OVERVIEW: What every practitioner needs to knowAre you sure your patient has a Legionella infection? What are the typical findings for this disease?
The bacterium, Legionella, causes two different diseases:
Legionnaire disease: the classic syndrome of pneumonia, which can be community acquired or hospital acquired
Pontiac fever: a self-limiting, flulike illness of short duration
Legionellosis is the term used to define any infection caused by Legionella species.
Legionnaire disease is considered a rare cause of pneumonia in children but is likely vastly underdiagnosed because it is unsuspected.
The clinical presentation is that of pneumonia. The clinical manifestations include fever, cough (often nonproductive), and tachypnea.
Pediatric legionellosis: when should I suspect Legionella infection?
The clinical experience for diagnosis of Legionnaire disease among pediatricians is extremely low. As an example, Legionnaire disease is not even mentioned in the guidelines for community-acquired pneumonia in infants and children, formulated by the Pediatric Infectious Disease and Infectious Disease Society of America. Therefore an index of suspicion on the part of the physician is necessary because the clinical familiarity of pediatricians with legionellosis in pediatrics is extremely limited.
Some clues to the diagnosis include a child with pneumonia and one or more of the following:
The causative microbe cannot be identified.
The child is not responding to β-lactam antibiotics.
The child is immunosuppressed.
The pneumonia is hospital acquired.
The Gram stain of sputum reveals many polymorphonuclear cuts and no bacteria.
Liver function test results are abnormal.
Hyponatremia is present (this laboratory abnormality is common in adults; its frequency in children is unknown).
Gastrointestinal symptoms of nausea, vomiting, or diarrhea should raise the suspicion of Legionnaire disease.
The most common symptoms and signs in pediatric patients are fever, cough, and dyspnea, followed by tachypnea, tachycardia, gastrointestinal symptoms (diarrhea, abdominal pain, vomiting), and lethargy.
Legionnaire disease: The clinical presentation is usually acute onset of high fever with nonproductive cough and tachypnea. Gastrointestinal symptoms (nausea, vomiting, and diarrhea) are common in adults but appear to be less common in children. Nevertheless, overt neurologic and gastrointestinal manifestations should raise the possibility of Legionella infection.
Pontiac fever: A self-limited “flu-like” illness without pneumonia. Recovery is complete without treatment. Symptoms in children are similar to those in adults. In an outbreak in Scotland, 31 children were symptomatic. The children had a shorter duration of illness (mean, 3.3 days) compared with adults (4.3 days), and had less arthralgia and shortness of breath (42% compared with 66%), but the rest of the disease was comparable between adult and pediatric patients.
The most common symptoms of Pontiac fever in children are headache, fatigue, and anorexia.
The most common sign of Pontiac fever in children is fever.
Other symptoms include arthralgia, myalgias, chills, nausea, cough (nonproductive), and shortness of breath.
Legionnaire disease is distinct from other forms of pneumonia in that a notable number of pediatric cases are hospital acquired. This probably results from diagnostic bias, since Legionnaire disease is rarely suspected as a cause of pediatric community-acquired pneumonia.
In contrast to community-acquired legionellosis, hospital-acquired cases are almost always identified in immunosuppressed patients or those with underlying respiratory disease. Again, this may be a result of diagnostic bias, in that in previously well children, the tests necessary for diagnosis of Legionnaire disease may not be obtained.
The source of many cases of community-acquired legionellosis has been the home water distribution system, although in many cases a water sample from the presumptive environmental source will fail to yield Legionella. In contast, cultures from the hospital drinking water or other water sources often yield Legionella of the same molecular subtype found in the patient.
Pediatric patients with hospital-acquired legionellosis are often neonates in the intensive care unit (ICU) with severe disease and a high mortality rate.
As already mentioned, for hospital-acquired acquired pneumonia, the source of
Legionella has been the hospital drinking water. Investigation often is undertaken in severely ill children in the ICU, in children with pneumonia unresponsive to β-lactam antibiotics, or in immunosupressed patients. However, if the hospital drinking water is known to be colonized with Legionella, laboratory testing for
Legionella is mandatory for all children with fever and pulmonary infiltrates.
Another risk factor for infection may be history of recent travel. The risk in adults is much higher than it is in children. Hotels or cruise ships are the commonly identified sources. History of travel in the 2 weeks preceding the illness should be obtained. In a Centers for Disease Control (CDC) survey, 20%-25% of Legionella cases were travel related in adults and 13% (6/48) were related to travel in children. Disease surveillance from Europe and the United States shows an increase in reportable cases of Legionella over the past several years.
What other disease/condition shares some of these symptoms?
Legionella pneumonia has no pathognomonic clinical manifestations. The distinguishing features of community-acquired pneumonia listed below reflect the art of medicine and have not been statistically validated.
Severe pneumonias of bacterial cause produce clinical manifestations that are commonplace. For example, patients with pneumococcal pneumonia often have abnormal liver function test results and, similar to pneumococcal pneumonia, Legionnaire disease often is associated with lobar infiltration on chest radiography. However, the cough of Legionnaire disease is less likely to be productive, and if sputum is produced it rarely is purulent. The Gram stain of sputum demonstrating gram-positive cocci can distinguish between these two causes. The urinary antigen test for Streptococcus pneumoniae, while accurate in adults, is less useful in children because of colonization by pneumococci in children.
All the “atypical” pneumonias listed below share common features with Legionnaire disease, especially headache and myalgias:
Mycoplasma pneumoniae can cause pneumonia that mimics mild cases of Legionnaire disease. Rash is extremely rare in Legionnaire disease but not uncommon in patients with pneumonia caused by a mycoplasma.
Chlamydophila pneumoniae rarely presents with severe pneumonia requiring ICU care, whereas severe pneumonia is common in Legionnaire disease.
Chlamydia psittaci, when severe, is a mimic of classic Legionnaire disease. Exposure to birds is the key distinguishing feature.
Chlamydia trachomatis can cause pneumonia in neonates of infected mothers. Unlike Legionaires’ disease, the infants are usually afebrile. Eosinophilia is not seen in legionellosis but is common in
C. trachomatis infection.
Pneumonias of viral cause can present with high fever, headache, and leukocytosis, so differentiation between severe viral pneumonias and Legionnaire disease can be difficult.
Q fever may present with headache, pulmonary infiltrates, and abnormal liver function test results and thus can mimic Legionnaire disease. Cough is often not a prominent symptom in Q fever.
What caused this disease to develop at this time?
Exposure to contaminated drinking water is the pivotal factor.
Predisposing factors for pediatric patients
Infants (<12 months)
Immunocompromised patients (primary immunodeficiency or secondary immunodeficiency resulting from transplantation, malignancy, steroid use)
Chronic lung disease
Heavy rainfall and flooding (has been associated with outbreaks in adults)
Hospitalization may suggest nosocomial infection
Travel history, although less common with children compared with adults
Fever greater than 39°C is usually present, in contrast to other “atypical” pneumonias
What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?
Standard laboratory tests are nonspecific; nevertheless, abnormal liver function test results, hyponatremia, elevated creatine phosphokinase levels, and renal dysfunction are commonly seen.
Leukocytosis is the most common abnormality of white blood cells, often with a left shift. Leukopenia can be seen, especially in severe cases.
Erythrocyte sedimentation rate and C-reactive protein levels are elevated.
Hyponatremia (common in adults; incidence in children unknown)
Specific laboratory tests for Legionella: Diagnosis can only be made with certainty by use of specialized laboratory tests.
Isolation of the organism in culture: This is the gold standard. The laboratory should be informed of your suspicion, since special selective media is required. Enriched buffered charcoal yeast extract (BCYE) culture media is necessary for Legionella growth. Antibiotics and inhibitors are added to BCYE culture plates to suppress competing growth of bacteria colonizing the oropharynx. Dye-containing medium allows ready color identification of the Legionella colony.
Culture for Legionella requires 3-7 days for confirmation. In contrast to the urinary antigen test, culture detects all serogroups and species of the Legionellaceae family. Isolation of Legionella also allows epidemiologic links to be made if the Legionella is also isolated from the environmental source to which the patient is exposed.
Gram stain: An important clue is Gram staining the sputum and the presence of polymorphonuclear cells without evidence of bacteria.
Urinary antigen testing: This is a rapid test in which results can be available within an hour. Previous antibiotic use will not affect the results. It is easy to perform and interpret and does not need laboratory expertise. It is now the test most commonly used for
Legionella diagnosis. The sensitivity is about 80%, but the specificity approaches 100%. The main drawback of the test is that it can identify only
Legionella pneumophila serogroup 1; other serogroups and species are not detected. The sensitivity of the test can be increased if the urine is concentrated before the test is performed.
Direct fluorescent antibody stain: This is a rapid test applied to respiratory tract specimens and lung tissue. The sensitivity ranges from 25%-75%, but the specificity is high (95%-99%). The test is more likely to give positive results if the pulmonary infiltrates are extensive.
Polymerase chain reaction (PCR): Sensitivity is uncertain, but the test is highly specific. Although it is a rapid point-of-care test, its accuracy has not proved to be superior to culture. PCR is not approved by the US Food and Drug Administration. Nevertheless, PCR for
Legionella species is commercially available in some countries, and home-grown tests are available in some hospital laboratories. The accuracy of such tests are poorly documented, so the results should be used in the context of an individual patient.
Serologic tests: Confirmation of infection requires a fourfold rise in antibody titer to 1:128 or more (usually within 8-12 weeks). Cross reactions have been reported with some gram-negative bacilli or other pathogens. The test is less useful to the pediatrician, since convalescent sera is required for definitive diagnosis. A single titer of 1:256 in a patient with pneumonia is presumptive evidence for Legionnaire disease.
Would imaging studies be helpful? If so, which ones?
Chest radiography is the definitive test for pneumonia; however, it is often not as revealing in the early stages of pneumonia in children. Radiographic findings in Legionella pneumonia are nonspecific. Pulmonary infiltrates can be lobar or diffuse and unilateral or bilateral. Pleural effusion occurred in 30% of reported pediatric cases.
Computed tomography (CT) may be more sensitive than chest radiography (Figure 1 and Figure 2), especially in neutropenic patients in whom chest chest radiography is equivocal.
In pediatric patients, radiation exposure should be taken into consideration. Routine CT or chest radiography need not to be used for monitoring. Clinical evaluation may be sufficient for monitoring response to therapy.
If you are able to confirm that the patient has Legionella pneumonia, what treatment should be initiated?
Treatment Options for Legionella
Anti-Legionella antibiotics should be started without delay in patients with suspected legionellosis. Legionella is an intracellular pathogen. Antibiotics with intracellular penetration are most effective: quinolones, macrolides, tetracyclines. The treatment of choice for pediatric patients is azithromycin. Clarithromycin is an excellent alternative (see Table I).
|Antibiotics||Intravenous Dosage||Oral Dosage||Length of Treatment|
|First Choice||Azithromycin||10 mg/kg/dUp to 500 mg/d||10 mg/kg/dUp to 500 mg/d||7-10 d|
|Clarithromycin||15 mg/kg/d in 2 divided dosesUp to 1 g/d||10-14 d|
|Roxithromycin||5-7.5 mg/kg/d in 2 divided dosesUp to 300 mg/d||10 d|
|Alternative Choices||Erythromycin||40 mg/kg/d in 4 divided dosesUp to 4 g/d||40 mg/kg/d in 4 divided dosesUp to 2 g/d||10-21 d|
|Levofloxacin(not approved for patients <18 y)||<5 y, 20 mg/kg/d in 2 divided doses>5 y, 10 mg/kg/dUp to 500-750 mg/d||<5y, 20 mg/kg/d in 2 divided doses>5y, 10 mg/kg/dUp to 500-750 mg/d||7-10 d|
|Ciprofloxacin(not approved for patients <18 y)||30 mg/kg/d divided into 2 dosesUp to 1000- 1500 mg/d||30 mg/kg/d divided into 2 dosesUp to 800-1000 mg/d||7-10 d|
|Doxycycline(not approved for children <8 y)||2-4 mg/kg/d divided into 2 dosesUp to 200 mg/d||2-4 mg/kg/d divided into 2 dosesUp to 200 mg/d||10-14 d|
|Trimethoprim-Sulfamethaxozole||15 mg/d divided into 2 dosesUp to 160 mg 3 times a day||15 mg/d divided into 2 dosesUp to 160 mg 2 times a day||10-14 d|
|± Rifampin always in combination||20 mg/kg/d divided into 2 dosesUp to 600-1200 mg/d||20 mg/kg/d divided into 2 dosesUp to 600-1200 mg/d||5-7 d|
Quinolones are not approved for this indication in the pediatric population, although they have been used short term in children; such therapy has been effective for children with community-acquired pneumonia with no serious adverse effects. Osteoarticular abnormalities have been seen in animal models and in rare anecdotal reports in children. Levofloxacin can be considered if the clinical response with the macrolide is suboptimal.
Doxycycline is effective but is not reccomended in children younger than 8 years because it is a tetracycline with adverse effects on teeth enamel in children.
Trimethoprim-sulfamethaxazole (TMP-SMX) has been effective in anecdotal reports in adults. However, legionellosis has developed in transplant patients receiving TMP-SMX for prophylaxis against pneumocystis pneumonia.
For severe cases (especially patients who require admission to the pediatric ICU) and for immunocompromised patients, the intravenous route is preferred over oral administration.
The efficacy of combination therapy is unproved, but it can be used for Legionnaire disease that is unresponsive to monotherapy. Azithromycin plus quinolone is one option. We use rifampin plus a quinolone in severe cases. Rifampin is given for only 5 days because it interacts with many drugs used for ICU care and will produce hyperbilirubinemia (which is readily reversible).
Although oral treatment has proved effective in Legionella, for hospitalized patients we suggest the intravenous administration of antibiotics because of the gastrointestinal symptoms associated with Legionella. Oral treatment can be given when the child feels well and tolerates food and the fever has responded.
For the azithromycin and levofloxacin, a duration of therapy of 7-10 days is usually sufficient. For clarithromycin, 10-14 days is sufficient, but 21 days has been recommended for severely ill patients who are also immunosupressed. Erythromycin is no longer recommended because of the high frequency of adverse effects and suboptimal in vitro and in vivo susceptibility. It is also associated with an increased frequency of idiopathic hypertrophic pyloric stenosis in neonates.
An infectious disease expert consultation is recommended for patients in the ICU or if extrapulmonary infection with Legionella has occurred.
What are the adverse effects associated with each treatment option?
We list the most common adverse effects of relevance to patients and physicians
Gastrointestinal side effects are more prominent with erythromycin and less so with azithromycin and clarithromycin.
Interaction with drugs in the cytochrome P-450 pathway are common with macrolides except for azithromycin. Ototoxicity has been seen in adults with prolonged administration.
Quinolones are not approved for children younger than 18 years. In animal models, damage to cartilage was seen. Joint toxicity has not been a problem in pediatric patients given short-term treatment. The drug is otherwise well tolerated.
Doxycycline and tetracycline
In children younger than 8 years of age, these drugs are contraindicated because of permanent staining of teeth. Tetracycline should not be taken during pregnancy. The drug should be taken with fluids to avoid esophageal perforation. Photosensitivity is rare.
Caution must be used with TMP-SMX in patients younger than 2 months of age. Hypersensitivity reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis, or erythema multiforme seen with the sulfa component) have been seen. Leukopenia, neutropenia, or pancytopenia have been documented.
Abnormal liver function test results, especially hyperbilirubinemia, are the most common adverse laboratory effects. If short courses are given (5-7 days), the liver function abnormalities are minimal and reversible.
What are the possible outcomes of Legionella pneumonia ?
With the advent of improved diagnostic tests leading to an earlier diagnosis of Legionnaire disease, mortality in adults has been reduced to less than 10%. Mortality is higher for immunocompromised patients (84%) and infants younger than 12 months (58%). The significant factor influencing outcome in studies was timely appropriate therapy (23% mortality among those who received treatment compared with 70% among those who did not ).
Neonates may be at higher risk. In a 2010 report, mortality was 54% in 13 cases. In 7 patients who died, only 2 received appropriate treatment compared with 6 patients who survived; all 6 survivors received appropriate treatment. In a cluster of 11 neonates in Cyprus, 3 died.
Fever responds to effective antibiotic therapy within 3-5 days.
Poor prognostic factors include the following:
Preterm infants, neonates, and infants younger than 12 months
Preexisting lung disease
Prognosis is good if antimicrobial agents active against Legionella are administered early in the course of the disease.
What causes this disease and how frequent is it?
Legionnaire disease is considered a rare cause of pneumonia in children.
There are numerous species in the family Legionellaceae, with Legionella pneumophila being the most common species, especially in community-acquired pneumonia. Other common species causing infection in children are L. micdadei, L. bozemanii, L. dumoffi and L. gormanii. Multiple serogroups of Legionella can be pathogenic, of which serogroup 1 is the most common. Serogroup 6 is often seen in patients with hospital-acquired pneumonia.
CDC surveillance of 23,076 cases of legionellosis from 1990-2005 showed a marked increase in incidence. Pediatric patients with legionellosis were reported rarely. Only 1.7% of the cases were patients younger than 18 years, and most of them were 15-19 years old or younger than 12 months.
Seroepidemiologic data in children demonstrated variable results, with Legionella seroconversion reported between 2% and 25%. It is likely that there are many unrecognized cases in children who either recover spontaneously or receive appropriate treatment without confirmatory diagnosis.
Pontiac fever: Cases usually occur as part of an outbreak. The incubation period is shorter (1-2 days), and the attack rate is much higher (>80%-90%).
How do these pathogens/genes/exposures cause the disease?
The modes of transmission are twofold: aerosolization from a water source and microaspiration of contaminated water. Virtually all reported hospital-acquired pediatric cases have occurred from aspiration of contaminated water.
The presumed entry is microaspiration during procedures that predispose to aspiration such as placement of nasogastric tubes or endotracheal tubes. Delivery of a newborn using the water birth method has been reported in which the water was contaminated with Legionella.
What complications might you expect from the disease or treatment of the disease?
The main complication is respiratory failure. In severe Legionnaire disease, multiorgan failure with disseminated intravascular coagulation and severe shock can occur. Other complications can include bacteremic dissemination and extrapulmonary focus of infection.
In adults, disseminated infections including endocarditis, peritonitis, pancreatitis, cellulitis, and myositis. Brain abscess has been reported, but no cases of culture-confirmed meningitis have ever been reported.
Are additional laboratory studies available; even some that are not widely available?
PCR is widely touted but has not been critically evaluated.
Elevated procalcitonin levels are an indication of severity of illness in adult cases of Legionnaire disease.
How can Legionnaire disease be prevented?
For community-acquired disease, the epidemiology remains essentially unknown, so no preventive measures are available at the current time.
For hospital-acquired disease, preventive measures have a solid evidence base. The hospital drinking water should be cultured periodically. The intervals between culturing are variable: Many guidelines including the Allegheny County (Pittsburgh, PA) guidelines for Legionella prevention recommend yearly culture. The Maryland state guidelines recommend cultures up to four times a year in high-risk units (transplant units and ICUs). Israel’s Ministry of Health recommends culturing one to two times a year (depending on the size of the hospital and numbers of beds), with up to four times a year in high-risk units.
If the culture results yield Legionella pneumophilia in the drinking water in 30% of distal sites (faucets), two options are given:
Surveillance of all patients with hospital-acquired pneumonia using Legionella culture or urinary antigen.
Disinfection of the water supply.
Effective measures include copper-silver ionization, chlorine dioxide, monochloramine, and thermal eradication (superheat and flush). To date, copper-silver has fulfilled the evidence-based criteria for Legionella disinfection as put forth by Stout.
What is the evidence?
(In this important article, the authors describe a prospective comparative trial of levofloxacin versus comparator antibiotics in 738 children with CAP, efficacy was virtually identical. Adverse effects were rare and no cases of cartilaginous toxicity were observed.
(The first reported outbreak of hospital-acquired legionellosis in which hospital drinking water of a children's hospital was implicated as the source.)
(In this important study, 11 neonates (7-11 days old) contracted legionellosis, and 3 of them died. Diagnosis was made by urine antigen (8 patients), culture of bronchoalveolar lavage (3 patients), or antibody serologic tests (2 patients). Legionella was isolated from hospital water.
(An important comprehensive review of 76 cases of pediatric legionellosis. Fifty-four percent of cases were hospital acquired and for those in whom the source was sought, 88% of the cases originated from the hospital drinking water.)
(This important article describes an outbreak of Pontiac fever caused by L. micdadei in a hotel in Scotland. Pontiac fever was diagnosed in 170 patients, including 31 children. L. micdadei was isolated from the whirlpool spa.)
(The first cases of community-acquired legionellosis in children ever reported. Both were infants who had no known underlying disease. The one infant who received erythromycin survived.)
(A newborn with hospital-acquired legionellosis was delivered by water birth in which the water was contaminated by L. pneumophila.)
(Nine cases of hospital-acquired neonatal Legionnaire disease are reviewed in this important article. Presentation was acute respiratory distress syndrome that required mechanical ventilation. All cases were diagnosed by culture. Six patients died, including 5 patients who did not receive erythromycin. Legionella was isolated from hospital water in five cases.)
(An important comprehensive review of disinfection modalities used by hospitals to eradicate Legionella from the drinking water.)
(A total of 23,076 cases of legionellosis reported to the CDC between the years 1990 and 2005 are described. Only 1.7% of them were pediatric cases. The incidence in the United States is increasing exponentially.)
(A comprehensive review of antibiotic efficacy and combination therapy for legionellosis. Clinical response appeared to be more rapid for quinolones compared with macrolides, but outcome was similar.)
(A commentary on the use of quinolones in children, which notes that quinolone use in children will be very limited because of fear of adverse effects on joints in children (although poorly documented), theoretic antibiotic resistance, and bureaucratic obstacles established by regulatory agencies.)
(An important case report of fatal hospital-acquired neonatal legionellosis plus a literature review of an additional 12 cases. The case was identified by culture and PCR of sputum and evaluation of a lung biopsy specimen. Prematurity and immunodeficiency were prominant risk factors. Mortality was 54% (7/13), with higher survival in those who received macrolides.)
(An important review of neonatal legionellosis with proposed solutions for prevention.)
(An important prospective clinical and environmental survey in 20 hospitals showed that the presence of Legionella in hospital water at 30% or more of distal water sites was predictive of occurrence of hospital-acquired legionellosis.)
Alexander, NT, Fields, BS, Hicks, LA. “Epidemiology of reported pediatric legionnaire disease in the United States, 1980-2004”. (A CDC survey found that 1% of the cases of legionellosis were found in children. Seventy percent of 66 children had no underlying disease. Mortality was 22%. Urine antigen was positive for only 9 patients. Antibody seroconversion or direct fluorescent antibody staining were the diagnostic tests used for most patients.)
Useful website:. March 6, 2012.
Ongoing controversies regarding etiology, diagnosis, treatment
The first discovery of pediatric legionellosis in two immunocompetent patients occurred by chance. The diagnosis was made fortuitously when specialized Legionella culture plates were available because a study of Legionnaire disease had been implemented in adults in that hospital. This raises the possibility that legionellosis is vastly underdiagnosed in pediatric patients.
Observational community-acquired pneumonia studies in which all children undergo specialized
Legionella testing would provide an evidence base for the epidemiology of pediatric legionellosis. Until this is done, reliance must be placed on the few case series of pediatric legionellosis that have been published, and the approach extrapolated for adults with Legionnaire disease.
We have recommended that all pediatric hospitals culture the drinking water. The evidence-based solution to the problem of hospital-acquired legionellosis is to perform routine surveillance for Legionella colonization of hospital water. This is a proactive approach that has been widely adopted in Europe and Israel. It has been adopted in selected US states, the US Veterans Affairs health care system, and in most US tertiary hospitals performing organ transplantation. Hospital units housing high-risk patients can be targeted, including transplant units and neonatal and pediatric ICUs.
Copyright © 2017, 2013 Decision Support in Medicine, LLC. All rights reserved.
No sponsor or advertiser has participated in, approved or paid for the content provided by Decision Support in Medicine LLC. The Licensed Content is the property of and copyrighted by DSM.
- OVERVIEW: What every practitioner needs to knowAre you sure your patient has a Legionella infection? What are the typical findings for this disease?
- What other disease/condition shares some of these symptoms?
- What caused this disease to develop at this time?
- Would imaging studies be helpful? If so, which ones?
- If you are able to confirm that the patient has Legionella pneumonia, what treatment should be initiated?
- What are the adverse effects associated with each treatment option?
- What are the possible outcomes of Legionella pneumonia ?
- What causes this disease and how frequent is it?
- How do these pathogens/genes/exposures cause the disease?
- What complications might you expect from the disease or treatment of the disease?
- Are additional laboratory studies available; even some that are not widely available?
- How can Legionnaire disease be prevented?
- What is the evidence?
- Ongoing controversies regarding etiology, diagnosis, treatment