrthymia was believed to be the result of myocarditis disturbance of the conduction system and not from an electrolyte abnormality (Table 2). Echocardiogram showed no pericardial effusion, vegetation, or other signs of pericarditis or endocarditis. Various structures of the heart can be involved in LD causing pericarditis, myocarditis and endocarditis. 2  Stout JE, et al 2 proposed that the heart is the second most common organ affected by legionella after pulmonary, but myocarditis by itself is a rare complication in adult. 9

The neurologic manifestations in this patient included confusion, limb ataxia and left hemiparesis with diffuse slow wave on EEG, consistent with toxic encephalopathy. Altered mental status is the most common neurologic symptoms in LD followed by headache. 7  Sometimes neurologic manifestation can precede the development of pulmonary infiltrate. 7  LD seems to cause encephalopathy out of proportion to metabolic derangement and anemia which is the case with our patient. 7  Slight leptomeningeal enhancement on initial head CT is indicative of possible meningoencephalitis even though lumbar puncture result was unremarkable (Fig. 4A). White matter disease and demyelination of brain stem and corpus callosum in LD has been reported as in this case (Fig. 4B). 12

Gastro-intestinal (GI) symptoms such as nausea, vomiting, anorexia, diarrhea and stress ulcer bleeding are commonly reported in LD. 2 10  Only diarrhea is statistically significant compared to other causes of CAP, and it occurs in 20 to 40 percent of cases. 2 3  One study found high incidence of bleeding from gastric or duodenal ulcer as late development of LD. 10  However in this patient GI bleeding with hematemesis was presenting symptom, most likely secondary to underlying peptic ulcer disease and GI malignancy. GI symptoms also preceded chest radiograph finding and pulmonary symptoms in this patient.

Hepatic dysfunction with abnormal liver enzymes and jaundice are common in severe Legionella infections. 10  Our patient also had abnormal liver tests with no other basis for hepatitis (Table 2). High levels of AST, ALT and hyperbilirubinemia were noted without signs of occult liver failure. PT/PTT and ammonia level were also slightly higher (Table 2). After LD was treated, liver function tests returned to normal.

The patient was empirically treated for CAP initially, then treatment tailored LD, using azithromycin and levofloxacin. He did extremely well after completion of recommended antimicrobial therapy- three weeks of fluoroquinolones or macrolides in invasive illness such as his. 2 13 14   Dysfunction of various organs gradually resolved. A patient’s survival after multi-organ failure is extremely dependent on early diagnosis, early initiation of antibiotics and coverage for atypical pneumonia. 2 13  As of the date of publication of this case, the source of this patient’s LD was not identified, but he was one of many cases of LD during an outbreak in New York City last year. From the fall of 2006 to date, the New York City Department of Health has noted an outbreak of LD in and around New York City, especially in Parkchester section of Bronx (where our hospital is located). 5  The majority of legionella infections in the United States are sporadic, and while it is essential to look for predisposing circumstances such as recent travel or use of a common water supply, no common environmental source of Legionnaire’s disease among the New York patients was found. 5

In conclusion, LD should be considered in the differential diagnosis of patients presenting with neurologic, gastrointestinal and cardiac symptoms, particularly in the presence of pneumonia. Failure to recognize the extrapulmonary manifestations of LD lead to a fatal outcome and curable disease may go untreated. 2 13  The initial empiric treatment for severe cases of community-acquired pneumonia should include an antimicrobial agent effective against Legionella species. 13  LD is an opportunistic infection; immunodepressed state and malignancy are among the risk factors associated with Legionnaire’s disease found in literature. 3  However, it is controversial whether or not to routinely look for causes of immunocompromised state without obvious etiology in patients who present with LD.

Ackowledgements

The authors thank Dr. K. Haider for his inputs and suggestions in preparation of the manuscript.

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