Mycoplasmal Pneumonia

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Background

Mycoplasma pneumoniae is a common cause of community-acquired pneumonia (CAP), and the disease usually has a prolonged, gradual onset.[1]  M pneumoniae was first isolated in cattle with pleuropneumonia in 1898.

In 1938, Reimann described the first cases of mycoplasmal pneumonia in man and coined the term "primary atypical pneumonia" after observing 7 patients in Philadelphia with marked constitutional symptoms, upper and lower respiratory tract symptoms, and a protracted course with gradual resolution.[2] Peterson discovered the phenomenon of cold agglutinin in 1943. High titers of cold agglutinins in patients with primary atypical pneumonia were discovered accidentally. In 1944, Eaton was credited with discovering a specific agent, coined Eaton's agent, as the principal cause of primary atypical pneumonia.[3] First thought to be a virus, Eaton's agent was proved to be a Mycoplasma species in 1961.

The breakdown of the Mollicutes class, which includes the Mycoplasma genus, is presented in the image below.



View Image

Diagram of the Mollicutes class, to which the Mycoplasma genus belongs.

Go to Community-Acquired Pneumonia, Bacterial Pneumonia, Mycoplasma Infections, and Imaging Atypical Bacterial Pneumonia for more information on these topics.

Pathophysiology

The organism responsible for mycoplasmal pneumonia, M pneumoniae, is a pleomorphic organism that, unlike bacteria, lacks a cell wall, and unlike viruses, does not need a host cell for replication. The prolonged paroxysmal cough seen in this disease is thought to be due to the inhibition of ciliary movement. M pneumoniae has a remarkable gliding motility and specialized tip organelles that allows it to burrow between cilia within the respiratory epithelium, eventually causing sloughing of the respiratory epithelial cells.

The organism has two properties that seem to correlate well with its pathogenicity in humans. The first is a selective affinity for respiratory epithelial cells and the second is the ability to produce hydrogen peroxide, which is thought to be responsible for much of the initial cell disruption in the respiratory tract and for damage to erythrocyte membranes.

The pathogenicity of M pneumoniae has been linked to the activation of inflammatory mediators, including cytokines. One study reported on an emergence of drug-resistant M pneumoniae infection. However, the study concluded that host immune maturity and not the virulence factor of the organism is a major determinant factor of disease severity.[4] Macrolide-resistant M pneumoniae has emerged in adult community-acquired pneumonia[5] as well as pediatric pneumonia.[6, 7, 8, 9, 10]

Mycoplasma pneumoniae has been identified with an increasing array of illnesses, such as acute hepatitis,[11, 12] immune thrombocytopenic purpura,[13] severe autoimmune hemolytic anemia,[14] Stevens-Johnson syndrome,[15, 16] arthritis,[17] and transverse myelitis.[18, 19]

Etiology

The causative agent of mycoplasmal pneumonia is M pneumoniae, a bacterium in the shape of a short rod, lacking a cell wall, which belongs to the class Mollicutes, the smallest known free-living microorganisms. The organism can be excreted from the respiratory tract for several weeks after the acute infection; therefore, isolation of the organism may not indicate acute infection. The organism is difficult to grow in the laboratory, requiring not only specialized growth medium, but also long growth times, which limits the clinical utility of culturing the organism.

Epidemiology

M pneumoniae is now recognized as one of the most common causes of community-acquired pneumonia in otherwise healthy patients younger than 40 years. Although mycoplasmal pneumonia is common in all age groups, it is most common in the first 2 decades of life, is rare in children younger than five years, and has the highest rate of infection in individuals aged 5-20 years. Although no difference in disease frequency is observed between males and females, illnesses are somewhat more severe in males.

M pneumoniae causes upper and lower respiratory illness in all age groups, particularly in temperate climates, and can occur at any time of the year, but large outbreaks tend to occur in the late summer and fall. Transmission of the organism is person-to-person by infected respiratory droplets. In summer, this organism may cause as many as 50% of all pneumonias.

The incubation of mycoplasmal pneumonia tends to be smoldering and averages a period of 2-3 weeks, in contrast to that of influenza and other viral pneumonias, which generally average a few days. Epidemics of mycoplasmal pneumonia tend to occur every 4-8 years in the general population and tend to be more frequent within closed populations, such as in military and prison populations. Although M pneumoniae is a common cause of pneumonia, only 5-10% of infected patients actually develop pneumonia. Many patients infected with M pneumoniae remain asymptomatic, but patients who become symptomatic develop a respiratory infection which can be lingering and quite bothersome.

Prognosis

With proper treatment, a full recovery is expected. In almost all patients, the pneumonia resolves without any serious complications. However, M pneumoniae can cause severe pneumonia in children and has been associated with acute chest syndrome in patients with sickle cell anemia.[20] Immunity after infection with M pneumoniae is not long lasting.

History

Mycoplasmal pneumonia is a disease of gradual and insidious onset of several days to weeks. A recent Cochrane Review determined that M pneumoniae cannot be reliably diagnosed in children and adolescents with community-acquired pneumonia based on clinical signs and symptoms.[21] The patient's history may include the following:

Physical Examination

Most cases of pneumonia due to M pneumoniae resolve after several weeks, although a dry cough can be present for as long as a month. Some patients can have a protracted illness lasting as long as six weeks. Other findings may also include the following:

M pneumoniae has long been associated with bullous myringitis, but this has been largely disproven. Bullous myringitis is defined as the appearance of vesicles or bulla on the tympanic membrane. Several studies and extensive reviews have refuted the claim that bullous myringitis is pathognomonic for M pneumoniae.[23, 24] In fact, M pneumoniae is rarely cultured from bullae on the tympanic membrane. Common middle ear pathogens in the clinical presentation of otitis media are much more commonly associated with tympanic membrane bullae.[25, 26, 27, 28]

Approach Considerations

Laboratory tests are generally of limited benefit in mycoplasmal pneumonia, as they tend to be nonspecific or within the normal range. For example, elevated erythrocyte sedimentation rates (ESR) may be present but are nonspecific. The white blood cell (WBC) count is generally not helpful in this condition because results may be normal or elevated, and, although hemolytic anemia has been described, it is rare.

Radiography

Chest radiographic findings vary, but abnormalities are usually more striking than the findings upon physical examination. Bronchopneumonia often appears as patchy consolidation and involves a single lower lobe, although lobar consolidation is rare. Distribution of the infiltrates can be unilateral or bilateral. Platelike atelectasis is noted as thin, flat areas of collapsed lung and is often seen on a lateral image of the chest. Pleural effusions develop in less than 20% of patients; when present, they can be seen on lateral decubitus films.

Reticulonodular or interstitial infiltrates, primarily in the lower lobes, may resemble other diseases with granulomatous pathology, such as tuberculosis, mycoses, and sarcoidosis; hilar adenopathy is sometimes mistaken for malignancy.

CT Scanning

High-resolution computed tomography (CT) scans of the chest are more sensitive than chest radiography in elucidating lung disease.[29] CT findings include a tree-in-bud pattern, centrilobular nodular opacities, patchy distribution, ground glass opacities, consolidation, and pleural effusion in 15-20%.

Sputum Culture

Sputum Gram stains and cultures are usually not helpful because M pneumoniae lacks a cell wall and cannot be stained. M pneumoniae is difficult to culture, requires special culture media, and needs 7-21 days to grow. Routine culturing is successful in only 40-90% of cases and does not provide information to guide patient management. Rapid pharyngeal culture for M pneumoniae has shown promising results.[30]

Serology

Serum cold agglutination is a nonspecific test for M pneumoniae, but findings are positive in only 50-70% of patients after 7-10 days of infection. Cold agglutinin tests can be obtained from diagnostic laboratories. A negative result does not exclude infection, and this test may be affected by cross-reactions with other pathogens, such as adenovirus, Epstein-Barr virus, and measles viruses. A quick bedside test can be performed by partially filling a purple-top tube with blood and placing it in ice. A positive finding is one in which "grains of sand" appear on the glass portion of the tube.

Serology tests that demonstrate a 4-fold or greater increase or decrease in paired sera titers or a single titer greater than or equal to 1:32 supports the diagnosis of mycoplasmal pneumonia. Serologic tests include complement fixation, enzyme-linked immunoassay, immunochromatography,[31] and indirect hemagglutination.[32] All of these have acceptable sensitivity and specificity.

Optimized serodiagnosis of M pneumoniae using a new set of antigens has shown comparable sensitivity to positive real-time polymerase chain reaction (PCR) results.[33]

Polymerase Chain Reaction

Polymerase chain reaction (PCR) has been shown to accurately diagnose atypical pneumonia and is becoming the criterion standard confirmatory test for M pneumoniae.[34, 35] This test has been used for epidemiologic studies but is not currently used in most clinical settings. Real-time PCR is a promising test that allows detection of M pneumoniae DNA in all phases of infection, including early periods when the serum may be negative for antibody.[36, 37]

DNA Probes

A radiolabeled DNA probe detects M pneumoniae ribosomal RNA in respiratory secretions with 90% sensitivity.

Eosinophil Cationic Protein

The role of eosinophil cationic protein (ECP) has been studied in M pneumoniae infection and asthma, in which ECP levels have been found to be increased.[38] This protein may play a role in damage to the respiratory epithelium and accelerated hypersensitivity in the respiratory system, although more studies are required.

Approach Considerations

Mycoplasmal pneumonia should be considered as a possible etiology in any patient who presents with three weeks or more of a steadily progressive cough. Patients are usually not critically ill but seek relief from the persistent, worsening cough. Occasionally, various pulmonary and extrapulmonary complications may occur and may require emergent attention.

Antibiotic prophylaxis for exposed contacts is not routinely recommended. However, macrolide or doxycycline prophylaxis should be used in households in which patients with underlying conditions may be predisposed to severe mycoplasmal infection, such as those with sickle cell disease or antibody deficiencies. One study indicated that macrolide-resistance rates were increasing among children and that clinicians should consider alternative antibiotics if the patient's condition continues to deteriorate after macrolide treatment.[7]

If patients with pneumonia due to M pneumoniae require admission, use of standard and droplet precautions are recommended for the duration of the illness. Supportive therapy and antimicrobial administration are the mainstays of treatment (See Medication).

Complications

The following are complications of mycoplasmal pneumonia:

Although most cases of pneumonia caused by Mycoplasma are mild and self-limited, fulminant disease can occur and result in the following:

Extrapulmonary complications may occur as a result of M pneumoniae infection, although the incidence is less than 10% when compared to respiratory problems. In many of the suspected extrapulmonary problems, it is unclear if the disease entity is caused by the organism itself, or by an immune response triggered by the M pneumoniae infection.

Cardiac problems

Cardiac involvement in M pneumoniae infection manifests as conduction abnormalities, either rhythm disturbances or heart blocks, seen on the ECG. Chest pain from pericarditis or myocarditis can be a clinical symptom, and these entities have been linked to anti-cardiolipin antibodies.[40] Congestive heart failure is another extrapulmonary complication of M pneumoniae infection. Myocardial damage has been reported in children with M pneumoniae pneumonia.[41]

Central nervous system problems

Central nervous system involvement is rare in most M pneumoniae infections, but hospitalized children are at particular risk of developing encephalitis, aseptic meningitis, transverse myelitis, peripheral neuropathy, or cerebellar ataxia. These complications can be seen in adults, although less frequently.[42, 43] Some of the CNS sequelae may be permanent.[44] How M pneumoniae causes neurologic damage is unclear, but may be linked to an immunologic reaction to antigens produced by the infection.[44]

Hematologic problems

Hemolytic anemia may develop if the IgM antibodies to M pneumoniae antigens cross react to antigens on human erythrocytes, causing destruction. Hemolysis in sickle cell patients with an M pneumoniae infection is concerning, but rarely fatal.[45]

Skin problems

M pneumoniae infection has been associated with erythema multiforme, macular exanthems, vesicular exanthems, urticaria, erythema nodosum, and Stevens-Johnson syndrome.[16] Cutaneous disease can develop in up to 25-33% of all M pneumoniae infections.[46]

Musculoskeletal problems

M pneumoniae has been associated with arthralgia and myalgias, although arthritis is rare. Rhabdomyolysis has been linked with M pneumoniae infections,[47] with very high CPK and myoglobin levels reported.[48, 49] Dermatomyositis has been associated with M pneumoniae infection.[50]

Gastrointestinal problems

Gastrointestinal symptoms are nonspecific, include hepatitis and pancreatitis, and are thought to be related to circulating antibodies to the M pneumoniae organisms.

Ophthalmologic problems

The ophthalmologic manifestation of M pneumoniae infection is most commonly conjunctivitis, but cranial neuropathies, optic papillitis, and anterior uveitis can occur.[51]

Renal problems

Glomerulonephritis is a rare complication of M pneumoniae infection, and is likely caused by immune complex deposits in the glomerulus.

Medication Summary

In the treatment of mycoplasmal pneumonia, antimicrobials against M pneumoniae are bacteriostatic, not bactericidal. Tetracycline and erythromycin compounds are very effective. The second-generation tetracyclines (doxycycline) and macrolides are the drugs of choice.[52] Macrolide resistance has been reported in several areas of the world, but most experts agree that macrolides are the antibiotics of choice for treating M pneumoniae infections in adults and children.[53, 54, 55, 56, 57] If a patient does not respond appropriately to a macrolide, a fluoroquinolone should be added to the treatment regimen.[53, 54] Penicillins and cephalosporins are ineffective, because the organism lacks a cell wall.

Macrolide resistance has been increasing throughout the world, with 0-15% resistance in Europe and the United States, 30% in Israel, and 90-100% in Asia,[58] but macrolides remain the mainstay of treatment. If symptoms do not resolve, consider prescribing tetracyclines (doxycycline and minocycline) or fluoroquinolones (levofloxacin).[59] Doxycycline has been avoided in children younger than 8 years because of fear of tooth staining, but the US Centers for Disease Control and Prevention has stated that short courses of newer formulations of doxycycline do not cause tooth staining.[60]

Erythromycin (E.E.S., Erythrocin, Ery-Tab)

Clinical Context:  Erythromycin is a macrolide antibiotic that is used in the treatment of staphylococcal and streptococcal infections. This agent acts by inhibiting bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes and causing RNA-dependent protein synthesis to arrest.

Azithromycin (Zithromax)

Clinical Context:  Azithromycin is a macrolide antibiotic that is very effective against M pneumoniae and may be the most common agent used to treat M pneumoniae given its ease of administration.

Clarithromycin (Biaxin, Biaxin XL)

Clinical Context:  Clarithromycin is a macrolide antibiotic that reversibly binds to the P site of the 50S ribosomal subunit of susceptible organisms and may inhibit RNA-dependent protein synthesis by stimulating the dissociation of peptidyl tRNA from ribosomes, which results in bacterial growth inhibition.

Doxycycline (Vibramycin, Vibra-Tabs)

Clinical Context:  Doxycycline is a tetracycline antibiotic that is used to treat susceptible bacterial infections of both gram-positive and gram-negative organisms, as well as infections caused by Mycoplasma, Chlamydophilia, and Rickettsia organisms. This agent is as effective as erythromycin and other macrolides in the treatment of M pneumoniae infection. Doxycycline inhibits bacterial protein synthesis by binding with the 30S subunit and possibly the 50S ribosomal subunit of susceptible bacteria.

Levofloxacin (Levaquin)

Clinical Context:  Levofloxacin is a fluoroquinolone antibiotic that can be used to treat Mycoplasma infections. It works by inhibiting the A subunits of DNA gyrase, resulting in inhibition of bacterial DNA replication and transcription.

Moxifloxacin (Avelox)

Clinical Context:  Moxifloxacin is a fluoroquinolone antibiotic that inhibits the A subunits of DNA gyrase, resulting in inhibition of bacterial DNA replication and transcription.

Class Summary

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.

What is mycoplasmal pneumonia?What is the pathophysiology of mycoplasmal pneumonia?How is M pneumoniae characterized?What is the prevalence of mycoplasmal pneumonia?What is the prognosis in mycoplasmal pneumonia?What are the signs and symptoms of mycoplasmal pneumonia?What are physical findings characteristic of mycoplasma pneumonia?What is the role of bullous myringitis in mycoplasmal pneumonia?What are diagnostic considerations for mycoplasmal pneumonia?What are the differential diagnoses for Mycoplasmal Pneumonia?What is the role of lab tests in the workup of mycoplasmal pneumonia?What is the role of radiography in the workup of mycoplasmal pneumonia?What is the role of CT scanning in workup for mycoplasmal pneumonia?What is the role of sputum culture in the workup of mycoplasmal pneumonia?What is the role of serology in the workup of mycoplasmal pneumonia?What is the role of polymerase chain reaction (PCR) in the workup of mycoplasmal pneumonia?What is the accuracy of DNA probes in the diagnosis of mycoplasmal pneumonia?What is the role of eosinophil cationic protein (ECP) measurement in the workup of mycoplasmal pneumonia?How is mycoplasmal pneumonia treated?What are complications of mycoplasmal pneumonia?What are cardiac complications of mycoplasmal pneumonia?What are central nervous system complications of mycoplasmal pneumonia?What are hematologic complications of mycoplasmal pneumonia?What are dermatologic complications of mycoplasmal pneumonia?What are musculoskeletal complications of mycoplasmal pneumonia?What are GI complications of mycoplasmal pneumonia?What are ophthalmologic complications of mycoplasmal pneumonia?What are renal complications of mycoplasmal pneumonia?What is the role of drug treatment for mycoplasmal pneumonia?Which medications in the drug class Antibiotic Therapy are used in the treatment of Mycoplasmal Pneumonia?

Author

Michael Joseph Bono, MD, FACEP, Professor of Emergency Medicine, Vice Chair, Emergency Medicine Residency Program, Department of Emergency Medicine, Eastern Virginia Medical School

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Paul Blackburn, DO, FACOEP, FACEP, Attending Physician, Department of Emergency Medicine, Maricopa Medical Center

Disclosure: Nothing to disclose.

Chief Editor

Guy W Soo Hoo, MD, MPH, Clinical Professor of Medicine, University of California, Los Angeles, David Geffen School of Medicine; Director, Medical Intensive Care Unit, Pulmonary and Critical Care Section, West Los Angeles Healthcare Center, Veteran Affairs Greater Los Angeles Healthcare System

Disclosure: Nothing to disclose.

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Diagram of the Mollicutes class, to which the Mycoplasma genus belongs.

Diagram of the Mollicutes class, to which the Mycoplasma genus belongs.