Legionella Species

Pathogenesis And Epidemiology

Legionella species are facultative intracellular pathogens capable of surviving and multiplying both in mammalian macrophages and monocytes (e.g., in the alveolar spaces) to cause human infection and in free-living amebas to survive in the environment. After internalization of bacteria in an antibody-independent process, the bacterial phagosome becomes covered by smooth vesicles that likely originate from the endoplasmic reticulum. This results in evasion of the endocytic pathways and avoidance of phagosomal acidification and fusion with lysosomes that otherwise would result in bacterial digestion. The Dot/Icm type IV secretion system encoded by genes in L. pneumophila is critical for evasion of killing, intracellular multiplication, and virulence. The pathogenesis of Pontiac fever may involve a host response to endotoxin from lipopolysaccharide of Legionella or other gram-negative bacteria without multiplication of Legionella in the host.

L. pneumophila is rarely transmitted from human to human. Infection usually results from the inhalation or aspiration of contaminated aerosol from environmental or aquatic sources. Legionella spp. naturally occur in freshwater habitats such as lakes, rivers, and ground water. From these sources, organisms gain entry into water systems of buildings, including hospitals. These bacteria grow optimally at 35°C−37°C but thrive in warm water (temperature range, 30°C−54°C) and generally are killed at temperatures above 60°C. ^, Legionella have been found in cooling towers and evaporative condensers, water heaters, plumbing systems, shower heads, respiratory therapy devices, air conditioners, whirlpool spas, and humidifiers. Survival and persistence of these nutritionally fastidious organisms in the environment make it likely that protozoa, particularly amebas, act as reservoirs in water sources. Legionnaires’ disease due to L. longbeachae has been associated with exposure to potting soil. ^,

Nosocomial infections and hospital outbreaks due to L. pneumophila or other Legionella spp. have occurred. The source generally is water, most commonly the hot water supply. Strains associated with nosocomial infection can colonize water supplies over long periods. Community-acquired outbreaks of legionnaires’ disease almost always are due to L. pneumophila, and such outbreaks frequently have been associated with a nearby cooling tower, as proved by isolation of the same strain as confirmed by DNA-based molecular typing from infected patients, the cooling tower, and aerosols from the cooling tower. In addition, outbreaks have been associated with other sources of water, including whirlpool baths, decorative fountains, and ultrasonic mist machines used to humidify fresh produce in a grocery store. Sporadic cases of legionellosis have been linked to home water heaters, particularly electric water heaters. In 40% of 20 sporadic cases studied, isolates identical to the infecting isolates were found in the potable water at the patient’s home or workplace or at an ambulatory medical facility visited by the patient.

Most cases of legionnaires’ disease occur in susceptible elderly or middle-aged adults. Based on the outbreak in Philadelphia, the incubation period is estimated to range from 2–10 days, with a mean of approximately 7 days. Risk factors for infection in adults include cigarette smoking, alcoholism, chronic lung or heart disease, and treatment with high doses of corticosteroids or other immunosuppressive drugs, including those given to prevent rejection of transplanted organs, and tumor necrosis factor antagonists. ^{, , ,} Legionellosis has been reported in adults with HIV infection, but it is unclear if these patients are at increased risk for Legionella pneumomia. L. pneumophila has caused pneumonia in patients infected with 2009 pandemic influenza A:H1N1. In the US, higher numbers of cases are reported during the summer months.

Legionellosis remains a rarely reported infection in children. Despite a 53% increase in rate of legionellosis from 2003–2012, only 16 cases (0.3%) of legionellosis reported to the Centers for Disease Control and Prevention (CDC) in 2017 were patients younger than 20 years. Legionella bacteria may be responsible for 1%–5% of episodes of pneumonia in immunocompetent children. Infection is being recognized increasingly in neonates related to healthcare-associated contaminated water sources that include potable water for preparing infant formula, water tubs for water births, and humidifiers in nurseries. In pediatric legionellosis, risk factors for serious infection are neonatal age group, immune compromise as a result of cancer or organ transplantation and their treatments, corticosteroid or adrenocorticotropic hormone therapy, primary immunodeficiency, or underlying lung disease ^, ( Table 177.1 ). Approximately 40% of cases of legionellosis in children reported to the CDC are healthcare-associated, as is the majority of published cases, but the latter may represent a reporting bias. In a review of legionellosis in children, the overall mortality rate was 33%, with the highest mortality rates in immunosuppressed children and children <1 year.

Clinical Manifestations

Legionella infection can be classified into the following four categories: (1) pneumonia; (2) subclinical infection; (3) nonpneumonic disease, referred to as Pontiac fever ; and (4) extrapulmonary infection. The most important clinical infection in children and adults is pneumonia, which manifests as an acute febrile illness with cough and often with respiratory distress. Initially, nonpulmonary symptoms can predominate and include chills, abdominal pain, myalgia, confusion, malaise, anorexia, and diarrhea. Extrapulmonary manifestations, particularly confusion and diarrhea, are common, but the combination of pulmonary and extrapulmonary clinical findings is not sufficiently specific to differentiate Legionella pneumonia from community-acquired or healthcare-associated pneumonia of other etiologies. The nonproductive cough suggests atypical pneumonia, which requires differentiation from Mycoplasma pneumoniae, viral, and Chlamydophila pneumoniae infections.

Chest radiograph shows patchy alveolar rather than interstitial infiltrates. In most cases, pulmonary disease is unilateral. Pulmonary nodules, with or without cavitation, or cavitating pneumonia can develop, particularly in immunocompromised hosts. ^{, , ,} Pleural effusion occurs, with an incidence similar to that of other bacterial pneumonias. Progressive respiratory distress and respiratory failure can develop over a period of several days. Co-pathogens are recovered from respiratory tract specimens in only a few cases. ^{, ,} Legionella infection causing fever and pulmonary nodules is relatively common in adult renal or cardiac transplant recipients and occurs within several weeks of transplantation. Alternatively, these patients may have prodromal symptoms of malaise, myalgia, and headache followed by an abrupt onset of symptoms indicative of pneumonia: dyspnea, cough, and pleuritic chest pain. ^,

Serious or fatal Legionella pneumonia is being reported increasingly in neonates. Many infants were born at term and manifested septicemia, pneumonia, or both, but several were born prematurely or had congenital heart disease. An outbreak of 11 cases of Legionella pneumonia in term neonates from a single nursery included 3 fatal cases; evaluation implicated a Legionella -contaminated humidifier in the nursery. Cases of L. pneumophila pneumonia with 2 fatalities have been reported after water birth at home or in a hospital birthing pool. A 40-day-old infant was hospitalized with severe L. pneumophila pneumonia after exposure to bathing using reused and reheated water. The mortality rate of neonatal legionellosis is high, and survival correlates with macrolide/azalide treatment.

Infections in immunocompromised hosts and neonates represent the most severe form of pediatric disease. At the other end of the clinical spectrum, community-acquired pneumonia due to Legionella in healthy children usually resolves without effective antibiotic therapy. Subclinical infection also occurs, as evidenced by increasing seroprevalence with age, ^{, ,} and by antibody rises in the absence of recognized episodes of pneumonia.

Epidemic, nonpneumonic disease, also known as Pontiac fever, is characterized by a high attack rate in exposed individuals. ^, After a short incubation period of 12–48 hours, infection is characterized by the abrupt onset of an influenza-like illness without pneumonia. Prominent signs and symptoms include fever, malaise, myalgia, and cough. The illness is self-limited, although a cluster of cases with respiratory compromise is described. The initial outbreak of Pontiac fever was associated with L. pneumophila serogroup 1, but other Legionella spp. have been associated with outbreaks.

In adults, a spectrum of extrapulmonary Legionella infections have been documented, including sinusitis, perirectal abscess, pyelonephritis, peritonitis, pancreatitis, pericarditis, panniculitis, and endocarditis. In children, extrapulmonary sites of infection in the liver, spleen, and brain have been documented at autopsy. ^, A febrile 2-month-old male with severe combined immune deficiency had hepatic lesions with bacilli visualized in biopsy material and detection of L. pneumophila with PCR amplification of 16S RNA. Localized extrapulmonary infection, such as infection of postoperative wounds after wound irrigation with Legionella -contaminated tap water, also can occur.

Laboratory Diagnosis

Nonspecific laboratory abnormalities in legionellosis can include leukocytosis with a left shift of neutrophils, hyponatremia, proteinuria, or elevated serum concentrations of hepatic enzymes. In adults, hyponatremia is significantly more frequent in the initial stage of legionellosis than in pneumonia of other etiologies.

A specific laboratory diagnosis can be established by (1) isolation of the organism in culture; (2) detection of organisms, bacterial antigens, or bacterial nucleic acids in clinical specimens; or (3) documentation of a serologic response to the organism. ^, Although culture is the gold standard for diagnosis, only ∼5% of diagnoses are based on culture, and most diagnoses are based on urine antigen testing that primarily detects L. pneumophila serogroup 1. Compared with culture, the common use of urine antigen assays for diagnosis may have biased the distribution of Legionella spp. and serogroups causing disease. A clue to suspect legionellosis is the presence of characteristic neutrophilic inflammatory response without bacteria on a gram-stained preparation of lower respiratory tract secretions because Legionella stain poorly with Gram stain. However, the failure to produce sputum or absence of neutrophils in specimens does not exclude the diagnosis. Microscopic screening protocols of sputa (to evaluate for the presence of leukocytes as a measure of adequacy of the specimen for bacterial culture) are not useful for selecting samples to be cultured for Legionella. Legionella spp., particularly L. micdadei, may stain with acid-fast stain ; modified acid-fast stain can be useful.