Legionella

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Chapter 200 Legionella

Lucy S. Tompkins

Legionellosis comprises Legionnaires disease (Legionella pneumonia), other invasive extrapulmonary Legionella infections, and an acute flulike illness known as Pontiac fever. In contrast to the syndromes associated with invasive disease, Pontiac fever is a self-limiting illness that develops after aerosol exposure and may represent a toxic or hypersensitivity response to Legionella.

Etiology

Legionellaceae are aerobic, non–spore-forming, unencapsulated gram-negative bacilli that stain poorly with Gram stain when performed on smears from clinical specimens. Microorganisms in tissue can be better visualized with the Gimenez or silver stains (Dieterle or Warthin-Starry). Stained smears of Legionella pneumophila taken from colonial growth resemble Pseudomonas. Unlike other Legionella species, L. micdadei stains acid fast. Although >30 species of the genus have now been identified, the majority (90%) of clinical infections are caused by L. pneumophila, and most of the remainder are caused by L. micdadei, L. bozemanii, L. dumoffii, and L. longbeachae.

The organisms are fastidious and require L-cysteine, ferric ion, and α-keto acids for growth. Colonies develop within 3-5 days on buffered charcoal yeast extract agar, which may contain selected antibiotics to inhibit overgrowth by other microorganisms; Legionella rarely grows on routine laboratory media.

Epidemiology

The environmental reservoir of Legionella in nature is fresh water (lakes, streams, thermally polluted waters, potable water), and invasive pneumonia (Legionnaires disease) is related to exposure to potable water or to aerosols containing the bacteria. Growth of Legionella occurs more readily in warm water, and exposure to warm water sources is an important risk factor for disease. Legionella organisms are facultative intracellular parasites and grow inside protozoans present in biofilms consisting of organic and inorganic material found in plumbing and water storage tanks and various other bacterial species. Epidemic and sporadic cases of community-acquired Legionnaires disease can be attributed to potable water in the local environment of the patient. Risk factors for acquisition of sporadic community-acquired pneumonia include exposure to cooling towers, nonmunicipal water supply, residential plumbing repairs, and lower water heater temperatures, which facilitate growth of bacteria or lead to release of a bolus of biofilm containing Legionella into potable water. The mode of transmission may be by way of inhalation of aerosols or by microaspiration. Outbreaks of Legionnaires disease have been associated with protozoans in the implicated water source; replication within these eukaryotic cells presumably amplifies and maintains Legionella within the potable water distribution system or in cooling towers. Outbreaks of community-acquired pneumonia and some nosocomial outbreaks have been linked to common sources, including potable hot water heaters, evaporative condensers cooling towers, whirlpool baths, humidifiers, and nebulizers. Travel-associated Legionnaires disease and Pontiac fever are increasingly recognized in major outbreaks.

Hospital-acquired infections are most often linked to potable water. Exposure may occur through 3 general mechanisms: (1) inhalation of contaminated water vapor through artificial ventilation; (2) aspiration of ingested microorganisms, including those in gastric feedings, that are mixed with contaminated tap water; and (3) inhalation of aerosols from showers and sinks. Extrapulmonary legionellosis may occur through topical application of contaminated tap water into surgical or traumatic wounds. In contrast to Legionnaires disease, Pontiac fever outbreaks have occurred through exposure to aerosols from whirlpool baths, ultrasonic humidifiers, and ventilation systems.

The incidence of community-acquired Legionnaires disease caused by L. pneumophila occurring sporadically in adults is estimated at 7-20 cases/100,000 per year and demonstrates geographic differences. Legionella infections are reported most frequently in fall and summer, and recent studies show an association with total monthly rainfall and humidity. Approximately 0.5-5.0% of those exposed to a common source develop pneumonia, whereas the attack rate in Pontiac fever outbreaks is very high (85-100%). In 1 large community-based study of adults, Legionella was associated with 3% of pneumonia cases. Taken together, Mycoplasma pneumoniae, Chlamydophila pneumoniae, and L. pneumophila account for 10-38% of all community-acquired pneumonia, and therefore the current clinical guidelines for community-acquired pneumonia in adults recommend empirical therapy with macrolides or quinolones. Acquisition of antibodies to L. pneumophila in healthy children occurs progressively over time, although these antibodies presumably reflect subclinical infection or mild respiratory disease or antibodies that cross react with other bacterial species. Community-acquired Legionnaires disease in children is increasingly reported (1.7% of reported cases), and most cases occur in children age 15-19 yr, followed by infants age <1 yr. The incidence in infants is reported to be 0.11/100,000. It is likely that legionellosis is significantly underreported, both in children and adults.

As estimated by seroconversion to L. pneumophila among children hospitalized with pneumonia, the Legionnaires disease rate is quite low. Most nosocomial infections have been reported as case reports; therefore, the true incidence of disease in children is unknown. Nosocomial infection rates in adults are difficult to determine, because many hospital laboratories do not attempt to isolate Legionella by culture. Hospital-acquired legionellosis in children is associated with clinical risk factors and with environmental exposure.

Pathogenesis

Although Legionella can be grown on artificial media, the intracellular environment of eukaryotic cells provides the definitive site of growth. Legionella organisms are facultative intracellular parasites of eukaryotic cells. In nature, Legionella replicate within protozoans found in fresh water. In humans, the main target cell for Legionella is the alveolar macrophage, although other cell types may also be invaded. After entry, virulent strains of L. pneumophila stimulate the formation of a special phagosome that permits bacterial replication to proceed. The phagosome is composed of components of the endoplasmic reticulum and escapes the degradative lysosomal pathway. Growth in macrophages occurs to the point of cell death, followed by reinfection of new cells, until these cells are activated and can subsequently kill intracellular microorganisms. Acute, severe infection of the lung provokes an acute inflammatory response and necrosis; early on, more bacteria are found in extracellular spaces as a result of intracellular replication, lysis, and release of bacteria. Subsequently, macrophage activation and other immune responses produce intense infiltration of tissue by macrophages that contain intracellular bacteria, ultimately leading to control of bacterial replication and killing. Corticosteroid therapy poses a high risk for infection by interfering with T-cell and macrophage function. Although community-acquired Legionnaires disease may occur in healthy, immunocompetent patients without other co-morbid conditions, those who have defects in cellular-mediated immunity are at high risk for infection. As in other diseases caused by facultative intracellular microorganisms, the outcome is critically dependent on the specific and nonspecific immune responses of the host, particularly macrophage and T-cell responses.

Clinical Manifestations

Legionnaires disease was originally believed to cause atypical pneumonia that was associated with extrapulmonary signs and symptoms including diarrhea, hyponatremia, hypophosphatemia, abnormal results of liver function tests, confusion, and renal dysfunction. Although a subset of patients may exhibit these classic manifestations, Legionella infection typically causes pneumonia that is indistinguishable from disease produced by other infectious agents. Fever, cough, and chest pain are common presenting symptoms; the cough may be productive of purulent sputum or may be nonproductive. Although the classic chest radiographic appearance demonstrates rapidly progressive alveolar filling infiltrates, in usual cases of pneumonia the chest radiographic appearance is widely variable, appearing as tumor-like shadows, evidence of nodular infiltrates, unilateral or bilateral infiltrates, or cavitation, although cavitation is rarely seen in immunocompetent patients. This picture overlaps substantially with disease caused by Streptococcus pneumoniae. Although pleural effusion is less commonly associated with Legionnaires disease, its frequency varies so widely that neither the presence nor absence of effusion is helpful in differential diagnosis. If present, pleural fluid should be obtained for culture.

A few clinical features may help to differentiate Legionella pneumonia from other causes. Legionella pneumonia produces an acute-onset febrile illness, the radiograph shows alveolar filling infiltrates, and usually there is no clinical response to broad-spectrum β-lactam (penicillins and cephalosporins) or aminoglycoside antibiotics.

Concomitant infection with other pathogens, including Mycoplasma pneumoniae and C. pneumoniae, occurs in 5-10% of cases of Legionnaires disease; therefore, detection of another potential pulmonary pathogen does not preclude the diagnosis of legionellosis.

Reports of nosocomial Legionella pneumonia in children demonstrate that rapid onset, temperature greater than 38.5°C, cough, pleuritic chest pain, and dyspnea are present in most. Abdominal pain, headache, and diarrhea are also common. Chest radiographs reveal lobar consolidations or diffuse bilateral infiltrates, and pleural effusions are noted. Symptoms do not respond to treatment with β-lactam antibiotics or aminoglycosides.

Risk factors for Legionnaires disease in adults include chronic diseases of the lung (smoking, bronchitis), older age, diabetes and renal failure, immunosuppression associated with organ transplantation, corticosteroid therapy, and episodes of aspiration. In surveys of community-acquired infection, a significant number of adults have no identified risk factors. The number of reported cases of community-acquired Legionnaires disease in children is small. Among these, immunocompromised status, especially corticosteroid treatment, coupled with exposure to contaminated potable water is the major risk factor. Infection in a few children with chronic pulmonary disease without immune deficiency has also been reported, but infection in children lacking any risk factors is very uncommon. The modes of transmission of community-acquired disease in children include exposure to mists, fresh water, water coolers, and other aerosol-generating apparatuses. Nosocomial Legionella infection occurs more frequently than community-acquired disease in children and occurs most commonly in those who are immunocompromised, although Legionnaires disease has been seen in immunocompetent children who are postoperative and receiving artificial ventilation. The modes of acquisition include microaspiration, frequently associated with nasogastric tubes, and aerosol inhalation. Bronchopulmonary Legionella infections occur in patients with cystic fibrosis and have been associated with aerosol therapy or mist tents. Legionnaires disease is also reported in pediatric patients with asthma and tracheal stenosis. Chronic corticosteroid therapy for asthma is a reported risk factor for Legionella infections in children. Molecular fingerprinting of strains has demonstrated that potable water serves as the major reservoir and source of nosocomial infection.

Pontiac fever in adults and children is characterized by high fever, myalgia, headache, and extreme debilitation, lasting for a few days. Cough, breathlessness, diarrhea, confusion, and chest pain may occur, but there is no evidence for invasive infection. The disease is self-limited without sequelae. Virtually all exposed individuals seroconvert to Legionella antigens. A very large outbreak in Scotland that affected 35 children was attributed to L. micdadei, which was isolated from a whirlpool spa. The onset of illness was 1-7 days (median 3 days), and all exposed children developed significant titers of specific antibodies to L. micdadei. The pathogenesis of Pontiac fever is not known. In the absence of evidence of true infection, the most likely hypothesis is that this syndrome is caused by a toxic or hypersensitivity reaction to microbial, or protozoan, antigens.

Diagnosis

Culture of Legionella from sputum, other respiratory tract specimens, blood, or tissue is the gold standard against which indirect methods of detection should be compared. Specimens obtained from the respiratory tract that are contaminated with oral flora must be treated and processed to reduce contaminants and plated onto selective media. Because these are costly and time-consuming methods, many laboratories do not process specimens for culture. The urinary antigen assay that detects L. pneumophila serogroup I has revolutionized the diagnosis of Legionella infection and has 80% sensitivity and 99% specificity. The assay is a useful method in the prompt diagnosis of Legionnaires disease caused by this serogroup, which accounts for the majority of symptomatic infections. In the USA, this test is frequently used because it is widely available in reference laboratories. Other methods, including direct immunofluorescence, have low sensitivity and are generally not employed. Retrospective diagnosis can be made serologically using the enzyme-linked immunosorbent assay or enzyme immunoassay to detect specific antibody production. Seroconversion may not occur for several weeks after onset of infection, and the available serologic assays do not detect all strains of L. pneumophila or all species. In view of the low sensitivity of direct detection and the slow growth of the microorganism in culture, the diagnosis of legionellosis should be pursued actively when there is suggestive clinical evidence, including the lack of response to usual antibiotics, even when results of other laboratory studies are negative.

Treatment

In community-acquired pneumonia in adults who are hospitalized, guidelines recommend empirical treatment with a broad-spectrum cephalosporin plus a macrolide or quinolone in order to treat atypical microorganisms (Legionella, Chlamydophilia pneumoniae, Mycoplasma pneumoniae). Evidence based guidelines for management of community acquired pneumonia in children do not yet include Legionella in the differential diagnosis or empiric treatment recommendations. Effective treatment of Legionnaires disease is based in part on the intracellular concentration of antibiotics. Erythromycin (40 mg/kg/day PO or IV) with or without rifampin (15 mg/kg/day) was considered effective therapy many years ago. Azithromycin (10 mg/kg on day 1, not to exceed 500 mg/day, and then 5 mg/kg daily for 4 days PO) and clarithromycin (15 mg/kg/day PO) and the quinolones (ciprofloxacin and levofloxacin) have generally replaced erythromycin as therapy for patients with diagnosed Legionella infection. Quinolones are not approved for children <18 yr of age. In serious infections or in high-risk patients, parenteral therapy is recommended initially; a switch to oral therapy can be made when a patient has had a clinical response. The duration of oral azithromycin therapy for Legionnaires disease in adults is 4 days, although therapy is usually continued for 10-14 days in more seriously ill or immunocompromised patients. Acute reversible hearing loss is associated with high-dose parenteral macrolide therapy. Treatment of extrapulmonary infections, including prosthetic valve endocarditis and sternal wound infections, may require prolonged therapy. Trimethoprim-sulfamethoxazole (TMP-SMZ; 15 mg TMP/kg/day and 75 mg SMZ/kg/day) has been used as an alternative.

Prognosis

The mortality rate for community-acquired Legionnaires disease in adults who are hospitalized is approximately 15% but may exceed 50% in immunocompromised patients. The prognosis depends on underlying host factors and possibly on the duration of illness before appropriate therapy is begun. Despite appropriate antibiotic therapy, patients may succumb to respiratory complications, such as acute respiratory distress syndrome, associated with artificial ventilation and intubation. A high mortality rate is noted in case reports of premature infants and children, virtually all of whom have been immunocompromised. Delay in diagnosis is also associated with increased mortality. Therefore, Legionella should be considered in the differential diagnosis of both community-acquired and nosocomial pneumonia in children.

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