Legionella Infection

Legionnaires disease (LD) was recognized in 1976 after an outbreak of pneumonia at an American Legion convention in Philadelphia. Soon after, the etiologic agent was identified as a fastidious gram-negative bacillus and named Legionella pneumophila. Although several other species of the genus Legionella were subsequently identified, L pneumophila is the most frequent cause of human legionellosis and a relatively common cause of community-acquired and nosocomial pneumonia in adults. In children, L pneumophila is also an important, although relatively uncommon, cause of pneumonia.

Legionellosis refers to 2 distinct clinical syndromes: Legionnaires disease, which most often manifests as severe pneumonia accompanied by multisystemic disease, and Pontiac fever, which is an acute, febrile, self-limited, viral-like illness.[1, 2]

Legionella organisms are aerobic, motile, and nutritionally fastidious pleomorphic gram-negative rods. The growth of the organisms depends on the presence of L-cysteine and iron in special media. The organism has been isolated in natural aquatic habitats (freshwater streams and lakes, water reservoirs) and artificial sources (cooling towers, potable water distribution systems). Freshwater amoebae appear to be the natural reservoir for the organisms.[3] Optimal growth temperature is 28-40°C; organisms are dormant below 20°C and are killed at temperatures above 60°C.

Although more than 70 Legionella serogroups have been identified among 50 species, L pneumophila causes most legionellosis. L pneumophila serogroup 1 alone is responsible for 70-90% of cases in adults. In a pediatric series, L pneumophila serogroup 1 accounted for only 48% of cases, serogroup 6 accounted for 33%, and the remaining cases involved other serotypes and species. Legionella micdadei and L dumoffii are the second and third most common species to cause Legionnaires disease in children, respectively.[4]

Transmission occurs by means of aerosolization or aspiration of water contaminated with Legionella organisms. Wounds may become infected after contact with contaminated water. The following systems are linked to transmission of Legionella organisms:

• Cooling towers

• Humidifiers

• Respiratory therapy equipment

• Whirlpool spas[5]

• Evaporative condensers

• Potable water distribution systems (eg, showers, faucets)[1, 6]

Most nosocomial infections and hospital outbreaks have been linked to contaminated hot water supply. However, contamination of cold-water supply has also been reported.[7] Nosocomial Legionnaires disease associated with water birth is reported in a few neonates, but the risk appears to be low.[8, 9] Person-to-person transmission has not been demonstrated.

Mucociliary action clears Legionella organisms are cleared from the upper respiratory tract. Any process that compromises mucociliary clearance (eg, smoking tobacco) increases risk of infection. Virulence varies between strains of L pneumophila. For example, some strains can adhere to the respiratory epithelial cells via pili, whereas strains with a mutated gene that encodes for the pili show reduced adherence in vitro.[10]

Organisms that reach the alveoli undergo phagocytosis by the alveolar macrophages but are not actively killed. Macrophages may actually support the growth of Legionella organisms. The bacteria multiply intracellularly until the cell ruptures. Liberated bacteria then infect other macrophages. Additional virulence factors include genes that potentiate infection of macrophages and inhibit phagosomal fusion, allowing intracellular growth.[11]

Cell-mediated immunity appears to be the primary host defense mechanism against Legionella infection. Activation of macrophages produces cytokines that regulate antimicrobial activity against Legionella organisms. Individuals with certain deficiencies in cell-mediated immunity are at increased risk for legionellosis.[4] Complicated cases have been reported in children treated with steroids.[12, 13]

The role of neutrophils in host defense against Legionella infection is unclear; neutropenia does not appear to predispose patients to legionellosis. Humoral immunity may play a secondary role.

Once infection is established, Legionella organisms cause an acute fibrinopurulent pneumonia with alveolitis and bronchiolitis. In addition to the lungs, Legionella organisms may infect the lymph nodes, brain, kidney, liver, spleen, bone marrow, and myocardium.[14]

Frequency

United States

An estimated 8000-18,000 cases of Legionnaires disease are reported in the United States each year. Most cases are not reported. More than 80% of cases are sporadic throughout the year, and the rest occur in outbreaks during the summer and early fall.

In adults, legionellosis causes 2-15% of all cases of community-acquired pneumonia (CAP) requiring hospitalization. Legionellosis is the second most frequent cause of severe pneumonia requiring ICU admission. Estimates for the proportion of nosocomial pneumonias caused by Legionella species widely vary, but the numbers probably represent an underestimation because most hospitals only test for serogroup 1.[15]

Serologic studies suggest that children are frequently exposed to Legionella species. However, this organism is a rare cause of acute respiratory disease in the pediatric population, with only scattered case reports available to determine its natural history in this age group. Moreover, it is not commonly seen in immunocompromised pediatric patients.[16]

The estimated frequency of Legionella pneumonia cases that require hospitalization is approximately 1-5%.[4, 17] The reported annual incidence of both CAPs and nosocomial pneumonias caused by Legionella species has increased. Most reported cases have involved neonates, children who are immunocompromised[4] (including those with prolonged courses of corticosteroids[12, 13] ), and children with underlying respiratory disease.[18]

The CDC reported 2,809 cases of Legionnaires’ disease in 2015, of which 3% were confirmed to be associated with a health-care facility and 17% were possibly associated. Among the definite health care-associated cases, 88% occurred in those 60 years of age and older. The fatality rate was 25% in definite health care- associated cases and 10% for the possibly associated cases.[19]  

A study reviewed case records to determine the epidemiology of and risk factors for the 1,449 cases reported to the New York City Department of Health and Mental Hygiene from 2002–2011. Incidence of Legionnaires’ disease in the city of New York increased 230% from 2002 to 2009 and followed a socioeconomic gradient, with highest incidence occurring in the highest poverty areas. The study also added that further studies are required to clarify whether neighborhood-level poverty and work in some occupations represent risk factors for this disease.[20, 21]

According to the CDC, passive surveillance for legionellosis in the United States showed a 249% increase in crude incidence during 2000-2011. In 2011, the Active Bacterial Core (ABC) surveillance system was instituted, Overall rates were similar to the passive system however, ABC’s data showed that during 2011-2013, 44% of patients with legionellosis required intensive care, and 9% died.[22, 23]

In 2016, a total of 6,141 of Legionella cases were reported, a 4.5-fold increase since 2000.[40, 41]

International

Legionnaires disease is believed to have worldwide distribution and to cause 2-15% of all CAP cases requiring hospitalization.

Mortality/Morbidity

The mortality rate in patients with Legionnaires disease is 5-80%, depending on certain risk factors. The factors associated with high mortality rates include the following:

• Age (especially those younger than 1 y and elderly patients)

• Predisposing underlying conditions, such as chronic lung disease, immunodeficiency, malignancies, end-stage renal disease, and diabetes mellitus

• Nosocomial acquisition

• Delayed initiation of specific antimicrobial therapy

Sex

Males are more than twice as likely as females to develop Legionnaires disease.

Age

Middle-aged and older adults have a high risk of developing Legionnaires disease while it is rare in young adults and children. Among children, more than one third of reported cases have occurred in infants younger than 1 year.

Pneumonia is the predominant clinical manifestation of Legionnaires disease (LD). After an incubation period of 2-10 days, patients typically develop the following nonspecific symptoms:

• Fever

• Weakness

• Fatigue

• Malaise

• Myalgia

• Chills

Respiratory symptoms may not be present initially but develop as the disease progresses. Almost all patients develop a cough, which is initially dry and nonproductive, but may become productive, with purulent sputum and, (in rare cases) hemoptysis. Patients may experience chest pain.

Neurologic and GI symptoms are usually prominent. Neurologic complaints may include the following:

• Headache

• Lethargy

• Confusion

• Cerebellar ataxia

• Agitation

• Stupor

Common GI symptoms include diarrhea (watery and nonbloody), nausea, vomiting, and abdominal pain.[24]

In neonates, Legionnaires disease can manifest as septicemia and/or pneumonia with a fulminant course, often diagnosed at autopsy.

Extrapulmonary legionellosis is rare; the most common site of extrapulmonary infection in adults is the heart. In children, extrapulmonary sites may include the liver, spleen, brain, and lymph nodes.[25] Manifestations of extrapulmonary legionellosis may include the following:

• Sinusitis

• Cellulitis

• Peritonitis

• Pyelonephritis

• Pancreatitis

• Wound infection

• Lymphadenopathy

• Prosthetic valve endocarditis

• Myocarditis

• Pericarditis

• Postcardiotomy syndrome

Pontiac fever is an influenzalike illness, typically with an abrupt onset. The incubation period is 24-48 hours. Prominent symptoms include fever, malaise, myalgia, cough, and headache. Pontiac fever tends to occur in outbreaks, and the infection rate is greater than 90%. The disease is self-limiting, persisting for approximately 1 week.

The severity of illness at presentation varies from mild nonspecific findings to profound respiratory and/or multiorgan failure.

• Fever is typically present (98%). Temperatures exceeding 40°C occur in 20-60% of patients. The occurrence of bradycardia relative to fever has been overemphasized, but it may occur in patients with advanced pneumonia.[24]

• Hypotension has been reported in 17% of patients with community-acquired pneumonia(CAP).

• Lung examination reveals rales and signs of consolidation late in the disease course.

• In patients with extrapulmonary legionellosis, physical findings relate to the involved organs.

• Manifestations in children who are immunocompromised appear similar to manifestations in adults. However, in neonates, signs of sepsis with multisystemic involvement appear to be more prominent. Progression to respiratory failure is very rapid, and the disease is likely to be fatal.[26]

In adults, recognized risk factors for legionellosis include the following:

• Cigarette smoking

• Alcoholism

• Chronic lung disease

• Chronic heart disease

• Immunosuppression (eg, malignancies, immunosuppressive therapy such as corticosteroids, human immunodeficiency virus [HIV], acquired immunodeficiency syndrome [AIDS])

• End-stage renal disease

• Diabetes mellitus

• Advanced age

Surgery, especially for head and neck malignancies and for solid organ transplantations, predisposes patients to nosocomial infections.

Risk factors for children are less well defined than they are in adults. Apparent predisposing factors, from reported cases, include the following:[4, 8]

• Immunodeficiency (primary or secondary) - Malignancies, severe combined immunodeficiency, chronic granulomatous disease, organ transplantation, and treatment with corticosteroids

• Preexisting respiratory disease - Acute or chronic lung disease, asthma, tracheal stenosis, and tracheobronchomalacia

• Young age (especially neonates)

• Water births

Rare cases of legionellosis are reported in children who are immunocompetent and who lack predisposing conditions.

General laboratory testing in patients with Legionnaires disease (LD) reveals several nonspecific abnormalities.[11]

Hematologic studies may reveal leukocytosis or leukopenia with left shift, thrombocytosis, or thrombocytopenia with disseminated intravascular coagulopathy (DIC).

Erythrocyte sedimentation rate and C-reactive protein levels are elevated.

Chemistry studies may reveal elevated aminotransferase levels, hyponatremia (more commonly associated with Legionnaires disease than with other pneumonias in adults), hypophosphatemia, elevated creatine kinase levels, and other abnormalities. These abnormalities are not as common in children as they are in adults.

Urinalysis commonly reveals proteinuria and hematuria.

Diagnosis cannot be excluded when one or more of the following results are negative (a combination of tests increases the probability of confirming the diagnosis):

• Urinary antigen test

  • This is the preferred initial test for Legionnaires disease.

  • The urine antigen test is a rapid, relatively inexpensive, and practical test for the detection of L pneumophila antigen excreted in the urine or present in pleural fluid.

  • The primary disadvantage of urinary antigen testing is that it detects only L pneumophila serogroup 1. However, because this serogroup causes most cases of Legionnaires disease, the test is recommended strongly as part of the workup.

  • Urine antigen testing has 70% sensitivity and approaches 100% specificity.[16]

  • Sensitivity improves if urine samples are concentrated by ultrafiltration and obtained within 7 days of the onset of pneumonia.

  • Test results may remain positive for weeks, even after appropriate antibiotic therapy.

• Gram stains and cultures of sputum, lower respiratory tract secretions, tissue, or blood

  • In children, the best samples are obtained by bronchoscopy.[16] Samples obtained by bronchoalveolar lavage (BAL) are better than those from bronchial washings. In addition, fluid or pus from normally sterile sites (eg, cerebrospinal fluid [CSF], pleural fluid, peritoneal fluid) should be cultured.

  • Gram stain may show small, pleomorphic, weakly staining, gram-negative bacilli or no organisms with a large number of polymorphonuclear leukocytes. L micdadei may stain with acid-fast stain.

  • Culturing, considered the criterion standard, requires the use of special media (buffered charcoal yeast extract [BCYE] agar with L-cysteine and ferric ions to support growth, antibiotics to prevent overgrowth of other organisms, and dyes to impart a distinctive color to the organisms).

  • Specialized techniques may require 2-7 days to isolate Legionella organisms. Routine sputum cultures provide 80% sensitivity and 100% specificity. Culture from BAL specimens has a sensitivity of 90% or greater.

  • Since co-infection with other pathogens often occurs, isolation of other pathogens does not exclude the possibility of concomitant Legionella infection.

  • Legionella species can also be isolated from blood cultures; yield can be optimized by blind subculture (before sample results turn positive) onto BCYE agar from radiometric culture bottles.

• Direct fluorescent antibody staining for Legionella species

  • Direct fluorescent antibody (DFA) staining is a rapid test that can be performed on respiratory samples and tissue and requires only 2-4 hours for results.

  • DFA using a monoclonal antibody is highly specific.

  • A cross-reaction with Pseudomonas species rarely occurs, and patients with tularemia may have a false-positive DFA result for Legionella organisms.

  • DFA staining has a low sensitivity of 33-70%.[16] Sensitivity depends on the specimen quality, the number of organisms present, and the experience of the technician. A negative DFA result does not exclude Legionella infection.

• Serologic tests for Legionella antibodies

  • Serologic assays are not helpful in clinical decision making but are valuable for epidemiologic studies.

  • Confirmation of legionellosis requires a 4-fold or greater rise in antibody titer in paired acute and convalescent indirect fluorescent antibody (IFA) tests obtained 4-8 weeks apart.

  • A single elevated titer greater than 1:256 does not confirm a diagnosis of Legionnaires disease; titers of 1:256 or more are found in 1-16% of healthy adults and children.

• Polymerase chain reaction (PCR) test

  • PCR assays to detect Legionella DNA in urine, BAL fluid, and serum samples have been used. Although commercial kits are available, the test is not widely used.

  • In adults, these assays appear highly specific but are no more sensitive than culture.

  • Published studies of Legionella diagnosis using PCR assays in children are limited but anecdotal cases continue to be reported.[12, 13, 27]

See the list below:

• Pneumonia is the predominant clinical syndrome of Legionnaires disease. Chest radiography findings vary and are nonspecific and indistinguishable from those observed with other pneumonias.

• Although initial chest radiography findings may be normal, especially in patients with nosocomial disease, the usual progression of findings on serial studies is from patchy areas or nodular appearance to multilobar, almost homogeneous, infiltrates.[17, 28]

• Unilateral involvement is more common than bilateral involvement. Purely interstitial infiltrates are rare. Pleural effusion, present in at least one third of patients, may be the only abnormality. In adults, cavitation is more common in patients who are immunocompromised but has been described both in immunocompromised and immunocompetent children.[29, 30, 31]

• Radiographic findings usually progress despite appropriate antibiotic therapy; infiltrates may take as long as 4 months to completely resolve. Permanent bullous emphysema requiring lobectomy has been reported.[32]

See the list below:

• Perform BAL in pediatric patients for DFA and culture. Consider PCR if index of suspicion is high.

• Perform thoracocentesis if the extent of pleural effusion is significant. Test fluids for Legionella antigen and perform DFA and culture. Consider PCR if suspicion is high.

See the list below:

• An intense intra-alveolar inflammation without clinically significant intrabronchial exudate is the histologic hallmark finding. Alveoli usually contain a large number of polymorphonuclear leukocytes, alveolar macrophages, and necrotic debris.

• Organisms are detected both intracellularly and extracellularly.

• Microabscesses may be present in the lung parenchyma.

• Fibrin formation and a predominance of histiocytes occur in more advanced stages of disease.

For Legionnaires disease (LD), a high level of suspicion and prompt initiation of adequate antimicrobial therapy are critical to improve clinical outcomes.[33] In contrast, for Pontiac fever, treatment is symptomatic, and no antimicrobial therapy is recommended.

Therapy effective in patients with legionellosis should be considered for initial empirical treatment for severe community-acquired pneumonia (CAP) and for specific patients with nosocomial pneumonia. Support therapy in patients with shock and respiratory failure is administered as needed.

• Situations suggesting Legionella disease

  • Gram stains of respiratory samples revealing many polymorphonuclear leukocytes with few or no organisms

  • Hyponatremia

  • Pneumonia with prominent extrapulmonary manifestations (eg, diarrhea, confusion, other neurologic symptoms)

  • Failure to respond to administration of beta-lactams, aminoglycoside antibiotics, or both

• Antimicrobial therapy for Legionella disease

  • Specific therapy includes antibiotics capable of achieving high intracellular concentrations (eg, macrolides, quinolones, ketolides, tetracyclines, rifampin). The reported rank order of in vitro and intracellular activity against L pneumophila is quinolones, then ketolides, and then macrolides[34] . Beta-lactams and aminoglycosides have activity against Legionella species in vitro but are not clinically effective.

  • No prospective randomized studies have been performed regarding antibiotic effectiveness in patients with Legionella disease. Recommendations are based on retrospective reviews and experimental (laboratory and animal) studies.

  • Azithromycin is the drug of choice for children with suspected or confirmed Legionella disease.[1] With rare exceptions, the initial course should be intravenously administered. After a good clinical response is observed, it can be switched to the oral route. In patients with severe disease or who appear to be unresponsive to monotherapy, the addition of rifampin is recommended.

  • Certain fluoroquinolones (eg, levofloxacin, moxifloxacin) are effective and are recommended for adults with severe disease.[35] Because macrolides may interfere with drugs metabolized by cytochrome P450 (CYP) 3A4 isoenzyme (eg, cyclosporine), the quinolones mentioned above are suitable alternatives to treat Legionnaires disease in patients taking cyclosporine or other CYP3A4 substrates. An older fluoroquinolone, ciprofloxacin, does inhibit CYP3A4. Although the US Food and Drug Administration (FDA) has not approved fluoroquinolones for persons younger than 18 years (because of concerns about arthropathy in studies of juvenile animals), they have been successfully used to treat children with Legionnaires disease[3, 36, 13] and may be used in children in special circumstances.

  • Other alternatives include doxycycline or trimethoprim (TMP) and sulfamethoxazole (SMZ).

  • The recommended duration of therapy is 5-10 days if azithromycin is used. If other drugs are used, the duration should be 2-3 weeks. For patients with severe disease or immunocompromise, prolonged courses may be required.

See the list below:

• Surgical drainage of pulmonary or extrapulmonary disease may be necessary.

See the list below:

• Infectious disease specialist

• Critical care specialist

• Pulmonologist

• Health-department officials: Confirmed cases of Legionnaires disease should be reported to local health-department officials. Legionellosis is a notifiable disease in the United States.

Early initiation of antibiotic therapy with antilegionellosis agents substantially reduces the mortality rate.

Class Summary

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the clinical setting. Whenever feasible, select antibiotics on the basis of blood-culture sensitivity.

Azithromycin (Zithromax)

Binds to 50S ribosomal subunit of susceptible microorganisms and blocks dissociation of peptidyl tRNA from ribosomes, arresting RNA-dependent protein synthesis. Nucleic acid synthesis not affected. Concentrates in phagocytes and fibroblasts, as demonstrated with in vitro incubation techniques. In vivo data suggest that concentration in phagocytes may contribute to drug distribution to inflamed tissues. Used to treat mild-to-moderate microbial infections. Plasma concentrations are low but tissue concentrations are high, giving it value in treating intracellular organisms. Has long tissue half-life, and single dose recommended.

Rifampin (Rifadin)

Use with azithromycin. Inhibits DNA-dependent RNA polymerase activity in susceptible cells. Specifically interacts with bacterial RNA polymerase but does not inhibit mammalian enzyme.

Doxycycline (Doryx, Vibramycin)

Broad-spectrum, synthetically derived bacteriostatic antibiotic in tetracycline class. Almost completely absorbed, concentrated in bile, and excreted in urine and feces as biologically active metabolite in high concentrations.

Inhibits protein synthesis and therefore bacterial growth by binding to 30S and possibly 50S ribosomal subunits of susceptible bacteria. May block dissociation of peptidyl t-RNA from ribosomes, arresting RNA-dependent protein synthesis.

Ciprofloxacin (Cipro)

Fluoroquinolone that inhibits bacterial DNA synthesis and consequently growth, by inhibiting DNA gyrase and topoisomerases, which are required for replication, transcription, and translation of genetic material. Quinolones have broad activity against gram-positive and gram-negative aerobic organisms. No activity against anaerobes. Continue for at least 2 d (7-14 d typical) after signs and symptoms disappear.

Levofloxacin (Levaquin)

Fluoroquinolone antibiotic for pseudomonal infections and infections caused by multidrug-resistant gram-negative organisms.

Trimethoprim and sulfamethoxazole, TMP-SMZ (Bactrim, Septra)

Inhibits bacterial growth by inhibiting synthesis of dihydrofolic acid. Antibacterial activity against common urinary tract pathogens, except Pseudomonas aeruginosa.

See the list below:

• Outpatient treatment with oral antibiotics may be considered for selected patients with mild disease if they can be closely monitored for signs of deterioration.

• Continue outpatient treatment after the patient is discharged from the hospital until antibiotic therapy is completed and symptoms resolve.

See the list below:

• Most patients with Legionnaires disease (LD) require initial hospitalization for intravenous antibiotics.

  • Closely monitor patients for signs of shock and/or respiratory or multiorgan failure and the need for ICU care.

  • Patients who begin to steadily improve can be switched to oral antibiotics.

  • Continue to monitor patients in the hospital for at least 1 day after switching to oral antimicrobial therapy because relapse is possible.

• Patients with Pontiac fever do not require hospitalization.

See the list below:

• See Medication.

See the list below:

• Patients with Legionnaires disease do not require contact or respiratory isolation (person-to-person transmission has never been demonstrated). Standard precautions are recommended.[1]

• For water births, the colonization of tap water with Legionella can be reduced by installation of a filter system into the supply hose of the birthing tub.

• Strategies the Centers for Disease Control and Prevention (CDC) recommend to prevent healthcare-associated (HCA) Legionnaires disease include the following:

  • Maintain a high index of suspicion for the diagnosis of HCA Legionnaires disease, and perform appropriate laboratory tests for Legionnaires disease.

  • Facilities with transplantation programs should consider routine Legionella cultures of water samples from the potable water systems as part of the facilities comprehensive program to prevent and control HCA Legionnaires disease.

  • Maintain potable water at the outlet at temperatures not suitable for the growth of Legionella species.

  • Cooling towers should receive routine maintenance, and only sterile water should be used to fill and rinse respiratory therapy devices.

  • Initiate an investigation for the source of Legionella organisms when one case of Legionnaires disease is identified in an inpatient transplant recipient or when 2 cases occurring within 6 months of each other are identified in transplant recipients who visited an outpatient unit during the 2-10 months before the onset of illness.

  • If the water system is implicated, decontaminate the system by superheating water to 71-77°C, and maintain until distal sites are flushed. If thermal shock is not possible, use shock chlorination as an alternative.[37]

• Some experts have recommended to culture the tap water of pediatric hospitals, especially to sample the higher risk areas (eg, NICU, PICU, transplant units) for Legionella. Children with hospital-acquired pneumonia in hospitals with positive surveillance cultures should undergo Legionella testing.[38]

• Additionally, it has been recommended that transplant recipients boil their water, cool it, and store it for drinking.[39]

See the list below:

• The following complications may persist for weeks to months after disease onset:

  • Empyema

  • Pulmonary cavitation

  • Bullous emphysema

  • Renal failure

  • Memory loss

  • Fatigue

  • Neurologic disorders

  • Multiorgan failure

• Legionnaires disease can be fatal.

See the list below:

• With early initiation of appropriate therapy, most patients experience defervescence and symptomatic improvement within 3-5 days.

• Factors that predict a poor outcome include advanced age, underlying disease (including prematurity), delayed therapy, and respiratory failure.

• Subsequent episodes are rare.