Mycoplasma pneumoniae

The Organism

Mycoplasmas are the smallest self-replicating prokaryotes known to cause disease in humans. Their size of 150-250 nm is more on the order of viruses than bacteria. Mycoplasma pneumoniae is a fastidious double-stranded DNA bacterium that is distinguished by a small genome (~800,000 base pairs) and a long doubling time, which makes culturing it a slow process (5-20 days) compared to other bacteria. M. pneumoniae isolates can be classified in 2 major genetic groups (subtype 1 and 2) based on the P1 adhesion protein. Distinguishing these 2 subtypes is important for epidemiologic and clinical purposes. Like other mycoplasmas, M. pneumoniae is distinguished by the complete absence of a cell wall that results in (1) their dependence to host cells for obtaining essential nutrients, (2) the intrinsic resistance to β-lactam agents, and (3) their pleomorphic shape and lack of visibility on Gram staining.

Epidemiology

M. pneumoniae infections occur worldwide and throughout the year. This organism is a frequent cause of community-acquired pneumonia (CAP) in children and adults, accounting for ~20% of all CAP in middle and high school children and up to 50% of CAP in college students and military recruits. The proportion of cases increases according to age, as recently shown in a population-based study of CAP conducted in the United States (5% in < 5 yr; 16% in 5-9 yr; and 23% in 10-17 yr).

In contrast to the acute, short-lived epidemics associated with some respiratory viruses, M. pneumoniae infection occurs endemically worldwide. Infections tend to occur most commonly during summer or early fall, although mycoplasma infections have been described all year long. Epidemic outbreaks of variable intensity occur every few years and they are likely related to the alternative circulation of the two M. pneumoniae subtypes. Transmission occurs through the respiratory route by large droplet spread during close contact with a symptomatic person. Community outbreaks have been described in closed settings (colleges, boarding schools, military bases) and can spread largely through school contacts. Attack rates within families are high, with transmission rates of 40 to > 80% for household adult and children contacts, respectively. In contrast to many other respiratory infections, the incubation period is 2-3 wk; hence, the course of infection in a specific population (family) may last several weeks.

The occurrence of mycoplasma illnesses is related, in part, to age and preexposure immunity. Overt illness is less common before 3 yr of age but can occur. Children younger than 5 yr of age appear to have milder illnesses associated with upper respiratory tract involvement, vomiting, and diarrhea. Immunity after infection is not long lasting, as evidenced by the frequency of reinfections over time. The 2 mycoplasma subtypes are immunologically different, and infection with 1 subtype does not appear to confer immunity against the other. Asymptomatic carriage after infection can last up to 4 mo despite antibiotic therapy and may contribute to prolonged outbreaks. Children are often the reservoir from whom mycoplasma spreads. In the clinical setting, there are no available tools yet to differentiate carriage vs. infection.

Pathogenesis

The pathogenicity of M. pneumoniae is dependent upon its extracellular attachment and the initiation of the host cell immune response. Cells of the ciliated respiratory epithelium are the target cells of M. pneumoniae infection. The organism is an elongated snake-like structure with a one-end organelle, which mediates the attachment to sialic acid receptors in the cilia through a complex set of adhesion proteins (P1, P30, proteins B and C, P116, and HMW1-3). M. pneumoniae rarely invades beyond the respiratory tract basement membrane. Virulent organisms attach to ciliated respiratory epithelial cell surfaces located in the bronchi, bronchioles, alveoli, and possibly upper respiratory tract and burrow down between cells, resulting in ciliostasis and eventual sloughing of the cells. M. pneumoniae also causes cytolytic injury to the host cells in part by the production of hydrogen peroxide and possibly through the adenosine diphosphate–ribosylating and vacuolating toxin termed CARDS (community-acquired respiratory distress syndrome). This exotoxin is associated with more severe or even fatal disease. This bacterium facilitates the formation of biofilms, with strain-specific phenotypic differences, which hinder antibiotic penetration and recognition by the immune system.

Once M. pneumoniae reaches the lower respiratory tract, it promotes the polyclonal activation of B lymphocytes and CD4+ T cells, and amplifies the immune response with the production of various proinflammatory and antiinflammatory cytokines and chemokines, such as tumor necrosis factor-α, interleukin (IL)-8, IL-1β, Il-6, and IL-10.

Although it is well documented that specific cell-mediated immunity and antibody titers against M. pneumoniae increase with age (and therefore probably follow repeated infections), the immune mechanisms that protect against or clear the infection are not well defined. In humans, nasal IgA antibodies correlated with protection after experimental challenge. A distinct aspect of M. pneumoniae is its ability to induce the production of cold agglutinins (IgM antibodies) directed against the I antigen expressed in the surface of erythrocytes. Even though antibody responses do not confer complete protection against reinfections, the importance of a robust humoral response is apparent, since patients with congenital antibody deficiencies, such as those with hypogammaglobulinemia, can develop severe and prolonged disease and have a higher risk of extrapulmonary manifestations. In children with sickle cell disease or sickle-related hemoglobinopathies, M. pneumoniae is a common infectious trigger of acute chest syndrome. These children and also children with Down syndrome can develop more severe forms of Mycoplasma pneumonia. On the other hand, M. pneumoniae does not seem to be a common opportunistic agent in patients with AIDS.

M. pneumoniae has been detected by polymerase chain reaction (PCR) in many nonrespiratory sites, including blood, pleural fluid, cerebrospinal fluid (CSF), and synovial fluid. The mechanisms of extrapulmonary disease associated with M. pneumoniae are unclear and appear to be different according to the duration of symptoms at the time of presentation: direct invasion vs. immune-mediated.