CHAPTER 84: INFECTIONS DUE TO MYCOPLASMAS

Mycoplasmas are prokaryotes of the class Mollicutes. Their size (150–350 nm) is closer to that of viruses than to that of bacteria. Unlike viruses, however, mycoplasmas grow in cell-free culture media; in fact, they are the smallest organisms capable of independent replication.

The entire genomes of many Mycoplasma species have been sequenced and have been found to be among the smallest of all prokaryotic genomes. Sequencing information for these genomes has helped define the minimal set of genes necessary for cellular life. The absence of genes related to the synthesis of amino acids, fatty acid metabolism, and cholesterol dictates the mycoplasmas’ parasitic or saprophytic dependence on a host for exogenous nutrients and necessitates the use of complex fastidious media to culture these organisms. Mycoplasmas lack a cell wall and are bound only by a cell membrane. The absence of a cell wall explains the inactivity of β-lactam antibiotics (penicillins and cephalosporins) against infections caused by these organisms.

At least 13 Mycoplasma species, two Acholeplasma species, and two Ureaplasma species have been isolated from humans. Most of these species are thought to be normal inhabitants of oral and urogenital mucous membranes. Only four species—M. pneumoniae, M. hominis, U. urealyticum, and U. parvum—have been shown conclusively to be pathogenic in immunocompetent humans. M. pneumoniae primarily infects the respiratory tract, while M. hominis, U. urealyticum, and U. parvum are associated with a variety of genitourinary tract disorders and neonatal infections. Some data indicate that M. genitalium may be a cause of disease in humans. Other mycoplasmas may cause disease in immunocompromised persons.

PATHOGENESIS

M. pneumoniae is generally thought to act as an extracellular pathogen. Although the organism has been shown to exist and replicate within human cells, it is not known whether these intracellular events contribute to the pathogenesis of disease. M. pneumoniae attaches to ciliated respiratory epithelial cells by means of a complex terminal organelle at the tip of one end of the organism. Cytoadherence is mediated by interactive adhesins and accessory proteins clustered on this organelle. After extracellular attachment, M. pneumoniae causes injury to host respiratory tissue. The mechanism of injury is thought to be mediated by the production of hydrogen peroxide and of a recently identified ADP-ribosylating and vacuolating cytotoxin of M. pneumoniae that has many similarities to pertussis toxin. Because mycoplasmas lack a cell wall, they also lack cell wall–derived stimulators of the innate immune system, such as lipopolysaccharide, lipoteichoic acid, and murein (peptidoglycan) fragments. However, lipoproteins from the mycoplasmal cell membrane appear to have inflammatory properties, probably acting through Toll-like receptors (primarily TLR2) on macrophages and other cells. Lung biopsy specimens from patients with M. pneumoniae respiratory tract infection reveal an inflammatory process involving the trachea, bronchioles, and peribronchial tissue, with a monocytic infiltrate coinciding with a luminal exudate of polymorphonuclear leukocytes.

Experimental evidence indicates that innate immunity provides most of the host’s defense against mycoplasmal infection in the lungs, whereas cellular immunity may actually play an immunopathogenic role, exacerbating mycoplasmal lung disease. Humoral immunity appears to provide protection against dissemination of M. pneumoniae infection; patients with humoral immunodeficiencies do not have more severe lung disease than do immunocompetent patients in the early stages of infection but more often develop disseminated infection resulting in syndromes such as arthritis, meningitis, and osteomyelitis. The immunity that follows severe M. pneumoniae infections is more protective and longer-lasting than that following mild infections. Genuine second attacks of M. pneumoniae pneumonia have been reported infrequently.

EPIDEMIOLOGY

M. pneumoniae infection occurs worldwide. It is likely that the incidence of upper respiratory illness due to M. pneumoniae is up to 20 times that of pneumonia caused by this organism. Infection is spread from one person to another by respiratory droplets expectorated during coughing and results in clinically apparent disease in an estimated 80% of cases. The incubation period for M. pneumoniae is 2–4 weeks; therefore, the time-course of infection in a specific population may be several weeks long. Intrafamilial attack rates are as high as 84% among children and 41% among adults. Outbreaks of M. pneumoniae illness often occur in institutional settings such as military bases, boarding schools, and summer camps. Infections tend to be endemic, with sporadic epidemics every 4–7 years. There is no seasonal pattern.

Most significantly, M. pneumoniae is a major cause of community-acquired respiratory illness in both children and adults and is often grouped with Chlamydia pneumoniae and Legionella species as being among the most important bacterial causes of “atypical” community-acquired pneumonia. For community-acquired pneumonia in adults, M. pneumoniae is the most frequently detected “atypical” organism. Analysis of 13 studies of community-acquired pneumonia published since 1995 (which included 6207 ambulatory and hospitalized adults) showed that the overall prevalence of M. pneumoniae was 22.7%; by comparison, the prevalence of C. pneumoniae was 11.7%, and that of Legionella species was 4.6%. M. pneumoniae pneumonia is also referred to as Eaton agent pneumonia (the organism having first been isolated in the early 1940s by Monroe Eaton), primary atypical pneumonia, and “walking” pneumonia.

CLINICAL MANIFESTATIONS

Upper respiratory tract infections and pneumonia

Acute M. pneumoniae infections generally manifest as pharyngitis, tracheobronchitis, reactive airway disease/wheezing, or a nonspecific upper respiratory syndrome. Little evidence supports the commonly held belief that this organism is an important cause of otitis media, with or without bullous myringitis. Pneumonia develops in 3–13% of infected individuals; its onset is usually gradual, occurring over several days, but may be more abrupt. Although Mycoplasma pneumonia may begin with a sore throat, the most common presenting symptom is cough. The cough is typically nonproductive, but some patients produce sputum. Headache, malaise, chills, and fever are noted in the majority of patients.

On physical examination, wheezes or rales are detected in ∼80% of patients with M. pneumoniae pneumonia. In many patients, however, pneumonia can be diagnosed only by chest radiography. The most common radiographic pattern is that of peribronchial pneumonia with thickened bronchial markings, streaks of interstitial infiltration, and areas of subsegmental atelectasis. Segmental or lobar consolidation is not uncommon. While clinically evident pleural effusions are infrequent, lateral decubitus views reveal that up to 20% of patients have pleural effusions.

Overall, the clinical presentation of pneumonia in an individual patient is not useful for differentiating M. pneumoniae pneumonia from other types of community-acquired pneumonia. The possibility of M. pneumoniae infection deserves particular consideration when community-acquired pneumonia fails to respond to treatment with a penicillin or a cephalosporin—antibiotics that are ineffective against mycoplasmas. Symptoms usually resolve within 2–3 weeks after the onset of illness. Although M. pneumoniae pneumonia is generally self-limited, appropriate antimicrobial therapy significantly shortens the duration of clinical illness. Infection uncommonly results in critical illness and only rarely in death. In some patients, long-term recurrent wheezing or reactive airway disease may follow the resolution of acute pneumonia. The significance of chronic infection, especially as it relates to asthma, is an area of active investigation.

Extrapulmonary manifestations

An array of extrapulmonary manifestations may develop during M. pneumoniae infection. The most significant are neurologic, dermatologic, cardiac, rheumatologic, and hematologic in nature. Extrapulmonary manifestations can be a result of disseminated infection, especially in patients with humoral immunodeficiencies (e.g., septic arthritis); postinfectious autoimmune phenomena (e.g., Guillain-Barré syndrome); or possibly ADP-ribosylating toxin. Overall, these manifestations are uncommon, given the frequency of M. pneumoniae infection. Notably, many patients with extrapulmonary M. pneumoniae disease do not have respiratory disease.

Skin eruptions described with M. pneumoniae infection include erythematous (macular or maculopapular), vesicular, bullous, petechial, and urticarial rashes. In some reports, 17% of patients with M. pneumoniae pneumonia have had an exanthem. Erythema multiforme major (Stevens-Johnson syndrome) is the most clinically significant skin eruption associated with M. pneumoniae infection; it appears to occur more commonly with M. pneumoniae than with other infectious agents.

A wide spectrum of neurologic manifestations has been reported with M. pneumoniae infection. The most common are meningoencephalitis, encephalitis, Guillain-Barré syndrome, and aseptic meningitis. M. pneumoniae has been implicated as a likely etiologic agent in 5–7% of cases of encephalitis. Other neurologic manifestations may include cranial neuropathy, acute psychosis, cerebellar ataxia, acute demyelinating encephalomyelitis, cerebrovascular thromboembolic events, and transverse myelitis.

Hematologic manifestations of M. pneumoniae infection include hemolytic anemia, aplastic anemia, cold agglutinins, disseminated intravascular coagulation, and hypercoagulopathy. When anemia does occur, it generally develops in the second or third week of illness.

In addition, hepatitis, glomerulonephritis, pancreatitis, myocarditis, pericarditis, rhabdomyolysis, and arthritis (septic and reactive) have been convincingly ascribed to M. pneumoniae infection. Septic arthritis has been described most commonly in hypogammaglobulinemic patients.

Clinical findings, nonmicrobiologic laboratory tests, and chest radiography are not useful for differentiating M. pneumoniae pneumonia from other types of community-acquired pneumonia. In addition, since M. pneumoniae lacks a cell wall, it is not visible on Gram’s stain. Although of historical interest, the measurement of cold agglutinin titers is no longer recommended for the diagnosis of M. pneumoniae infection because the findings are nonspecific and assays specific for M. pneumoniae are now available.

Acute M. pneumoniae infection can be diagnosed by polymerase chain reaction (PCR) detection of the organism in respiratory tract secretions or by isolation of the organism in culture (Table 84-1). Oropharyngeal, nasopharyngeal, and pulmonary specimens are all acceptable for diagnosing M. pneumoniae pneumonia. Other bodily fluids, such cerebrospinal fluid, are acceptable for extrapulmonary infection. M. pneumoniae culture (which requires special media) is not recommended for routine diagnosis because the organism may take weeks to grow and is often difficult to isolate from clinical specimens. In contrast, PCR allows rapid, specific diagnosis earlier in the course of clinical illness.

The diagnosis can also be established by serologic tests for IgM and IgG antibodies to M. pneumoniae in paired (acute- and convalescent-phase) serum samples; enzyme-linked immunoassay is the recommended serologic method. An acute-phase sample alone is not adequate for diagnosis, as antibodies to M. pneumoniae may not develop until 2 weeks into the illness; therefore, it is important to test paired samples. In addition, IgM antibody to M. pneumoniae can persist for up to 1 year after acute infection. Thus its presence may indicate recent rather than acute infection.

The combination of PCR of respiratory tract secretions and serologic testing constitutes the most sensitive and rapid approach to the diagnosis of M. pneumoniae infection.

TREATMENT

EPIDEMIOLOGY

M. hominis, M. genitalium, U. urealyticum, and U. parvum can cause urogenital tract disease. The significance of isolation of these organisms in a variety of other syndromes is unknown and in some cases is being investigated. M. fermentans has not been shown convincingly to cause human disease.

While urogenital mycoplasmas may be transmitted to a fetus during passage through a colonized birth canal, sexual contact is the major mode of transmission, and the risk of colonization increases dramatically with increasing numbers of sexual partners. In asymptomatic women, these mycoplasmas may be found throughout the lower urogenital tract. The vagina yields the largest number of organisms; next most densely colonized are the periurethral area and the cervix. Ureaplasmas are isolated less often from urine than from the cervix, but M. hominis is found with approximately the same frequency at these two sites. Ureaplasmas are isolated from the vagina of 40–80% of sexually active, asymptomatic women and M. hominis from 21–70%. The two microorganisms are found concurrently in 31–60% of women. In men, colonization with each organism is less prevalent. Mycoplasmas have been isolated from urine, semen, and the distal urethra of asymptomatic men.

CLINICAL MANIFESTATIONS

Urethritis, pyelonephritis, and urinary calculi

In many episodes of Chlamydia-negative nongonococcal urethritis, ureaplasmas may be the causative agent. These organisms may also cause chronic voiding symptoms in women. The common presence of ureaplasmas in the urethra of asymptomatic men suggests either that only certain serovars are pathogenic or that predisposing factors, such as lack of immunity, must exist in persons who develop symptomatic infection. Alternatively, disease may develop only upon initial exposure to ureaplasmas. Ureaplasmas have been implicated in epididymitis. M. genitalium also appears to cause urethritis. M. genitalium and ureaplasmas do not have a known role in prostatitis. M. hominis does not appear to play a primary etiologic role in urethritis, epididymitis, or prostatitis.

Evidence suggests that M. hominis causes up to 5% of cases of acute pyelonephritis. Ureaplasmas have not been associated with this disease.

Ureaplasmas play a limited role in the production of urinary calculi. The frequency with which ureaplasmas reach the kidney, the predisposing factors that allow them to do so, and the relative frequency of urinary tract calculi induced by this organism (compared with other organisms) are not known.

Pelvic inflammatory disease

M. hominis can cause pelvic inflammatory disease. In most episodes, M. hominis occurs as part of a polymicrobial infection, but the organism may play an independent role in a limited number of cases. Some data also support an association of M. genitalium with pelvic inflammatory disease. Ureaplasmas are not thought to cause pelvic inflammatory disease.

Postpartum and postabortal infection

Studies implicate M. hominis as the primary pathogen in ∼5–10% of women who have postpartum or postabortal fever; ureaplasmas have been implicated to a lesser degree. These infections are generally self-limited; however, if symptoms persist, specific antimicrobial therapy should be given. Ureaplasmas also appear to play a role in occasional postcesarean wound infections.

Non-urogenital infection

In rare instances, M. hominis causes non-urogenital infections, such as brain abscess, wound infection, poststernotomy mediastinitis, endocarditis, and neonatal meningitis. These infections are most common among immunocompromised and hypogammaglobulinemic patients. Ureaplasmas and M. hominis can cause septic arthritis in immunodeficient patients. Ureaplasmas probably cause neonatal pneumonitis; their significant role in the development of bronchopulmonary dysplasia—the chronic lung disease of premature infants—has been documented in a number of studies. It is unclear whether ureaplasmas and M. hominis cause infertility, spontaneous abortion, premature labor, low birth weight, or chorioamnionitis.

DIAGNOSIS

Culture and PCR are both appropriate methods for the isolation of urogenital mycoplasmas. Culture of these organisms, however, requires special techniques and media that generally are available only at larger medical centers and reference laboratories. Serologic testing is not recommended for the clinical diagnosis of urogenital Mycoplasma infections.

TREATMENT