Current Diagnosis & Treatment in Infectious Diseases

Section V - Bacterial Infections

58. Legionella

Michael Bell MD

Essentials of Diagnosis

• Key signs and symptoms may include minimally productive cough, low-grade fever, headache, and altered mental status.
• Risk factors include smoking, advanced age, history of cardiac or pulmonary disease, male gender, and cell-mediated immune suppression.
• Common infections include pneumonia with multisystem involvement (Legionnaires' disease) and nonspecific febrile illness without pulmonary involvement (Pontiac fever).
• Gram stain of respiratory secretions may reveal numerous neutrophils without evident organisms.
• Aerobic, pleomorphic, faintly staining gram-negative rods are non-spore forming and unencapsulated.

General Considerations

1975. Epidemiology.More than 25 species and 48 serogroups of Legionellahave been identified. Legionella pneumophila (especially serogroup 1) causes ~ 70–80% of cases of legionellosis, but L micdadei, L bozemanii, L dumoffi, L feelei, L longbeacheii, and other species are also pathogenic. The true incidence of legionellosis, which includes Legionnaires' disease and Pontiac fever, is difficult to establish. Although most developed countries conduct surveillance for infection, underdetection is common, in part because laboratory tests are often not performed or, when performed, lack sensitivity. Between 500 and 1500 cases in the United States are reported annually to the Centers for Disease Control and Prevention (CDC), but the true incidence is believed to be between 13,000 and 20,000 cases a year. Few population-based incidence studies have been conducted. Among members of a prepaid health plan in Seattle, Washington, the annual incidence was 12 cases per 100,000 between 1963 and 1975. In Nottingham, England, 1.4 cases per 100,000 population occurred annually between 1977 and 1991.

Legionella species have been detected in virtually all sources of fresh water, including lakes, ponds, rivers, and soil runoff, especially in areas where there is thermal pollution. However these natural water supplies are rarely identified as sources of human infection. Aerosols from artificial reservoirs of water, including cooling towers, evaporative condensers, air conditioners, humidifiers, fountains, and whirlpool spas, are most often implicated in outbreaks. Cooling towers and evaporation condensers are especially prone to Legionella colonization because they recycle warm, unfiltered water and accumulate organic debris and biofilm over time. This milieu supports the growth of other microflora, including amoebae. Amoebae may be essential to the life cycle of Legionella species; the organism appears to multiply intracellularly in these protozoa in the same way it multiplies in human monocytes. Removal of amoebae by filtration will also eliminate viable Legionella species from water reservoirs.

Potable-water (especially hot-water) distribution systems are also important reservoirs supporting growth of Legionella species. Environmental sampling in hospitals, hotels, and homes has demonstrated colonization in 10–50% of hot-water faucets or water heaters, even at sites where no cases of legionellosis have occurred. Electric water heaters are especially prone to colonization because, unlike gas systems that apply heat to the bottom of the tank, electrical heating elements are in the sides of the tank. The temperature of the sediment deposited in the bottom of the tank is thus cool enough to support growth of the organism. Temperature appears to influence the risk of Legionella colonization in all water systems. Growth is promoted between 35°C and 45°C, and organisms may remain viable at temperatures ≤ 66°C.

Legionella species are transmitted to humans through aspiration, inhalation, or instillation of infected water. There is no evidence to support person-to-person transmission. Cooling-tower exhausts proximate to air conditioning intake vents are an important cause of large outbreaks among occupants of hospitals, hotels, and other buildings. Transmission to persons residing as far as 1–2 miles from the cooling towers has also been suggested. Residential air conditioners that do not use water for cooling do not promote Legionella transmission, but home air humidifiers probably do. Showers, faucets, and respiratory therapy equipment have also been sources of outbreaks. One major outbreak of Legionnaires' disease on a cruise ship, involving at least nine separate week-long cruises, was associated with contamination of a whirlpool spa. The water taken aboard the ship probably contained L pneumophila, but the potable water supply was properly disinfected (chlorinated) before consumption. However, the water reserved for the spa was not adequately decontaminated by the brominator. L pneumophila colonized the organic debris trapped in the sand filter of the spa, creating the potential for infectious aerosols that caused exposure and infection among passengers. In another important outbreak, the humidification mist used to preserve vegetables in a grocery store was linked to transmission of legionellosis to several shoppers.

The sources of sporadic cases of Legionella infection are not clear, although > 65% of known cases are not associated with outbreaks. Given the enormous number of potential water sources, it is not surprising that establishing a source of exposure is difficult in the absence of an obvious outbreak. As mentioned above, persons residing near cooling towers may be at increased risk. Tobacco use, alcohol abuse, and conditions that affect pulmonary defense mechanisms are risk factors for legionellosis. Some experts believe that aspiration of infected potable water may be an important source of sporadic and also epidemic legionellosis.

Nosocomially acquired Legionnaires' disease accounts for ~ 23% of all cases reported to CDC. After one case of nosocomial infection is identified, subsequent cases are usually detected. Hence, the CDC recommends that identification of one definite or two possible cases of nosocomial Legionnaires' disease within 6 months should prompt an epidemiologic investigation and intensified surveillance. The capacity of Legionella species to colonize hospital plumbing systems for prolonged periods provides an ongoing source for transmission to patients. In older facilities or in those in which renovation results in areas of water stagnation and build-up of organic and inorganic sediments, Legionella colonization is not uncommon. In one recent investigation, the hospital water distribution system was associated with cases of Legionnaires' disease among immunosuppressed patients over a period of 17 years. Mortality from nosocomially acquired Legionnaires' disease in the United States is ~ 40%, compared with 20% for community-acquired cases.

1. Microbiology.Legionellaspecies are slender, aerobic gram-negative bacilli that may appear as coccobacilli measuring 1–2 µm in clinical specimens. Legionella species are fastidious; visible colonies appear on agar only after 2–7 days of culturing at 35°C. Buffered charcoal yeast extract agar is the preferred culture medium. Legionella species are not encapsulated and do not form spores. They are catalase positive and oxidase negative.
2. Pathogenesis.Legionellaspecies reach the lower respiratory tract via aspiration, inhalation, or instillation of infected water. They are facultative intracellular bacteria that infect host alveolar macrophages and reside within ribosome-lined phagocytic vacuoles. Much as the organism evades the lysosomal defenses of host amoebae, it interferes with macrophage lysosomal fusion and multiplies within that cell's phagosome. New bacilli are released when the infected macrophage ruptures. This process initiates the inflammatory response and pulmonary infiltrates that are the hallmark of Legionnaires' disease. Humoral antibodies develop in infected persons as well as those with subclinical exposures, but they do not appear to be protective. However, cell-mediated responses may confer resistance to subsequent infections. Cytokine production, which activates macrophages and enhances intracellular killing of Legionella species, may also be an important host defense.

CLINICAL SYNDROMES

Legionella species are associated with outbreaks of either Pontiac fever, a self-limited influenzalike condition in otherwise healthy people, or Legionnaires' disease, a severe pneumonic disease more common among elderly and immunocompromised individuals (Box 58-1). The spectrum of illness is much broader than these two clinical entities suggest, ranging from completely asymptomatic infection to fulminant respiratory failure and death.

1. PONTIAC FEVER

In 1968, the first documented outbreak of Pontiac fever syndrome affected people in a health department building in Pontiac, Michigan. Epidemiologic investigation demonstrated that the infection was airborne and implicated water aerosols that were produced by a faulty air conditioning system as the source of exposure. Sentinel guinea pigs exposed to air in the building developed bronchopneumonia, and lung tissue cultures grew L pneumophila (serogroup 1). Paired acute and convalescent serum specimens from 37 patients were tested by the indirect fluorescent antibody technique, using L pneumophila serogroup 1 antigen, and 31 (84%) had rises in titer from < 32 to ≥ 64. Since that time, numerous outbreaks of Pontiac fever, almost always attributable to an obvious source of contaminated water, have been detected in communities across the country.

Pontiac fever is a self-limited infection characterized by fever, chills, headache, myalgia, fatigue, and upper respiratory tract symptoms. It is not associated with a pneumonia or pulmonary infiltrates, although some patients do have a mild nonproductive cough. The incubation period is short, usually 36 h, and the attack rate is high (≤ 95%), even among individuals with no underlying illness. Patients recover spontaneously, usually within 1 week of symptom onset.

BOX 58-1 Legionella Syndromes

Legionnaires'Disease1 Pontiac Fever More Common · Pneumonia · Self limited, acute flulike illness characterized by malaise, myalgia, fever, chills, and headache Less Common · Diarrhea, nausea, vomiting, abdominal pain · Lethargy, encephalopathy · Hypotension, adult respiratory distress syndrome · Nonproductive cough, nausea 1Among immunosuppressed patients, extrapulmonary disease has included sinusitis, cellulitis, pericarditis, endocarditis, pyelonephritis, pancreatitis, and perirectal abscess.

2. LEGIONNAIRES' DISEASE

Legionella species cause both community-acquired and nosocomial pneumonia among normal individuals, as well among those with depressed cell-mediated immunity (transplant recipients, patients treated with corticosteroids, and those with AIDS). Immunosuppressed patients, those who smoke tobacco, elderly persons, and patients with underlying cardiovascular and pulmonary illnesses are at increased risk. Men are two- to threefold more likely than women to acquire this infection.

Unlike Pontiac fever, for which the incubation period is short (1–2 days), the onset of Legionnaires' disease may occur ≤ 14 days after exposure, although onset usually occurs within 2–10 days. The attack rate is also relatively low (< 8%), when compared with Pontiac fever.

1. Signs and Symptoms.The clinical severity of Legionnaires' disease is highly variable. In mild cases, dry cough and low-grade fever are predominant symptoms. Severe cases, especially among immunosuppressed patients, are complicated by multisystem organ failure and adult respiratory distress syndrome.

Early symptoms are nonspecific and do not distinguish Legionnaires' disease from other causes of pneumonia. Common symptoms include fever, headache, malaise, myalgia, nausea, anorexia, and a minimally productive cough. Neurologic symptoms in addition to headache include changes in mental status that range from lethargy to encephalopathy. Chest pain, which may be pleuritic, and modest hemoptysis are sometimes associated with this infection. Nausea, vomiting, and abdominal pain occur in a minority of patients.

1. Laboratory Findings.Laboratory abnormalities are nonspecific, although hyponatremia (Na <130 mEq/L) is more likely in legionellosis than in other causes of pneumonia.
2. Imaging.Chest x-ray findings are almost always present by the third day of illness and tend to begin as a unilateral lower-lobe infiltrate. The infiltrate may progress despite antibiotic treatment, but the degree of radiographic abnormality does not correlate with severity of clinical illness. In one recent report, cardiac disease, diabetes mellitus, creatinine ≥ 1.8 mg/dL), septic shock, progressive infiltrates, mechanical ventilation, hyponatremia, and blood urea levels ≥ 30 mg/dL) were factors related to poor outcome, but appropriate antibiotic treatment and improvement in chest radiographic appearance were favorable prognostic factors. Multivariate analysis showed that an Acute Physiology and Chronic Health Evaluation (APACHE II [see Rutledge et al, 1991]) score of ≥ 15 at admission and severe hyponatremia were independent predictors of mortality.
3. Differential Diagnosis.The differential diagnosis includes pulmonary embolus as well as the usual bacterial and viral causes of pneumonia. A prospective study designed to identify factors that distinguished Legionnaires' disease from other causes of community-acquired pneumonia in the emergency department of a university hospital was recently published. Epidemiologic and demographic data and clinical, laboratory, and radiologic features of patients with Legionnaires' disease were compared with those of patients with community-acquired pneumonia caused by other bacterial pathogens. Legionnaires' disease was more frequent in middle-aged, healthy alcohol-drinking male patients than other causes of pneumonia. Lack of response to initial treatment with β-lactam antibiotic and headache, diarrhea, severe hyponatremia, and elevation in serum creatine kinase levels on presentation were also more common among patients with Legionnaires' disease. In contrast, cough, sputum production, and thoracic pain were less common in Legionnaires' patients than in other pneumonia patients. Multivariate analysis demonstrated that underlying disease, diarrhea, and elevation in the creatine kinase were independent predictors of Legionnaire's disease.

1. Complications.In the increasingly large population of immunocompromised individuals, Legionellaspecies have been documented to cause extrapulmonary disease that can include cellulitis, wound infection, perirectal abscess, pancreatitis, pyelonephritis, peritonitis, hemodialysis fistula infection, pericarditis, myocarditis, and prosthetic valve endocarditis.

Diagnosis

Diagnosis of Legionella infection depends on a high index of suspicion and special laboratory tests. Definitive diagnosis of legionellosis is based on recovery of the organism from respiratory secretions or tissues. Cultures of sputum, transtracheal aspirates, and blood are each 100% specific, although the sensitivities are 80%, 90%, and 20%, respectively. Pretreating respiratory specimens with acid and use of selective media can improve culture sensitivity. In special cases, coculture with amoebae or intraperitoneal inoculation of guinea pigs will increase the diagnostic yield.

Serologic comparison of acute and convalescent serum specimens demonstrating a fourfold rise in titer (≥ 128) of immunoglobulin G antibody (indirect fluorescent antibody assay) is > 95% specific when the L pneumophila serogroup 1 antigen is used (but less specific with other Legionella antigens) and demonstrates a sensitivity of ~ 50%. Clinical utility of serologic diagnosis is limited, however, because 4–12 weeks are required for the human body to mount a full antibody response. This test is therefore mainly useful as an epidemiologic tool.

Direct fluorescent antibody tests can identify Legionella antigens in respiratory specimens and tissue with a high degree of specificity, but, as with other tests, the direct fluorescent antibody test is not sensitive (< 60%). Commercially available tests for excreted urinary antigen detect only infections caused by L pneumophila serogroup 1, but because this serogroup accounts for > 70% of Legionella infections, they are useful rapid tests in many clinical settings.

Finally, tests using polymerase chain reaction amplification of ribosomal RNA and DNA sequences specific to L pneumophila are now available and have been demonstrated to be sensitive and specific for confirming the presence of the organism in cultures. However, the sensitivity of these tests when performed on respiratory tract samples may not be better than that of direct fluorescent antibody tests, and their specificity is worse.

Treatment

Erythromycin is the recommended treatment for Legionnaires' disease and other serious Legionella infections; however, failures have occurred, and adverse effects are common (Box 58-2). Erythromycins, intravenous azithromycin, and levofloxacin are currently approved by the US Food and Drug Administration for treatment of Legionnaires' disease. Although prospective controlled comparisons have not been performed, clarithromycin and quinolone antibiotics are also effective. Other agents with activity against Legionellaceae include doxycycline, minocycline, rifampin, and trimethoprim-sulfamethoxazole. For severe illness and for treatment of immunosuppressed patients, combination treatment either with rifampin plus a macrolide or quinolone or with a quinolone plus a macrolide (eg, levofloxacin plus azithromycin) is recommended.

Prevention & Control

Isolation of patients with known or suspected Legionella infection is not required, because direct person-to-person transmission has not been observed (Box 58-3). Epidemiologic investigation of sporadic community-acquired cases of Legionella infection is not usually productive because of the large number of exposures to potential water sources. When a community outbreak is suspected, conventional epidemiologic methods (ie, case definition, hypothesis generation, and case control study) should be used to confirm the presence of an outbreak and identify the source of exposure. Samples from suspicious water reservoirs should be cultured, and in some cases the potential for these sources to produce aerosol particles in the respirable size range should be evaluated with an air particle-size sampler. Smoke or other tracer materials can be used to evaluate the movement of aerosols and routes of access to ventilation systems, air intake passages, or other modes of dispersion.

In cases of known or suspected nosocomial infection, a detailed environmental investigation of all sources of water exposure is often indicated, especially when two or more unexplained cases have occurred. In addition to evaluating water reservoirs in the facility (eg, cooling towers and evaporative condensers), respiratory-therapy equipment should be checked and procedures should be reviewed to identify occult sources of exposure to potable water. In addition, samples from the water distribution system (eg, showers, faucets, and taps) should be cultured for Legionella species.

It is very difficult if not impossible to decontaminate water supplies. Cooling towers and evaporative condensers must be drained, scoured to remove organic debris and sediment, and then disinfected with chlorine. Follow-up maintenance must include periodic chlorination or treatment with alternate disinfectants.

Similarly, contaminated water heaters should be drained, cleaned, and then disinfected. Superheating (> 60°C) is also recommended for water heaters and distal water distribution systems. However, this procedure can result in severe scalding and must be used with caution. Hyperchlorination has also been used, but can result in high levels of trihalomethanes, which are putative carcinogens. Over time, hyperchlorination corrodes the plumbing system, leading to enhanced opportunities for sediments that promote the growth of Legionella species.

BOX 58-2 Treatment of Legionnaires' Disease

Adults Children First Choice · Erythromycin, 2 g orally daily in divided doses or 4 g IV daily in divided doses (latter dos- age is associated with reversible ototoxicity) OR · Azithromycin, 500 mg IV daily · Clarithromycin, 500 mg orally twice daily · Levofloxacin, 250–500 mg orally or IV daily · Ciprofloxacin, 500–700 mg orally twice daily; 200–400 mg IV every 12 h · Ofloxacin, 200–400 mg orally or IV every 12 h · Erythromycin, 30–60 mg/kg orally daily in divided doses OR · Azithromycin (age > 2 y), 12 mg/kg orally daily (not to exceed 500 mg/d) · Clarithromycin (age > 6 mo), 7.5 mg/kg orally twice daily (not to exceed 500 mg/dose) Second Choice · Doxycycline, 100 mg orally or IV every 12 h · Doxycycline, (age > 8 y), 2–4 mg/kg orally daily in two doses Considerations for Immunosuppressed Patients1 · Combination treatment with macrolide/azolide plus quinolone or macrolide/azolide plus rifampin 1When treating transplant recipients, consider the influences of macrolides and rifampin on cyclosporine metabolism; a quinolone alone may be preferable.

BOX 58-3 Prevention and Control of Legionella Infection

Isolation Requirements None indicated. No evidence of person-to-person transmission Environmental Control · In hospitals with a significant immunocompromised population, superheating and flushing of water supplies identified as reservoirs of L pneumophila has been attempted with variable success. · Adjunctive use of copper-silver ionization and ultraviolet systems has been reported effective. Hyperchlorination is no longer recommended. · Drain, scrub, and disinfect water reservoirs; periodic maintenance treatment required.

Metal ionization procedures are advocated by some, but are not known to work better than conventional methods. One copper-silver ionization system was sequentially installed onto the hot-water recirculation lines of two hospital buildings colonized with L pneumophila serogroup 1. A third building with the same water supply, also colonized with L pneumophila, served as a control. Within 4–12 weeks of application, the levels of detectable L pneumophila in the two treated systems dropped to zero, but remained positive in the untreated system. However, concentrations of copper and silver in excess of Environmental Protection Agency standards can accumulate at the bottoms of hot-water tanks subjected to this type of treatment. Its long-term effectiveness has not been determined.

In cases in which water treatments fail, the entire current and past water distribution system engineering and structural design should be reviewed to identify old pipes that may bypass the part of the system undergoing disinfection. These pipes may introduce contaminated water downstream if they are not disinfected.

Detailed guidelines for preventing nosocomial legionellosis and for decontaminating water reservoirs and distribution systems are available from CDC at http://www.cdc.gov.ncidod/diseases/hip/pneumonia/pneu_mmw.htm.

REFERENCES

Bhopal RS, Barr G: Maintenance of cooling towers following two outbreaks of Legionnaires' disease in a city. Epidemiol Infect 1990;34:189.

Centers for Disease Control and Prevention: Sustained transmission of nosocomial Legionnaires' disease. Morbid Mortal Wkly Rep 1997;46:416.

Edelstein P: Antimicrobial chemotherapy for Legionnaires' disease: a review. Clin Infect Dis 1995;21:S265.

el-Ebiary M, et al: Prognostic factors of severe Legionella pneumonia requiring admission to ICU. Am J Respir Crit Care Med 1997;156:1467.

Fields BS et al: Virulence of a Legionella anisa strain associated with Pontiac fever: an evaluation using protozoan, cell culture, and guinea pig models. Infect Immun 1990; (9):3139.

Foy HM et al: Legionnaires' disease in a prepaid medical-care group in Seattle 1963–75. Lancet 1979;i:767.

Friedman H et al: Immunologic response and pathophysiology of Legionella infection. Semin Respir Infect 1998;13:100.

Goetz A, Yu VL: Copper-silver ionization: cautious optimism for Legionella disinfection and implications for environmental culturing. Am J Infect Control 1997; 25(6):449.

Hoge CW, Breirman RF: Advances in the epidemiology and control of Legionella infections. Epidemiol Rev 1991;13:329.

Jernigan DB et al: Outbreak of Legionnaires' disease among cruise ship passengers exposed to a contaminated spa. Lancet 1996;347:494.

Kaufmann AF et al: Pontiac fever: isolation of the etiologic agent (Legionella pneumophila) and demonstration of its mode of transmission. Am J Epidemiol 1981;114:337.

Keller DW et al: Community outbreak of Legionnaires' disease: an investigation confirming the potential for cooling towers to transmit Legionella species. Clin Infect Dis 1996;22:257.

Klein NC, Cunha BA: Treatment of Legionnaires' disease. Semin Respir Infect 1998;13:140.

Koide M et al: Relation between the polymerase chain reaction and the indirect fluorescent antibody method in thediagnosis of Legionella infection. Clin Infect Dis 1996;23:656Lin YS et al: Disinfection of water distribution systems for Legionella. Semin Respir Infect 1998;13:147.

Liu Z et al: Intermittent use of copper-silver ionization for Legionella control in water distribution systems: a potential option in buildings housing individuals at low risk of infection. Clin Infect Dis 1998;26:138.

Rutledge R et al: Acute Physiology and Chronic Health Evaluation (APACHE II) score and outcome in the surgical intensive care unit: an analysis of multiple intervention and outcome variables in 1,238 patients. Crit Care Med 1991;19(8):1048.

Sopena N et al: Comparative study of the clinical presentation of Legionella pneumonia and other community-acquired pneumonias. Chest 1998;113:1195.