Mycoplasma pneumoniae and Atypical Pneumonia

Reviewed for currency January, 2020

The concept of atypical pneumonia antedated the start of the antibiotic era. At least as early as World War I it was recognized that “…in the larger number of cases observed in the [military] camps the pneumonia was of an atypical nature. The onset tended to be slower than that of the lobar pneumonia of civil life; the course more prolonged. Crisis was relatively rare; physical signs were slow of development and of patchy distribution and scattered in several lobes.”

With the introduction of sulfonamides in the 1930s and penicillins in the 1940s, it was recognized that some cases of pneumonia did not respond to these antibiotics and that many of these could not be attributed by Gram stain or culture to a known bacterial cause. The term “primary atypical pneumonia” was given to these cases; the prefix “primary” indicated that no causative agent could be determined.

Since then, as diagnostic microbiology and virology advanced, it was recognized that, in addition to Mycoplasma pneumoniae , multiple etiologic agents can produce the atypical pneumonia syndrome, including influenza virus, adenovirus, respiratory syncytial virus, cytomegalovirus, Chlamydia spp., Legionella spp., Pneumocystis jirovecii , and metapneumovirus. Additional agents will surely be recognized in the course of time, and the prefix “primary” is now mostly of historical interest. Atypical pneumonia is best regarded as a syndrome to be contrasted with the classic symptom complex of “typical” or lobar pneumonia, as exemplified by pneumococcal pneumonia.

History

In 1938 Reimann described seven patients with similar clinical characteristics that he termed atypical pneumonia . During World War II the syndrome assumed special importance because the majority of pneumonias encountered in the military were atypical.

In 1944 M. pneumoniae was first identified as a transmissible cause of atypical pneumonia by Monroe Eaton and coworkers and became known as the Eaton agent. In these original experiments sputum and homogenized lung tissue from autopsied patients with primary atypical pneumonia were inoculated into cotton rats, where they produced pneumonitis. The agent was then serially passed and titered in cotton rats and in hamsters, where it also produced pneumonitis. The agent produced no lesions when inoculated and passed in chick embryos. However, when transferred from chick embryo into cotton rats or hamsters, it produced pneumonia. The agent could be passed through a Millipore filter, was neutralized by sera from patients convalescing from atypical pneumonia, and could not be grown on standard bacteriologic media. Thus it was originally thought to be a virus. Demonstration that the agent could be inactivated by certain antibiotics cast doubt on this hypothesis, and the organism was subsequently grown on artificial media and shown to share properties with the group of infectious agents known as the pleuropneumonia-like organisms, or PPLOs.

In 1943 Maxwell Finland and coworkers identified “cold agglutinins,” isohemagglutinins that were active at 4°C, in the blood of some patients with atypical pneumonia, and in subsequent work they showed that the cold agglutinins were present in cases associated with the Eaton agent but not in cases associated with influenza virus.

The relation of the Eaton agent to the atypical pneumonia syndrome was established by the observations that human serum from some patients recovering from atypical pneumonia neutralized the agent. The causal link with atypical pneumonia was strengthened with the demonstration that neutralizing activity was present in convalescent serum from volunteers who were infected by inoculation of ultrafiltrates from those with naturally occurring disease. Subsequently, the agent was grown in tissue culture and cell-free media, and its morphology was described. The Koch postulates were completely fulfilled when the cultivated organism produced the disease in volunteers. Although the similarity of the Eaton agent with organisms that caused pneumonia in cattle led to its initial description as a pleuropneumonia-like organism, they were rapidly identified as mycoplasmas and named Mycoplasma pneumoniae .

Microbiology

The genus Mycoplasma falls within the class Mollicutes, prokaryote microorganisms that lack cell walls. M. pneumoniae is one of several members of this genus that cause disease in humans. It is among the smallest of free-living organisms that cause disease in man (≈10 × 200 nm) and has a relatively small genome of 816,394 base pairs of DNA encoding 679 genes. Because it lacks a cell wall, M. pneumoniae is insensitive to penicillin and other β-lactam antibiotics and does not take up Gram stain.

M. pneumoniae can be grown in cell-free artificial media but has complex growth requirements and grows slowly. On horse serum and yeast extract–enriched agar medium, it requires 6 to 7 days to form granular or characteristically “fried egg”–appearing colonies. The fried egg appearance results because the centers of the colonies are dense and embedded in the agar medium, whereas the less dense periphery is spread on the agar surface. At maturity colonies may range in size from 50 to 100 microns in diameter. When stained with Dienes stain, colonies contain densely stained small granules. M. pneumoniae ferments glucose and other sugars, including xylose, mannose, maltose, dextrin, and starch. It produces a hemolysin that will lyse human, guinea pig, or horse erythrocytes within 24 to 48 hours in artificial media.

Lacking a cell wall, M. pneumoniae is bounded by a trilaminar cell membrane that is rich in sterols. It divides by binary fission and is pleomorphic when grown on an inert surface.

M. pneumoniae adheres to respiratory epithelial cells and to red blood cells via sialic acid receptors. Adherence is mediated by a complex set of adhesion proteins, including P1, P30, proteins B and C, P116, and HMW1-3. These form an organelle at one end of the rodlike structure of the organism. The adhesion organelle also allows the organism to have gliding motility. Types 1 and 2 M. pneumoniae strains differ because of major variations of the P1 adhesion protein. Distinguishing among these types is important for surveillance, epidemiologic, and clinical purposes.

M. pneumoniae also elaborates a cytotoxin that has been called the community-acquired respiratory distress syndrome (CARDS) toxin. This is a cell-associated adenosine diphosphate ribososylating and vacuolating cytotoxin that is present in the inflamed airways of infected experimental animals and elicits antibodies that appear as the infection wanes.

M. pneumoniae forms biofilms. These are volcano-like structures composed of polysaccharide, protein, and lipid. The organisms become encased in the biofilm. It has been shown that types 1 and 2 M. pneumoniae strains form very different biofilms and that these confer differential resistance to antibiotics and may alter the ability of antibodies, complement, and white blood cells to penetrate to and attack the organisms.

As macrolide resistance has become more prevalent, case reports have suggested that resistant isolates might be more virulent than sensitive ones ; however, in one family, a wide spectrum of severities were found. Also, in a single case report severe disease was seen in a 14-year-old adolescent with infectious mononucleosis. At present, any association between macrolide resistance and disease severity must be judged speculative.

Epidemiology

M. pneumoniae are distributed worldwide with minor, if any, effects of climate on the incidence of disease. Long-term studies have shown a pleomorphic annual cycle: In some years there are seasonal peaks in fall and winter, whereas in other years there is little evidence of seasonality.

Infection has been described at all ages; however, it is primarily a disease of childhood and adolescence, with the peak incidence of infection between 5 and 15 years of age. It has been reported that children younger than 3 years develop primarily upper respiratory tract infection, whereas those 5 to 20 years of age tend to develop bronchitis and pneumonia. In older infected adults pneumonia predominates. Because asymptomatic infection is common, descriptions of the disease's epidemiology must be interpreted in light of whether the data was collected from cases of symptomatic disease or from systematic survey of defined populations.

Seroepidemiologic studies in the United States showed an incidence of mycoplasmal pneumonia of 5 per 1000 per year among those 10 years of age and 1 per 1000 per year among those 25 to 50 years of age. Annual incidence fell as age increased further. There were no major sex differences. It was estimated that, overall, at least one case of mycoplasmal pneumonia occurs annually for each 1000 persons, or more than 2 million cases annually. The total incidence of mycoplasmal infection at all sites in the respiratory tract may be 10 to 20 times higher.

A prospective study of all adults from two counties in Ohio, who required admission for community-acquired pneumonia during 1991, demonstrated similar rates of hospitalization for M. pneumoniae and Streptococcus pneumoniae for those between 15 to 34, 34 to 65, and 66 to 79 years of age, with a continued increase in the incidence of disease from each pathogen in those older than 80 years, but in this oldest group there was a divergence, with the rate of S. pneumoniae disease rising above that resulting from M. pneumoniae . M. pneumoniae was not seasonal in this study, whereas S. pneumoniae had a clearly defined seasonality,

M. pneumoniae is spread from person to person. Spread of infection appears to be by droplet infection. The infection is transmitted by coughing and spread of droplets, and patients may remain infectious for prolonged periods after many of the symptoms other than cough have disappeared. The organism and disease associated with it can relapse or be transmitted even after treatment of patients with effective antibiotics.

When assessed within families, the rate of spread is slow, but, because of prolonged carriage, it is extensive. In one study, spread occurred in 23 of 36 families, and among the 23, 84% of children and 41% of the adults became infected. In another study the total infection rate was 58% (81% in children).

In closed populations, such as military recruit camps and boarding schools, M. pneumoniae disease can be epidemic. Outbreaks have been described in schools, hospital workers, and even the confined spaces of nuclear submarines. M. pneumoniae also can cause nosocomial infections in long-term care (LTC) facilities. A report from the Centers for Disease Control and Prevention (CDC) described an outbreak that occurred in an LTC facility in Nebraska. The respiratory illness, characterized by cough and fever, occurred in 55 residents of the LTC and resulted in 12 hospitalizations and 7 deaths. M. pneumoniae DNA was detected by polymerase chain reaction (PCR) in 40% of the specimens collected. The outbreak was terminated by strict observance of good infection control practices. This report points out that serious M. pneumoniae infections are not confined to children and young adults, can cause disease in the elderly, and should be considered in clusters of nosocomial pneumonia.

Reports of two outbreak scenarios illustrate how transmission occurs and the disease spreads. One occurred among 26 of 55 members of a college fraternity who attended a pledging banquet. Symptoms occurred in the first of the infected fraternity members 1 week after the banquet, and the epidemic reached its peak 6 days later. In this instance multiple members of the fraternity were simultaneously exposed to a high concentration of infectious M. pneumoniae and developed disease synchronously. In a second outbreak employees of a large hospital in New York City developed illness over a 6-month period (July–December), but a single source for the outbreak could not be identified.

Because infection is often asymptomatic or mild in children, and shedding persists long after illness, even after treatment children are often the reservoir from which spread can occur.

Immunology and Resistance

Innate Immunity

Initial host-parasite interactions with M. pneumoniae are likely to involve the innate immune system; however, the details are just beginning to be elucidated. Cathelin-related antimicrobial peptide, a molecule that protects the host from other infectious agents, was shown to inhibit the growth of M. pneumoniae , and its presence was increased in the cells of M. pneumoniae –infected mice. Mice lacking the gene for heat shock factor 1, a transcription-controlling molecule that is active in the response to a wide variety of stresses, had a higher concentration of M. pneumoniae in their lungs than did those with the gene. Mice that lacked the gene for human SPLUNC1 (short palate, lung, nasal, and epithelial clone 1) protein had lower concentrations of M. pneumoniae than did those in which it had been inserted.

Infection of cell cultures of A549 lung cancer cells with M. pneumoniae has been shown to increase the level of proinflammatory cytokines (interleukin [IL]-8, IL-1) in the cultures.

In a guinea pig model peritoneal and alveolar macrophages ingested and killed opsonized M. pneumoniae at a rate slightly slower than other bacteria; however, the authors, Erb and Bredt, concluded that the delay was not clinically significant. Of note, the cell-adherent but unopsonized organisms were relatively resistant to killing mediated by complement.

Adaptive Immunity

M. pneumoniae induces a rich immune response. The humoral response includes protective immunoglobulin G (IgG) and IgA antibodies. Mice born to immune mothers were protected from infectious challenge, whereas those born to nonimmune mothers were not. The protection was shown to be due to IgG antibody in maternal colostrum. Similar protective effects were shown in a hamster model in which passive transfer of serum conferred humoral but not cellular immunity. In human studies the level of IgA antibody in nasal secretions correlated with protection after experimental challenge. Protection is probably mediated by antibody against M. pneumoniae polysaccharide rather than against its proteins, and the antibody may act by blocking the binding of the pathogen to epithelial surfaces.

One of the striking aspects of the immune response to M. pneumoniae is the production of isohemagglutinins directed against the I antigen expressed on the surface of adult erythrocytes. As discussed above, the presence of “cold agglutinins” was described in 1942 by Finland and coworkers. They showed that such antibodies were present in 50% to 70% of patients with Eaton agent pneumonia and that the agglutination, produced by holding erythrocytes at 4°C, was reversible by warming them to 37°C.

Cold Agglutinins

Cold agglutinins are IgM antibodies and are often present at the start of or in the first week of clinical illness. They may persist for several months after illness. Several theories have been suggested to account for their appearance. One is that the I antigen, present on erythrocytes, is also present in respiratory epithelium and is part of the receptor through which the organism attaches to the cell. Thus the antibody is actually directed at the binding complex or a part of it. Another theory suggests that the antibody is actually directed against a polysaccharide component of M. pneumoniae . This is based on the observation that immunization of rabbits with either M. pneumoniae , Streptococcus MG (a group F α-hemolytic streptococcus), or Listeria monocytogenes produced cold agglutinins that were inactivated by incubation with M. pneumoniae membrane-associated lipopolysaccharide.

Cold agglutinins have no known role in the development of pneumonitis, but they may occasionally be directly pathogenic, particularly when the antibody titers are high, producing hemolysis, capillary obstruction with the Raynaud phenomenon, renal failure, and, rarely, gangrene ( Fig. 183.1B and C ).

FIG. 183.1, Skin conditions associated with Mycoplasma pneumoniae infection.

Complement-fixing M. pneumoniae –specific antibodies also appear early in the course of illness and high levels persist for several months after infection. Seroprevalence surveys suggest that these antibodies persist at a low level for much more prolonged periods.

Resistance and Susceptibility to Infection

There are few or no data relating specific conditions to the infectious inoculum of M. pneumoniae . Knowledge about which factors affect severity and duration of M. pneumoniae infection rests primarily on case reports or small series of patients with severe disease. Because severe disease is also seen in those without obvious predisposition, such associations must be considered tentative.

Although the immune systems may play a role in pathogenesis of clinical disease, the humoral response to infection provides immunity to reinfection for some period of time. Reinfections with M. pneumoniae are generally milder than initial infections, and both antibody (human and murine) and colostrum (murine) were protective against M. pneumoniae in murine models. Intensity of antibody response was inversely correlated with severity of M. pulmonis infections in rats. Additional studies in mice showed that in comparison with immunocompetent mice, those with X-linked immunodeficiency failed to show severe lung lesions despite Mycoplasma pulmonis in their lungs. Mice with severe combined immunodeficiency also had milder lung lesions but allowed the mycoplasma infection to spread to the joints, where they produced severe pathology.

Several reports have suggested that children with sickle cell SS or SC hemoglobinopathy are predisposed to severe disease, but severe disease has not been reported in association with sickle trait (hemoglobin SA). M. pneumoniae has been found to be responsible for 16% to 20% of cases of sickle cell anemia–associated “chest syndrome.” Children with Down syndrome have also been reported to be disposed to severe disease. Neither adults with chronic obstructive lung disease nor cigarette smokers are predisposed to M. pneumoniae infection.

M. pneumoniae is not generally considered an opportunistic pathogen in immunocompromised patients; however, a few reports suggest that cytotoxic chemotherapy and neutropenia may be associated with severe and prolonged disease. A 7-year-old boy with hypogammaglobulinemia was reported to recover completely from mycoplasmal pneumonia but had continued carriage over a 2-year period despite additional courses of antibiotics.

Many studies suggest that genetic factors, as yet undefined, may play a role. In the mouse there are marked strain differences in disease severity, and male sex is associated with severe disease. Reviews of severe mycoplasmal pneumonia in humans have also shown a predominance of males. One case report documents markedly different disease severity in identical twins, demonstrating that severity is not solely conditioned by genetic factors.

Suprainfection during the course of mycoplasmal pneumonia is unusual; however, there are suggestions that when there is concomitant pulmonary inflammation or coinfection the clinical severity is worsened. Thus, in a study of Kenyan refugee camps, persons coinfected with “atypical pathogens” and respiratory viruses were significantly more likely to have severe respiratory illness. Acute exposure of mice to nitrogen dioxide worsened the pathologic findings when the exposed mice were subsequently infected with Mycoplasma pulmonis .

Pathology

M. pneumoniae infections are common in children and young adults but are very uncommonly fatal. Postmortem examination in one fulminant case showed extensive exudates in the lungs, with abscess formation, pericarditis, and disseminated intravascular coagulation with involvement of skin, lungs, and adrenals. A review of 11 other autopsied cases showed similar findings.

There are several mechanisms by which M. pneumoniae can cause disease. First, attachment of the organism to sialic acid receptors on respiratory epithelium, via its attachment organelle, may directly damage the respiratory epithelium and its ciliary activity. Second, M. pneumoniae elaborates a cytotoxin, the CARDS toxin, that may also directly damage the respiratory tract. Third, the organism may alter antigens on the surface of cells to which it is attached to the extent that autoantibody formation is elicited. This is presumed to be the mechanism by which the anti-I cold hemagglutinin antibody is formed. Finally, M. pneumoniae and/or its CARDS cytotoxin may elicit the influx of inflammatory cells, which then produce proinflammatory cytokines that may result in damage to the host.

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