Legionellosis refers to the two clinical syndromes caused by bacteria of the genus Legionella. Pontiac fever is an acute, febrile, self-limited illness that has been serologically linked to Legionella species, whereas Legionnaires′ disease is the designation for pneumonia caused by these species. Legionnaires′ disease was first recognized in 1976, when an outbreak of pneumonia took place at a Philadelphia hotel during an American Legion convention.
The family Legionellaceae comprises more than 50 species with more than 70 serogroups. The species L. pneumophila causes 80–90% of human infections and includes at least 16 serogroups; serogroups 1, 4, and 6 are most commonly implicated in human infections. To date, 18 species other than L. pneumophila have been associated with human infections, among which L. micdadei (Pittsburgh pneumonia agent), L. bozemanii, L. dumoffii, and L. longbeachae are the most common. Members of the Legionellaceae are aerobic gram-negative bacilli that do not grow on routine microbiologic media. Buffered charcoal yeast extract (BCYE) agar is the medium used to grow Legionella.
The natural habitats for L. pneumophila are aquatic bodies, including lakes and streams. L. longbeachae has been isolated from natural soil and commercial potting soil. Legionellae can survive under a wide range of environmental conditions; for example, the organisms can live for years in refrigerated water samples. Natural bodies of water contain only small numbers of legionellae. However, once the organisms enter human-constructed aquatic reservoirs (such as drinking-water systems), they can grow and proliferate. Factors known to enhance colonization by and amplification of legionellae include warm temperatures (25°–42°C) and scale and sediment. L. pneumophila can form microcolonies within biofilms; its eradication from drinking-water systems requires disinfectants that can penetrate the biofilm. The presence of symbiotic microorganisms, including algae, amebas, ciliated protozoa, and other water-dwelling bacteria, promotes the growth of legionellae. The organisms can invade and multiply within free-living protozoa. Rainfall and humidity have been identified as environmental risk factors.
Sporadic community-acquired Legionnaires′ disease has been linked to colonization of residential, hotel, and industrial water supplies. Drinking-water systems in hospitals and extended-care facilities have been linked to health care–associated Legionnaires′ disease.
Cooling towers and evaporative condensers have been overestimated as sources of Legionella. Early investigations that implicated cooling towers antedated the discovery that the organism could also exist in drinking water. In many outbreaks attributed to cooling towers, cases of Legionnaires′ disease continued to occur despite disinfection of the cooling towers; drinking water was the actual source. Koch's postulates have never been fulfilled for cooling tower–associated outbreaks as they have been for hospital-acquired Legionnaires′ disease. Nevertheless, cooling towers have occasionally been identified in community-acquired outbreaks, including an outbreak in Murcia, Spain, in which several hundred suspected cases of Legionnaires′ disease occurred over a 3-week period. As mentioned above, L. longbeachae infections have been linked to potting soil, but the mode of transmission remains to be clarified.
Multiple modes of transmission of Legionella to humans exist, including aerosolization, aspiration, and direct instillation into the lungs during respiratory tract manipulations. Aspiration is now known to be the predominant mode of transmission, but it is unclear whether Legionella enters the lungs via oropharyngeal colonization or directly via the drinking of contaminated water. Oropharyngeal colonization has been demonstrated in patients undergoing transplantation. Nasogastric tubes have been linked to hospital-acquired Legionnaires′ disease; microaspiration of contaminated water was the hypothesized mode of transmission. Surgery with general anesthesia is a known risk factor that is consistent with aspiration. Especially compelling is the reported 30% incidence of postoperative Legionnaires′ disease among patients undergoing head and neck surgery at a hospital with a contaminated water supply; aspiration is a recognized sequela in such cases. Studies of patients with hospital-acquired Legionnaires′ disease have shown that these individuals underwent endotracheal intubation significantly more often and for a significantly longer duration than patients with hospital-acquired pneumonia of other etiologies.
Aerosolization of Legionella by devices filled with tap water, including whirlpools, nebulizers, and humidifiers, has been implicated. An ultrasonic mist machine in the produce section of a grocery store was the source in a community outbreak. Pontiac fever has been linked to Legionella-containing aerosols from water-using machinery, a cooling tower, air-conditioners, and whirlpools.
The incidence of Legionnaires′ disease depends on the degree of contamination of the aquatic reservoir, the immune status of the persons exposed to water from that reservoir, the intensity of exposure, and the availability of specialized laboratory tests on which the correct diagnosis can be based. Numerous prospective studies have ranked Legionella among the top four microbial causes of community-acquired pneumonia, accounting for 2–9% of cases. (Streptococcus pneumoniae, Haemophilus influenzae, and Chlamydophila pneumoniae are usually ranked first, second, and third, respectively.) On the basis of a multihospital study of community-acquired pneumonia in Ohio, the Centers for Disease Control and Prevention (CDC) estimated that as many as 18,000 cases of sporadic community-acquired Legionnaires′ disease occur annually in the United States and that only 3% of these cases are correctly diagnosed. Legionella is responsible for 10–50% of cases of nosocomial pneumonia when a hospital's water system is colonized with the organisms. The incidence of hospital-acquired Legionnaires′ disease depends on the degree of contamination of drinking water as defined by the rate of positivity of distal water sites (not as defined quantitatively by the number of colony-forming units per milliliter).
Risk factors for Legionnaires′ disease include cigarette smoking; chronic lung disease; advanced age; prior hospitalization, with discharge within 10 days before onset of pneumonia symptoms; and immunosuppression. Immunosuppressive conditions that predispose to Legionnaires′ disease include transplantation, HIV infection, and treatment with glucocorticoids or tumor necrosis factor α antagonists. However, in a large prospective study of community-acquired pneumonia, 28% of patients with Legionnaires′ disease did not have these classic risk factors. Surgery is a prominent predisposing factor in hospital-acquired infection, with transplant recipients at highest risk. Hospital-acquired cases are now being recognized among neonates and immunosuppressed children.
Pontiac fever occurs in epidemics. The high attack rate (>90%) reflects airborne transmission.
Pathogenesis and Immunity
Legionella enters the lungs through aspiration or direct inhalation. Attachment to host cells is mediated by bacterial type IV pili, heat-shock proteins, a major outer-membrane protein, and complement. Because the organism possesses pili that mediate adherence to respiratory tract epithelial cells, conditions that impair mucociliary clearance, including cigarette smoking, lung disease, or alcoholism, predispose to Legionnaires′ disease.
Both the innate and adaptive immune responses play a role in host defense. Toll-like receptors mediate recognition of L. pneumophila in alveolar macrophages and enhance early neutrophil recruitment to the site of infection. Alveolar macrophages phagocytose legionellae by a conventional or a coiling mechanism. The macrophage infectivity potentiation (MIP) surface protein enhances infection of the macrophages. After phagocytosis, L. pneumophila evades intracellular killing by inhibiting phagosome-lysosome fusion. Although many legionellae are killed, some proliferate intracellularly until the cells rupture; the bacteria are then phagocytosed again by newly recruited phagocytes, and the cycle begins anew. The role of neutrophils in immunity appears to be minimal: neutropenic patients are not predisposed to Legionnaires′ disease. Although L. pneumophila is susceptible to oxygen-dependent microbiologic systems in vitro, it resists killing by neutrophils. The humoral immune system is active against Legionella. Type-specific IgM and IgG antibodies are measurable within weeks of infection. In vitro, antibodies promote killing of Legionella by phagocytes (neutrophils, monocytes, and alveolar macrophages). Immunized animals develop a specific antibody response, with subsequent resistance to Legionella challenge. However, antibodies neither enhance lysis by complement nor inhibit intracellular multiplication within phagocytes.
Some L. pneumophila strains are clearly more virulent than others, although the precise factors mediating virulence remain uncertain. For example, although multiple strains may colonize water-distribution systems, only a few cause disease in patients exposed to water from these systems. At least one surface epitope of L. pneumophila serogroup 1 is associated with virulence. Monoclonal antibody subtype mAb2 has been linked to virulence. L. pneumophila serogroup 6 is more commonly involved in hospital-acquired Legionnaires′ disease and is more likely to be associated with a poor outcome.
The genome of L. pneumophila has been sequenced. A broad range of membrane transporters within the genome are thought to optimize the use of nutrients in water and soil.
Clinical and Laboratory Features
Pontiac fever is an acute, self-limiting, flu-like illness with an incubation period of 24–48 h. Pneumonia does not develop. Malaise, fatigue, and myalgias are the most common symptoms, occurring in 97% of cases. Fever (usually with chills) develops in 80–90% of cases and headache in 80%. Other symptoms (seen in <50% of cases) include arthralgias, nausea, cough, abdominal pain, and diarrhea. Modest leukocytosis with a neutrophilic predominance is sometimes detected. Complete recovery occurs within a few days; antibiotic therapy is unnecessary. A few patients may experience lassitude for many weeks after recovery. The diagnosis is established by antibody seroconversion.
Legionnaires′ Disease (Pneumonia)
Legionnaires′ disease is often included in the differential diagnosis of “atypical pneumonia,” along with pneumonia due to C. pneumoniae, Chlamydophila psittaci, Mycoplasma pneumoniae, Coxiella burnetii, and some viruses. The clinical similarities among these types of pneumonia include a relatively nonproductive cough and a low incidence of grossly purulent sputum. However, the clinical manifestations of Legionnaires′ disease are usually more severe than those of most “atypical” pneumonias, and the course and prognosis of Legionella pneumonia more closely resemble those of bacteremic pneumococcal pneumonia than those of pneumonia due to other “atypical” pathogens. Patients with community-acquired Legionnaires′ disease are significantly more likely than patients with pneumonia of other etiologies to be admitted to an intensive care unit on presentation.
The incubation period for Legionnaires′ disease is usually 2–10 days, although longer incubation periods have been documented. The symptoms and signs may range from a mild cough and a slight fever to stupor with widespread pulmonary infiltrates and multisystem failure. Nonspecific symptoms—malaise, fatigue, anorexia, and headache—are seen early in the illness. Myalgias and arthralgias are uncommon but are prominent in a few patients. Upper respiratory symptoms, including coryza, are rare.
The mild cough of Legionnaires′ disease is only slightly productive. Sometimes the sputum is streaked with blood. Chest pain—either pleuritic or nonpleuritic—can be a prominent feature and, when coupled with hemoptysis, can lead to an incorrect diagnosis of pulmonary embolism. Shortness of breath is reported by one-third to one-half of patients. Gastrointestinal difficulties are often pronounced; abdominal pain, nausea, and vomiting affect 10–20% of patients. Diarrhea (watery rather than bloody) is reported in 25–50% of cases. The most common neurologic abnormalities are confusion or changes in mental status; however, the multitudinous neurologic symptoms reported range from headache and lethargy to encephalopathy.
Patients with Legionnaires′ disease virtually always have fever. Temperatures in excess of 40.5°C (104.9°F) were recorded in 20% of the cases in one series. Relative bradycardia has been overemphasized as a useful diagnostic finding; it occurs primarily in older patients with severe pneumonia. Chest examination reveals rales early in the course and evidence of consolidations as the disease progresses. Abdominal examination may reveal generalized or local tenderness.
Although the clinical manifestations often considered classic for Legionnaires′ disease (Table 147-1) may suggest the diagnosis, prospective comparative studies have shown that clinical manifestations are generally nonspecific and that Legionnaires′ disease is not readily distinguishable from pneumonia of other etiologies. In a review of 13 studies of community-acquired pneumonia, clinical manifestations that occurred significantly more often in Legionnaires′ disease included diarrhea, neurologic findings (including confusion), and a temperature of >39°C. Hyponatremia, elevated values in liver function tests, and hematuria also occurred more frequently in Legionnaires′ disease. Other laboratory abnormalities include creatine phosphokinase elevation, hypophosphatemia, serum creatinine elevation, and proteinuria.
Table 147-1 Clinical Clues Suggestive of Legionnaires' Disease |Favorite Table|Download (.pdf)
Table 147-1 Clinical Clues Suggestive of Legionnaires' Disease
High fever (>40°C; >104°F)
Numerous neutrophils but no organisms revealed by Gram's staining of respiratory secretions
Hyponatremia (serum sodium level <131 mg/dL)
Failure to respond to β-lactam drugs (penicillins or cephalosporins) and aminoglycoside antibiotics
Occurrence of illness in an environment in which the poTable water supply is known to be contaminated with Legionella
Onset of symptoms within 10 days after discharge from the hospital
Sporadic cases of Legionnaires′ disease appear to be more severe than outbreak-associated and hospital-acquired cases, presumably because their diagnosis is delayed. Results of the German CAPNETZ Study showed that, among cases of community-acquired Legionella pneumonia, ambulatory cases were as common as cases requiring hospitalization.
Since the portal of entry for Legionella is the lung in virtually all cases, extrapulmonary manifestations usually result from bloodborne dissemination from the lung. Legionella has been identified in lymph nodes, spleen, liver, or kidneys in autopsied cases. The most common extrapulmonary site of legionellosis is the heart; numerous reports have described myocarditis, pericarditis, postcardiotomy syndrome, and prosthetic-valve endocarditis. Most cases have been hospital-acquired. In some patients without overt evidence of pneumonia, the organisms may gain entry through a postoperative sternal wound exposed to contaminated tap water or through a mediastinal-tube insertion site. Sinusitis, peritonitis, pyelonephritis, skin and soft tissue infection, septic arthritis, and pancreatitis have been seen predominantly in immunosuppressed patients.
Virtually all patients with Legionnaires′ disease have abnormal chest radiographs showing pulmonary infiltrates at the time of clinical presentation. In a few cases of hospital-acquired disease, fever and respiratory tract symptoms have preceded the radiographic appearance of the infiltrate. Radiologic findings are nonspecific. Pleural effusion is evident in 28–63% of patients on hospital admission. In immunosuppressed patients, especially those receiving glucocorticoids, distinctive rounded nodular opacities may be seen; these lesions may expand and cavitate (Fig. 147-1). Likewise, abscesses can occur in immunosuppressed hosts. The progression of infiltrates and pleural effusion on chest radiography despite appropriate antibiotic therapy within the first week is common, and radiographic improvement lags behind clinical improvement by several days. Complete clearing of infiltrates requires 1–4 months.
Chest radiographic findings in a 52-year-old man who presented with pneumonia subsequently diagnosed as Legionnaires' disease. The patient was a cigarette smoker with chronic obstructive pulmonary disease and alcoholic cardiomyopathy; he had received glucocorticoids. L. pneumophila was identified by direct fluorescent antibody staining and culture of sputum. Left: Baseline chest radiograph showing long-standing cardiomegaly. Center: Admission chest radiograph showing new rounded opacities. Right: Chest radiograph taken 3 days after admission, during treatment with erythromycin.
Given the nonspecific clinical manifestations of Legionnaires′ disease and the high mortality rates for untreated Legionnaires′ disease, the use of Legionella testing—especially the Legionella urinary antigen test—is recommended for all patients with community-acquired pneumonia, including patients with ambulatory pneumonia and hospitalized children. Legionella cultures should be made more widely available since the urinary antigen test can diagnose only L. pneumophila serogroup 1. Hospitals in which the drinking water is known to be colonized with Legionella species should have Legionella cultures routinely available for all patients with hospital-acquired pneumonia.
The diagnosis of Legionnaires′ disease requires special microbiologic tests (Table 147-2). The sensitivity of bronchoscopy specimens is similar to that of sputum samples for culture on selective media; if sputum is not available, bronchoscopy specimens may yield the organism. Bronchoalveolar lavage fluid gives higher yields than bronchial wash specimens. Thoracentesis should be performed if pleural effusion is found, and the fluid should be evaluated by direct fluorescent antibody (DFA) staining, culture, and the antigen assay designed for use with urine.
Table 147-2 Utility of Special Laboratory Tests for the Diagnosis of Legionnaires' Disease |Favorite Table|Download (.pdf)
Table 147-2 Utility of Special Laboratory Tests for the Diagnosis of Legionnaires' Disease
|Test||Sensitivity, %||Specificity, %|
|Direct fluorescent antibody staining of sputum||50–70||96–99|
|Urinary antigen testingb||70||100|
Gram's staining of material from normally sterile sites, such as pleural fluid or lung tissue, occasionally suggests the diagnosis; efforts to detect Legionella in sputum by Gram's staining typically reveal numerous leukocytes but no organisms. When they are visualized, the organisms appear as small, pleomorphic, faint, gram-negative bacilli. L. micdadei organisms can be detected as weakly or partially acid-fast bacilli in clinical specimens.
The DFA test is rapid and highly specific but is less sensitive than culture because large numbers of organisms are required for microscopic visualization. This test is more likely to be positive in advanced than in early disease.
The definitive method for diagnosis of Legionella infection is isolation of the organism from respiratory secretions, although culture for 3–5 days is required. Antibiotics added to the medium suppress the growth of competing flora from nonsterile sites, and dyes color the colonies and assist in identification. The use of multiple selective BCYE media is necessary for maximal sensitivity. When culture plates are overgrown with other microflora, pretreatment of the specimen with acid or heat can markedly improve the yield. L. pneumophila is often isolated from sputum that is not grossly or microscopically purulent; sputum containing more than 25 epithelial cells per high-power field (a finding that classically suggests contamination) may still yield L. pneumophila.
Antibody testing of both acute- and convalescent-phase sera is necessary. A fourfold rise in titer is diagnostic; 12 weeks are often required for the detection of an antibody response. A single titer of 1:128 in a patient with pneumonia constitutes circumstantial evidence for Legionnaires′ disease. Serology is of use primarily in epidemiologic studies. The specificity of serology for Legionella species other than L. pneumophila is uncertain; there is cross-reactivity with Legionella species and some gram-negative bacilli.
The assay for Legionella soluble antigen in urine is rapid, relatively inexpensive, easy to perform, second only to culture in terms of sensitivity, and highly specific. Several enzyme immunoassays and a rapid immunochromatographic assay are commercially available. The rapid immunochromatographic assay is relatively inexpensive and easy to perform. The urinary antigen test is available only for L. pneumophila serogroup 1, which causes ∼80% of Legionella infections. Cross-reactivity with other L. pneumophila serogroups and other Legionella species has been detected in up to 22% of urine samples from patients with culture-proven cases. Antigen in urine is detectable 3 days after the onset of clinical disease and disappears over 2 months; positivity can be prolonged when patients receive glucocorticoids. The test is not affected by antibiotic administration.
DFA stains can identify a number of Legionella species. Both polyclonal and monoclonal antibody stains are commercially available. Although its application is currently limited to research investigations, polymerase chain reaction (PCR) with DNA probes is theoretically more sensitive and specific than other methods. A molecular probe is undergoing evaluation. PCR has proven somewhat useful in the identification of Legionella from environmental water specimens. In PCR (unlike culture), epidemiologic links cannot be made since the infecting pathogen is not available for molecular subtyping.
Treatment: Legionella Infection
Because Legionella is an intracellular pathogen, antibiotics that can attain high intracellular concentrations are most likely to be effective. The dosages for various drugs used in the treatment of Legionella infection are listed in Table 147-3.
Table 147-3 Antibiotic Therapy for Legionella Infection |Favorite Table|Download (.pdf)
Table 147-3 Antibiotic Therapy for Legionella Infection
500 mgb PO or IVc q24h
500 mg PO or IVc q12h
750 mg IV q24h
500 mgb PO q24h
400 mg IV q8h
750 mg PO q12h
400 mgb PO q24h
|Telithromycin||800 mg PO q24h|
100 mgb PO or IV q12h
100 mgb PO or IV q12h
500 mg PO or IV q6h
100-mg IV load, then 50 mg IV q12h
160/800 mg IV q8h
160/800 mg PO q12h
300–600 mg PO or IV q12h
The macrolides (especially azithromycin) and the respiratory quinolones are now the antibiotics of choice and are effective as monotherapy. Compared with erythromycin, the newer macrolides have superior in vitro activity, display greater intracellular activity, reach higher concentrations in respiratory secretions and lung tissue, and have fewer adverse effects. The pharmacokinetics of the newer macrolides and quinolones also allow once- or twice-daily dosing. Quinolones are the preferred antibiotics for transplant recipients because both macrolides and rifampin interact pharmacologically with cyclosporine and tacrolimus. Retrospective uncontrolled studies have shown that complications of pneumonia are fewer and clinical response is more rapid in patients receiving quinolones than in those receiving macrolides. Alternative agents include tetracycline and its analogues doxycycline and minocycline. Tigecycline is active in vitro but clinical experience is minimal. Anecdotal reports have described both successes and failures with trimethoprim-sulfamethoxazole, imipenem, and clindamycin. For severely ill patients with extensive pulmonary infiltrates, a two-drug combination of a newer macrolide or a quinolone with rifampin may be considered for initial treatment. Rifampin is highly active in vitro and in cell models, but its interaction with many other medications, including macrolides, is problematic. Initial therapy should be given by the IV route. A clinical response usually occurs within 3–5 days, after which oral therapy can be substituted. The total duration of therapy in the immunocompetent host is 10–14 days; a longer course (3 weeks) may be appropriate for immunosuppressed patients and those with advanced disease. For azithromycin, with its long half-life, a 5- to 10-day course is sufficient.
Pontiac fever requires only symptom-based treatment, not antimicrobial therapy.
Mortality rates for Legionnaires′ disease vary with the patient's underlying disease and its severity, the patient's immune status, the severity of pneumonia, and the timing of administration of appropriate antimicrobial therapy. Mortality rates are highest (80%) among immunosuppressed patients who do not receive appropriate antimicrobial therapy early in the course of illness. With appropriate and timely antibiotic treatment, mortality rates from community-acquired Legionnaires′ disease among immunocompetent patients range from 0 to 11%; without treatment, the figure may be as high as 31%. In a study of survivors of an outbreak of community-acquired Legionnaires′ disease, sequelae of fatigue, neurologic symptoms, and weakness were found in 63–75% of patients 17 months after receipt of antibiotics.
Routine environmental culture of hospital water supplies is recommended as an approach to the prevention of hospital-acquired Legionnaires′ disease. Guidelines mandating this proactive approach have been adopted throughout Europe and in several U.S. states. Positive cultures from the water supply mandate the use of specialized laboratory tests (especially culture on selective media and the urinary antigen test) for patients with hospital-acquired pneumonia. Studies have shown that neither a high degree of outward cleanliness of the water system nor routine application of maintenance measures decreases the frequency or intensity of Legionella contamination. Thus, engineering guidelines and building codes, although routinely advocated as preventive measures, have little impact on the presence of Legionella.
Disinfection of the drinking water supply is effective. Two methods have proved reliable and cost-effective. The superheat-and-flush method requires heating of the water so that the distal-outlet temperature is 70–80°C and flushing of the distal outlets with hot water for at least 30 min. This method is ideal for emergency situations. Commercial copper and silver ionization systems have proven effective in numerous hospitals. Chlorine dioxide is a promising modality. Tap water filters have been effective for high-risk patient areas, such as transplantation or intensive care units. Hyperchlorination is no longer recommended because of its expense, carcinogenicity, corrosive effects on piping, and unreliable efficacy.