INTRODUCTION — Mycoplasma pneumoniae is one of the smallest free-living organisms and a common bacterial respiratory tract pathogen. Upper respiratory tract infections and acute bronchitis are the most common manifestations of M. pneumoniae infection, but pneumonia can also occur. Manifestations outside the respiratory tract (eg, encephalitis, hemolytic anemia, and carditis) are rare and can occur with respiratory tract infections or independently.
The clinical features, diagnosis, and treatment of infections, primarily pneumonia, caused by M. pneumoniae in adults will be reviewed here. M. pneumoniae infections in children as well as Mycoplasma hominis infections are discussed separately. (See "Mycoplasma pneumoniae infection in children" and "Mycoplasma hominis and Ureaplasma infections".)
MICROBIOLOGY — The term "mycoplasma" is widely used to refer to any organism within the class Mollicutes, which is composed of five genera (Mycoplasma, Ureaplasma, Acholeplasma, Anaeroplasma, and Asteroleplasma). Mycoplasmas are bacteria and are the smallest free-living organisms.
Over 120 named Mycoplasma species exist and 13 Mycoplasma species, 2 Acholeplasma species, and 1 Ureaplasma species have been isolated from humans. However, only four species are well-established human pathogens [1]:
●M. pneumoniae
●M. hominis
●Mycoplasma genitalium
●Ureaplasma urealyticum
Mycoplasma amphoriforme is less well-established as a human pathogen but has been reported to cause relapsing pneumonia through person-to-person spread in both immunocompetent and patients with primary antibody deficiency [2,3].
Among Mycoplasma species, M. pneumoniae is the most common cause of human respiratory illness. The organism is a short rod that lacks a cell wall. Because it lacks a cell wall, M. pneumoniae is not visible on Gram stain and is not susceptible to beta-lactams and other antibiotics that inhibit cell wall synthesis. These features designate M. pneumoniae as an "atypical" pathogen.
PATHOGENESIS — The mechanisms by which mycoplasmas produce infection are becoming better understood. Pathogenic mycoplasmas possess specialized tip organelles that mediate their interactions with host cells through a P1 adhesin protein that contributes to adherence and gliding motility along the respiratory epithelium [4-6].
M. pneumoniae most commonly exists in a filamentous form, and its adherence proteins attach to epithelial membranes with particular affinity for the respiratory tract [7,8]. Once attached, M. pneumoniae produces hydrogen peroxide and superoxide, causing injury to epithelial cells and their associated cilia. Toll-like receptor 2 is also believed to be important for binding of Mycoplasma and activation of inflammatory mediators, including cytokines [9-11]. Robust immune responses, especially, production of interleukin 17, may play a role in the severity of disease [12]. Host-adapted survival is achieved by surface parasitism of target cells, the acquisition of essential biosynthetic precursors, and, in some cases, cell entry and intracellular survival [13].
There are two major subtypes of M. pneumoniae, type 1 and type 2, which differ in their P1 adhesin gene sequence [14]. Type 2 strains exhibit higher expression of community-acquired respiratory distress syndrome toxin, which has been shown to be a virulence factor causing vacuolization and which may play a role in respiratory epithelial destruction [15-18]. In addition, type 2 elaborates a more robust biofilm, which may protect the organism against antimicrobial penetration and host immune response [19].
Some of the pathogenic features of M. pneumoniae infection, particularly those that occur outside of the respiratory tract (eg, hemolysis, encephalitis) are believed to be immune mediated rather than caused by direct bacterial invasion [8,20]. Antibodies produced against the glycolipid antigens of M. pneumoniae may act as autoantibodies, since they cross-react with human brain cells and erythrocytes [21], as manifested in the cold agglutination phenomenon. (See 'Hemolysis' below.)
Following acute infection, prolonged asymptomatic carriage can develop [22-24]. While the mechanisms that mediate prolonged carriage are poorly understood, intracellular invasion, bacterial-induced cytoskeleton rearrangement, and tissue remodeling may be contributing factors [24]. Antibodies against M. pneumoniae made during acute infection seem to prevent against adhesion to respiratory epithelium, but these antibodies do not play a role in preventing chronic carriage [25].
EPIDEMIOLOGY — M. pneumoniae is endemic worldwide and causes both sporadic and epidemic infections.
Incidence and prevalence — M. pneumoniae is among the most common bacterial causes of upper respiratory tract infection (URI), acute bronchitis, and community-acquired pneumonia (CAP). Serologic surveys suggest that approximately 1 percent of the United States population is infected with M. pneumoniae annually [26]. However, the incidence of specific clinical manifestations (eg, URI, acute bronchitis) are difficult to estimate as these infections are often mild and underdiagnosed.
Although URI and acute bronchitis are more common manifestations, the epidemiology of pneumonia has been better studied [27-38]. Based on epidemiologic studies that have used molecular techniques for the microbiologic diagnosis of CAP, estimates of M. pneumoniae infection range from 2 to 12 percent among adults with CAP [36,38]. During epidemic periods, rates can rise considerably. (See 'Outbreaks' below.)
Generally, CAP caused by M. pneumoniae is more common in young children than in adolescents and adults [39]. As an example, in a United States Centers for Disease Control and Prevention (CDC) surveillance study evaluating 2259 adults hospitalized with CAP over a two-year time period, M. pneumoniae was detected in 2 percent of cases [36]. By contrast, in a companion study evaluating 2359 children hospitalized with CAP over the same time period, M. pneumoniae was detected in 7.5 percent of cases [40]. M. pneumoniae was more common among children aged ≥5 years than among younger children (19 versus 3 percent).
Clinically significant manifestations rarely occur outside the respiratory tract.
Transmission — M. pneumoniae is primarily transmitted from person to person via respiratory droplets. The incubation period after exposure averages two to three weeks [41]. While M. pneumoniae infections occur year round, rates tend to rise in summer and peak in late fall or winter during nonepidemic periods [21,36,40,42-44].
Outbreaks — Epidemics tend to occur every few years [42,44-47]. Because M. pneumoniae is spread via respiratory droplets, epidemics frequently arise among persons living in close quarters. As examples, epidemics have been reported in households [48], schools [49], universities [50-52], health care facilities [53-55], and the military [56-58]. Based on household outbreaks, cumulative attack rates among persons living in close quarters can be as high as 90 percent [26].
Epidemics can extend into the community, encompass broad geographic regions, and persist for months to years [59,60]. Epidemics in a given geographic region tend to begin in winter months in countries of highest latitude and spread southward [61]. As an example, a marked rise in M. pneumoniae infections occurred in several northern European countries (ie, United Kingdom, Ireland, Norway, Sweden, Finland, Denmark, Germany, France) from 2010 to 2011 [62-65]. During this period, M. pneumoniae was estimated to cause 10 to 13 percent of CAP cases. In the three-year period following the epidemic, rates decreased to 1 to 2 percent [60,62-65].
Epidemics offer the opportunity to study risk factors for symptomatic infection. In an outbreak in a military unit, 41 of 91 trainees (45 percent) developed M. pneumoniae respiratory tract infections [57]. Among them, 10 (11 percent of all trainees) developed pneumonia. Smoking and low pre-existing Mycoplasma-specific immunoglobulin (Ig)G were independently associated with symptomatic infection (adjusted odds ratio [aOR] 5.6, 95% CI 1.5-20.4 and 7.8, 95% CI 1.3-42.5, respectively).
CLINICAL MANIFESTATIONS — The spectrum of illness associated with M. pneumoniae infection is wide [66]. Infection is often asymptomatic [22,41]. When infection is symptomatic, the most common manifestations include upper respiratory tract infection (URI), acute bronchitis, and pneumonia. Although a broad range of manifestations that do not involve the respiratory tract have been associated with M. pneumoniae infection, they are rare [41,67].
Asymptomatic carriage — Asymptomatic infection appears to be common, and prolonged carriage can occur following symptomatic infection [22,23,57,68-70]. Carriage rates in healthy persons range widely in epidemiologic studies, from approximately 0 to 50 percent [22,23,68,71]. Variance among studies likely reflects differences in local prevalence, patient age, diagnostic assays used, and study sample size. Following acute infection, asymptomatic carriage can persist for weeks to months, with a median duration of approximately seven weeks [22,23,46].
Studies using nucleic acid-based assays have demonstrated the presence of M. pneumoniae deoxyribonucleic acid (DNA) in the respiratory secretions of asymptomatic individuals with no recent history of respiratory illness, indicating the existence of a carrier state. The prevalence of this state is to be determined but may play a significant role in M. pneumoniae transmission [22]. (See 'Transmission' above.)
Respiratory tract disease
URI and acute bronchitis — Upper respiratory tract infection (URI) and acute bronchitis are the most common syndromes associated with M. pneumoniae infection [67,72,73]. The clinical features associated with URI and acute bronchitis caused by M. pneumoniae are similar to those caused by other pathogens.
URI symptoms associated with M. pneumoniae infection include cough, sore throat, rhinorrhea, coryza, and ear pain [20,72]. Cough is typically a dominant symptom and can be nonproductive or productive [52,72]. Wheezing can accompany the cough. The cough can be intractable or prolonged, which is the hallmark of acute bronchitis. Dyspnea is uncommon in the absence of pneumonia. Sinusitis can co-occur with respiratory symptoms but is typically clinically inapparent [20]. Like URIs and acute bronchitis caused by other pathogens (eg, respiratory viruses), URI and acute bronchitis caused by M. pneumoniae are typically self-limited; microbiologic testing and antibiotic treatment are usually unnecessary. (See "The common cold in adults: Diagnosis and clinical features" and "Acute bronchitis in adults", section on 'Clinical features'.)
Pneumonia — Pneumonia is a less common manifestation of M. pneumoniae infection, affecting about 3 to 10 percent of patients with respiratory tract disease [72]. Pneumonia caused by M. pneumoniae is often termed an "atypical pneumonia," which may refer to its mild nature or alternatively to the intrinsic resistance of M. pneumoniae to penicillins.
M. pneumoniae pneumonia is typically community acquired and mild. Signs and symptoms vary with stage of illness (figure 1). Illness onset is gradual and may be heralded by headache, malaise, low-grade fever, and sometimes sore throat [21,33,41,52,66]. Cough (either productive or nonproductive) typically follows and may be accompanied by pleuritic chest pain or shortness of breath [33]. Chest soreness from persistent coughing is a common complaint. Other signs and symptoms of URI (eg, rhinorrhea, otitis media, sinusitis, cervical lymphadenopathy) can co-occur with pneumonia. Dyspnea, hypoxemia, hypotension, and altered mental status may be less common when compared with CAP caused by other pathogens [33,41].
Chest auscultation may be unremarkable early in the course of the disease; rales and wheezes may develop later [41]. Chest imaging tends to show reticular nodular opacities or patchy consolidations rather than large or lobar consolidations (see 'Chest radiograph' below). While the presence of these features support the diagnosis of M. pneumoniae pneumonia, none are pathognomonic and the diagnosis cannot be made without testing. (See 'Pneumonia' below.)
Compared with pneumonia caused by other pathogens, M. pneumoniae pneumonia is more commonly associated with mild extrapulmonary phenomena. For example, over half of patients have evidence of hemolysis, though this is often subclinical (see 'Hemolysis' below). Mild hepatic transaminitis may also be more common, although this association is less certain. White blood cell counts are often normal [33,74].
For most patients, the course is mild and recovery is full, even in the absence of antibiotic therapy. For some, constitutional symptoms can linger for one to two weeks following resolution of respiratory illness, making the total course of illness about one month [41]. Rarely, fulminant cases resulting in respiratory failure and death have been reported, particularly in young, previously healthy individuals [39,52,75-78].
Association with asthma — M. pneumoniae infection may worsen asthma symptoms in children, adolescents, and adults and can also produce wheezing in children who do not have asthma. A separate question, for which there has been some experimental and clinical evidence, is whether M. pneumoniae plays a role in the pathogenesis of asthma. This is discussed in detail separately. (See "Risk factors for asthma", section on 'Respiratory infections'.)
Non-respiratory tract disease — Manifestations outside the respiratory tract can occur with or independently of respiratory tract disease. While a wide array of disorders have been associated with M. pneumoniae infection, only a few have an established causal relationship. These include hemolysis, central nervous system (CNS) disease, dermatitis, carditis, joint disease, and gastrointestinal disease.
Hemolysis — Hemolysis accompanies M. pneumoniae infection in about 60 percent of cases and is typically mild or subclinical [21]. During the course of infection, Mycoplasma induces an alteration in the I antigen on the erythrocytes membrane. This, in turn, leads to the development of an IgM autoantibody directed at this antigen and immune-mediated hemolysis (also termed cold agglutinin disease) [79]. M. pneumoniae organisms have been shown to elaborate hydrogen sulfide, which may contribute to hemolysis [80]. (See "Cold agglutinin disease", section on 'Pathogenesis'.)
For most patients, hemolysis is self-limited; neither transfusion nor immunosuppressive treatment is needed. Rarely, hemolysis can be severe and life-threatening, particularly in patients with underlying hematologic disorders such as sickle cell disease [21,81,82]. (See "Cold agglutinin disease", section on 'Management'.)
CNS involvement — Central nervous system (CNS) manifestations occur in approximately 0.1 percent of all patients with M. pneumoniae infections and in up to 7 percent of those patients requiring hospitalization [72,83,84]. Overall, CNS involvement occurs more frequently in children than in adults. In cases of CNS involvement due to M. pneumoniae, a history of an antecedent respiratory illness is usually, but not always, found [85].
Encephalitis is the most common CNS manifestation. Other manifestations include meningitis, peripheral neuropathy, transverse myelitis, acute disseminated encephalomyelitis (ADEM), Guillain-Barré syndrome (GBS), cranial nerve palsies, and cerebellar ataxia [86-89]. Some of these manifestations, such as meningitis, are thought to be due to direct bacterial invasion of the CNS and occur at illness onset [90]. Others such as ADEM and GBS are thought to be postinfectious immune phenomena, caused by cross-reaction of Mycoplasma antibodies with galactocerebroside [83,91,92]. Stroke can also occur following M. pneumoniae infection, most likely due to vascular injury. However, the pathogenesis of CNS disorders has not been fully defined and the boundaries between infectious, vascular, and immune phenomena are not always clear.
The prognosis varies with the type and extent of CNS involvement but can be poor. As an example, in a review of 61 individuals with neurologic disease attributed to M. pneumoniae found that 5 patients (8 percent) died and 14 (23 percent) had severe sequelae [83]. Among CNS disorders, transverse myelitis and ADEM can be particularly morbid. In one literature review, 59 percent of patients presenting with spinal cord involvement suffered permanent neurologic sequelae [93].
Mucocutaneous disease — Mucocutaneous and cutaneous disease are among the more common non-respiratory tract manifestations of M. pneumoniae infection. Manifestations include mild erythematous maculopapular or vesicular rashes, urticaria, erythema multiforme, Stevens-Johnson syndrome (SJS), and M. pneumoniae-induced rash and mucositis [94-98] (see "Mycoplasma pneumoniae-induced rash and mucositis (MIRM)"). Concurrent or antecedent respiratory symptoms are often present but not always prominent.
Like other nonrespiratory tract manifestations, some cutaneous manifestations may result directly from bacterial infection while others may be immune phenomena. Rashes or exanthema are often mild and self-limiting. They are reported to accompany approximately 17 percent of respiratory tract infections and can be confused with hypersensitivity reactions to antibiotics [90].
Erythema multiforme caused by M. pneumoniae is similar to other forms of this syndrome but more frequently occurs with mucosal and respiratory tract involvement [98]. While SJS is an uncommon manifestation of M. pneumoniae infection, M. pneumoniae appears to be among the most common infectious causes of SJS [94]. Among patients with SJS due to M. pneumoniae, concurrent pneumonia is more common than mild upper respiratory tract infection [99]. (See "Erythema multiforme: Pathogenesis, clinical features, and diagnosis" and "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis".)
M. pneumoniae-associated mucositis is a syndrome characterized by erosive oral, ocular, and genital lesions that occurs most often in children. (See "Mycoplasma pneumoniae infection in children", section on 'Mucocutaneous disease'.)
Cardiac involvement — Cardiac involvement is a less common non-respiratory tract manifestation of M. pneumoniae infection. The range of reported manifestations include pericarditis, myocarditis, cardiac thrombi, and conduction abnormalities [52,100-104]. There is a single but convincing report of M. pneumoniae endocarditis [101]. There is a putative associated with M. pneumoniae infection and atherosclerotic heart disease based on the seroprevalence of infection in people with atherosclerosis and the detection of M. pneumoniae nucleic acid in atheroma [105].
While most cardiac manifestations are thought to be due to direct bacterial infection, some cases of myocarditis and cardiac thrombosis may be immune related [103]. More so than other nonrespiratory tract manifestations, cardiac manifestations tend to occur independently of respiratory tract disease.
Other associations — Hepatitis, typically manifested as mild elevations in hepatic transaminases, is commonly reported among patients with M. pneumoniae infections [106,107]. Other gastrointestinal complaints tend to be mild and nonspecific.
Common musculoskeletal manifestations include arthralgias and myalgias; actual arthritis is rare [78,108]. Most cases of M. pneumoniae arthritis are believed to be immune mediated. However, M. pneumoniae has been isolated from synovial fluid in some patients with polyarthritis, suggesting that direct infection is also possible [109].
A wide variety of other conditions have been associated with M. pneumoniae infection in the medical literature, ranging from anterior uveitis [110-112], glomerulonephritis [113,114], pancreatitis [21], thrombotic microangiopathies [115,116], and rhabdomyolysis [117,118]. Because of the challenges in accurately diagnosing M. pneumoniae infection and the infrequent occurrence of these conditions, the extent to which M. pneumoniae plays a causal role in their pathogenesis is uncertain.
Previously, M. pneumoniae was believed to cause bullous myringitis [119]. However, accumulating microbiologic and epidemiologic data suggest that this association is spurious [120].
COVID-19 coinfection — Probable coinfection with coronavirus disease 2019 (COVID-19) and M. pneumoniae has been reported [121]. In one study, patients with COVID-19 who were believed to have concurrent M. pneumoniae infection, had more persistent cough, slightly longer hospitalization, and a longer recovery period than those without evidence of mycoplasma disease [121]. These patients also had higher bilirubin levels and more severe hypercoagulability and thrombosis. Mortality in this study was minimal in both groups. However, signs and symptoms of COVID-19 and M. pneumoniae infection overlap, it is difficult to parse which clinical factors were associated with which pathogen and whether they are additive. (See "COVID-19: Clinical features".) .
DIAGNOSIS
URI and acute bronchitis — In general, the diagnosis of upper respiratory tract infection (URI) and acute bronchitis are made clinically; we do not pursue a microbiologic diagnosis in patients with mild infections that are expected to improve without treatment, such as URIs and acute bronchitis. (See "The common cold in adults: Diagnosis and clinical features" and "Acute bronchitis in adults", section on 'Clinical features'.)
Pneumonia
Approach to diagnosis — For most adults with community-acquired pneumonia (CAP), pursuing a microbiologic diagnosis of M. pneumoniae is not necessary, as results would not change management [122]. Treatment for CAP is typically empiric, and most recommended regimens for adults in the United States include an agent that targets atypical pathogens, such as M. pneumoniae [122]. Most available diagnostic assays for M. pneumoniae have limitations including lack of validation, variable specificity, limited availability, and/or long turnaround times [123].
We therefore typically reserve M. pneumoniae testing for selected patients with suggestive clinical features or severe pneumonia in whom directing antibiotic therapy at M. pneumoniae would provide benefit (eg, narrowing an otherwise broad empiric regimen) or when having a specific diagnosis would provide prognostic value. As examples:
●For patients with a compelling clinical presentation (eg, indolent onset pneumonia with concurrent hemolysis or mucocutaneous disease), we generally obtain a Mycoplasma polymerase chain reaction (PCR) from a respiratory tract sample (eg, nasopharyngeal swab, sputum, bronchoalveolar lavage fluid) to help direct therapy.
●For patients with severe CAP, we sometimes obtain a multiplex PCR-based assay that includes testing for M. pneumoniae from an upper or lower respiratory tract sample when pursuing a broad microbiologic evaluation. (See 'Molecular testing' below and "Clinical evaluation and diagnostic testing for community-acquired pneumonia in adults", section on 'Differential diagnosis'.)
During outbreaks, testing (often under the direction of public health authorities) is prudent to help define the nature and duration of the outbreak.
As the availability of molecular diagnostics increases and turnaround times fall, indications for testing for and subsequently providing pathogen-directed therapy are expected to expand. Presently, some clinicians and experts with multiplex PCR panels or nucleic acid-based tests available at their institutions perform this test on most hospitalized patients with CAP and target therapy at M. pneumoniae when this organism is detected and typical pyogenic bacteria have been ruled out.
Although PCR-based assays are the tests of choice for diagnosing M. pneumoniae pneumonia, caution is needed when interpreting results. Both asymptomatic carriage and coinfection with M. pneumoniae and other pathogens is relatively common [22,41,124]. PCR-based assays cannot distinguish between active infection caused by M. pneumoniae alone and either asymptomatic carriage or coinfection. Thus, we generally consider positive test results to provide presumptive diagnoses and consider the completeness of the microbiologic evaluation and the clinical context heavily when interpreting results.
Because these assays are not available at all institutions and turnaround times can be long sending tests to reference laboratories, we also consider the likelihood of obtaining a timely result when deciding to test. Serology using enzyme immunoassay of paired acute and convalescent sera has traditionally been the mainstay of laboratory diagnosis. However, serology is now used as an alternative when a PCR-based assay is not available or as an adjunct to PCR [123]. (See 'Mycoplasma-specific assays' below.)
Laboratory studies — Hemolysis is the most distinctive laboratory finding associated with M. pneumoniae infection and is typically manifest as a reduction in hemoglobin levels with concurrent rises in unconjugated bilirubin, lactate dehydrogenase, and reticulocyte count [78]. Because the hemolysis is immune mediated (driven by M. pneumoniae-induced cold agglutinins, which target the I antigen on the red blood cell), a direct Coombs test and cold-agglutinin titers are typically positive [125]. While these tests support the diagnosis of M. pneumoniae infection, we do not routinely obtain them as part of our evaluation because M. pneumoniae-associated hemolysis is typically mild and self-limited. Occasionally, cold agglutinins can be used to support a clinical diagnosis of M. pneumoniae infection when a rapid diagnosis must be made. More often, these tests are obtained as part of the evaluation for hemolytic anemia of uncertain cause. (See "Diagnosis of hemolytic anemia in adults".)
Other laboratory features that support the diagnosis of M. pneumoniae infection are nonspecific but include mildly elevated hepatic transaminases and a normal or mildly elevated white blood cell count. One retrospective study found that a high ratio of serum C-reactive protein to procalcitonin is a strong predictor of M. pneumoniae infection in patients with CAP [126]. However, additional study is needed to help determine whether these results can be used to help guide therapy.
Chest radiograph — The radiographic features of M. pneumoniae pneumonia are generally similar to those seen with other atypical or viral pneumonias. The most common radiographic findings on chest radiograph are reticulonodular and/or patchy opacities, which can be unilateral or bilateral (image 1) [127]. Other findings may include a thickened bronchial shadow, streaks of interstitial infiltrates, and areas of atelectasis. Nodular infiltrates and hilar adenopathy are less common [41,127]. Small pleural effusions, usually unilateral, may be seen in 15 to 20 percent of cases; empyema is rare. Computed tomography (CT) scanning is typically not indicated for patients with CAP, but reported findings among patients with M. pneumoniae pneumonia include centrilobular nodular and tree-in-bud opacities in a patchy distribution, lobular or segmental ground-glass opacities or consolidation, and thickening of the bronchovascular bundle [127-129]. In one study using high-resolution CT to evaluate patients with bacterial CAP, lateral bronchial wall thickening coupled with minimal air bronchograms were indicative of M. pneumoniae pneumonia [130]. Although these radiographic features have been reported among patients with M. pneumoniae pneumonia, they are ultimately not specific enough to distinguish definitively M. pneumoniae pneumonia from other interstitial pneumonias.
Mycoplasma-specific assays
Molecular testing — Nucleic acid amplification tests (NAATs) are the diagnostic method of choice for M. pneumoniae pneumonia. Available assays include direct DNA amplification tests, such as PCR (which detect M. pneumoniae DNA only) and multiplex assays (which detect multiple respiratory tract pathogens on a single sample).
●We generally use direct PCR or other NAAT when our clinical suspicion for M. pneumoniae pneumonia is high (eg, for patients with indolent onset pneumonia and concurrent hemolysis or mucocutaneous disease). NAATs can be performed on most respiratory tract specimen types, including nasopharyngeal swabs, sputum, and bronchoalveolar lavage (BAL) fluid. Direct NAATs can also be performed on other sample types (eg, cardiac tissue, joint fluid, or oral lesions) and thus can be helpful in diagnosing non-respiratory tract infections [52,100,108,109,131]. In the United States, the Illumigene Direct DNA Amplification assay is approved for the diagnosis of M. pneumoniae infections. Assays that concurrently detect macrolide resistance are in development [132-135].
●Multiplex PCR-based assays are increasingly being used for the diagnosis of respiratory tract infections [136]. In the United States, the Biofire FilmArray respiratory panel includes M. pneumoniae and has been US Food and Drug Administration (FDA) approved for the diagnosis of respiratory tract infections [137,138]. While the assay is approved for use on nasopharyngeal swabs, it has also been used on sputum and BAL fluid with comparable results [139].
For patients with severe pneumonia in whom we are pursuing a broad microbiologic evaluation, we sometimes send multiplex PCR assays on respiratory tract specimens. Although multiplex PCR has been FDA cleared only for use on nasopharyngeal samples, PCR has also been evaluated using other respiratory tract specimens such as throat swabs, sputum, and BAL fluid with varying results [123,140]. In summary, a number of NAAT have been developed. These may be available as part of multiplex assay with variable sensitivities for M. pneumoniae, or as uniplex assay platforms, which may have higher sensitivity. Newer tests use methods other than PCR to detect M. pneumoniae genetic material. In practical terms, the practitioner will be bound by the preference of a given laboratory for one type of test over another [141,142].
Under optimal study conditions, NAATs have high sensitivity and specificity when compared with serology or culture [138,143-145], but caution is needed in interpreting results. NAATs cannot distinguish between active infection and either coinfection with other pathogens or asymptomatic carriage. In addition, the sensitivity of the assay likely varies with the timing of collection in the disease course [23,146]. As an example, in one study that reviewed the performance characteristics of real-time PCR in outbreak settings, the overall sensitivity of real-time PCR was 40 percent sensitivity compared with 40 and 35 percent for the IgM and IgG/IgM assays [147]. The sensitivity of PCR declined with time from 48 percent during the first 21 days of illness to 29 percent at days 22 to 59 days and 12 percent ≥60 days following symptom onset. Specificity of real-time PCR was 98 percent. In another study, PCR of specimens obtained from pharyngeal swabs was more likely to be positive than serology during the early phases of infection, but, for patients presenting during the third week of illness, PCR and serology were equivalent [23]. These studies suggest that PCR (particularly real-time PCR) is most useful during acute illness, when the bacterial burden is high. A test combining loop-mediated isothermal amplification (LAMP) with nanoparticle-based lateral flow biosensor (LAMP-LFR) and targeted at the community-acquired respiratory distress syndrome toxin appears to have high sensitivity and specificity [148].
Serology — Serology can be used as an alternative to molecular testing (when not available) or as an adjunct to molecular testing [146].
As with other infections, the gold standard for serologic diagnosis requires detection of a fourfold rise in IgG titers when comparing acute and convalescent serum samples [149]. Because this requires obtaining serologies both during acute infection and during recovery (approximately four weeks later), this is generally impractical. If the disease is encountered late in its course, a fourfold fall in titer may be as useful as a fourfold rise, although this approach is not well validated. Because IgM titers rise earlier than IgG titers (approximately seven to nine days into illness), using a single high IgM titer to make a presumptive diagnosis is an alternate strategy. However, the specificity of this diagnostic approach is likely low [150]. When molecular testing is also available, a single positive IgM in combination with a positive NAAT result helps corroborate the diagnosis.
When obtaining serologic testing, enzyme immunoassays are preferred over complement fixation tests due to their higher specificity. Performance characteristics of these assays may also vary considerably among laboratories [150,151].
Culture and other assays — Gram stain and culture are generally not helpful for the diagnosis of M. pneumoniae pneumonia. Because the organism lacks a cell wall, it is not visible on Gram stain. Culture is possible but requires specialized media. In addition, M. pneumoniae is a fastidious organism and takes approximately two to three weeks to grow. Thus, most clinical laboratories do not attempt to culture this organism. (See 'Microbiology' above.)
Antigen detection tests are available but have been largely replaced by NAATs [149].
Non-respiratory tract disease — The diagnostic approach for M. pneumoniae manifestations that occur outside of the respiratory tract varies with the suspected site of infection, presence of concurrent respiratory tract disease, and whether the manifestation is believed to be immune mediated or a direct result of bacterial infection. We generally pursue diagnosis when the testing results are likely to change management or provide helpful prognostic information.
When the manifestation is thought to be due to direct infection, diagnosis can be made by detecting or isolating M. pneumoniae at the affected site. When the manifestation is believed to be immune related and/or if direct detection is unrevealing, acute and convalescent serologies are the primary means of making a microbiologic diagnosis. When current respiratory tract disease is present, the diagnosis manifestation is often made presumptively based on detection of M. pneumoniae in the respiratory tract.
Because the boundaries between direct bacterial infection and immune-mediated processes are not always clear and because available diagnostics have limitations, we generally individualize our approach to diagnosis, keeping the above parameters in mind. As examples:
●Hemolysis typically co-occurs with respiratory tract disease and is mild or subclinical. Thus, diagnosis is most often made presumptively based on the presence of hemolytic anemia in a patient with known M. pneumoniae respiratory tract disease.
Rarely, hemolysis is severe and is the dominant presenting sign of infection. In this scenario, a positive direct Coombs test and/or cold-agglutinin titer can help corroborate the diagnosis of M. pneumoniae infection [152]. Acute or convalescent serologies and/or detection of M. pneumoniae in the respiratory tract (if respiratory symptoms are present) can help confirm the diagnosis [82].
●For patients with neurologic involvement, cerebrospinal fluid (CSF) typically reveals a lymphocytic pleocytosis, elevated protein, and normal glucose [84]. If the manifestation is thought to be due to direct bacterial invasion of the CNS (eg, meningitis), PCR or culture can be used to detect M. pneumoniae in the CSF. However, the diagnostic yield of this approach is uncertain [83,84,93]. Mycoplasma-specific serologies from peripheral blood and from the CSF can also be used to help make microbiologic diagnosis; however, their sensitivity and specificity are also uncertain. (See "Molecular diagnosis of central nervous system infections".)
For other non-respiratory tract manifestations such as carditis, arthritis, and mucocutaneous disease, diagnosis can sometimes be made by detection of M. pneumoniae at the affected site by PCR (eg, from myocardial tissue, synovial fluid, oral lesions, or vesicular fluid) [52,100,108,109,131].
TREATMENT
Pneumonia
Empiric therapy — For most patients with community-acquired pneumonia (CAP), the etiology is not known at the time of diagnosis, and empiric treatment is appropriate. In the United States, most recommended empiric regimens include an agent that targets both "typical" pathogens (eg, Streptococcus pneumoniae) as well as atypical pathogens, such as M. pneumoniae [122].
●For outpatients, empiric regimens generally include a macrolide (eg, azithromycin), doxycycline, or a respiratory fluoroquinolone (eg, levofloxacin or moxifloxacin). Each of these agents is active against M. pneumoniae, although there is regional resistance to macrolides (algorithm 1) (see 'Macrolide resistance' below).
●For hospitalized patients not requiring intensive care unit (ICU) admission, treatment with either a respiratory fluoroquinolone or treatment with a beta-lactam (eg, ceftriaxone or cefotaxime) plus a macrolide are first-line options for most patients (algorithm 2).
Although M. pneumoniae pneumonia is rarely severe enough to require ICU admission, most recommended empiric regimens for patients admitted to the ICU with CAP include either a respiratory fluoroquinolone or a macrolide (algorithm 3). Modifications to these regimens may be needed based on severity of illness, patient comorbidities and drug intolerances, local epidemiology, and risk factors for multidrug-resistant organisms. Antibiotic selection and duration of therapy vary with treatment setting and are discussed separately. (See "Treatment of community-acquired pneumonia in adults in the outpatient setting" and "Treatment of community-acquired pneumonia in adults who require hospitalization".)
Mycoplasma-specific therapy — For patients with microbiologically confirmed M. pneumoniae pneumonia, first-line treatment options include macrolides (eg, azithromycin), tetracyclines (eg, doxycycline), and respiratory fluoroquinolones (eg, levofloxacin or moxifloxacin).
We generally select among these agents based on patient comorbidities, potential drug interactions, and the likelihood of macrolide resistance. (See 'Macrolide resistance' below.)
●For most patients with M. pneumoniae pneumonia in regions where macrolide resistance is low (ie, <20 percent), such as the United States, we use azithromycin (either 500 mg orally on day 1 followed by 250 mg orally for four additional days or 500 mg orally for three days).
●When macrolide resistance is suspected based on local epidemiology (eg, in most of Asia and some parts of Europe) or other factors, we recommend either doxycycline (100 mg orally daily) or a respiratory fluoroquinolone (levofloxacin 500 mg orally daily or moxifloxacin 400 mg orally once daily).
When using an antibiotic other than azithromycin (which has a prolonged half-life), we base treatment duration on the patient's clinical response. For most patients with M. pneumoniae pneumonia, infection is mild and a five- to seven-day treatment course is sufficient. In more severe cases, 7 to 14 days may be needed. In all cases, we ensure that the patient is afebrile, clinically stable, and improving before stopping antibiotics.
Among antibiotics with activity against M. pneumoniae, azithromycin is the least likely to develop resistance based on in vitro studies [153,154]. Azithromycin's side effect profile is also generally favorable; by contrast, because of their higher side effect profile fluoroquinolones are often avoided in patients with mild disease and in younger patients. Clinical trial data are limited but do support azithromycin's high efficacy [155]. Levofloxacin and moxifloxacin also appear to be effective based on clinical trial data; however, the number of patients with M. pneumoniae infection in these trials is small [156,157]. Tetracyclines have been most well studied in children and also appear to be effective [158]. Beta-lactams such as penicillin and other antibiotics that target cell wall synthesis are ineffective because Mycoplasma species do not have a cell wall [159].
While our preference is to determine treatment duration based on clinical response, the optimal length of therapy for M. pneumoniae infection is not established. Because the organism can cause persistent infection, shedding can be prolonged, and clinical relapse has been reported [22,23,160], our threshold to extend the treatment course (eg, 7 to 14 days) is low. This is particularly true for immunocompromised patients and those with delayed resolution and/or chronic comorbidities. Patients with non-respiratory tract disease may also require longer courses of treatment. (See 'Non-respiratory tract disease' below.)
Non-respiratory tract disease — Antibiotic therapy is the mainstay of treatment for non-respiratory tract M. pneumoniae disease. When selecting an antibiotic for the treatment of M. pneumoniae infections outside of the lung, we generally select among active agents (ie, azithromycin, fluoroquinolones, and tetracyclines) based on patient age, the degree to which the agent penetrates the site of infection, and the likelihood of drug resistance. (See 'Macrolide resistance' below.)
Because some forms of manifestations of M. pneumoniae infection that occur outside the respiratory tract may be immune mediated rather than directly caused by bacterial infection, use of immunosuppressive agents or immunomodulatory therapy may be warranted for some patients. We generally individualize the decision to use these adjunctive therapies based on the site of infection, severity of illness, and clinical suspicion for an active immune-mediated process (eg, Guillain-Barré syndrome, acute demyelinating encephalomyelitis, severe hemolysis).
As examples, glucocorticoids, plasmapheresis, and intravenous immune globulin have each been used in addition to antibiotics for the treatment of central nervous system diseases [84,161,162]. Although most cases of M. pneumoniae-related hemolysis are mild or subclinical and self-limited, for severe cases of hemolytic anemia, warming, glucocorticoids, and plasmapheresis have been reported to help [8,114,163].
Macrolide resistance — When selecting an antibiotic for the treatment of known or suspected M. pneumoniae infection, it is important to take the likelihood of macrolide resistance into account. Macrolide resistance has been increasing in frequency in various regions worldwide, particularly in Asia. In a surveillance study from Japan from 2008 to 2013, 50 to 93 percent of isolates from children were resistant to macrolides, and the incidence of macrolide resistance increased over the time period assessed in the study [164]. In a report from China, 95 percent of M. pneumoniae isolates from adult patients with respiratory tract infections were resistant to macrolides [165]. Macrolide resistance has also been reported in 5 to 13 percent of isolates studied in France and the United States, with the highest regional rates reported in the eastern and southern United States [46,166-169]. Resistance in the United States from 2014 to 2021 averaged 10 percent [170]. Although a significant proportion of isolates worldwide remain susceptible to macrolides, alternative therapy should be considered in patients with severe or refractory disease, particularly in those who reside in areas with higher macrolide resistance rates. Macrolide resistance is not uniformly nor frequently measured in geographic areas where it has not been high. Macrolide resistance tests using NAAT methodology have been developed and are expected to lead to increased testing [141]. Lefamulin, a pleuromutilin, has in vitro efficacy against M. pneumoniae and might be a potential alterative when macrolide resistance is known or suspected and other agents cannot be used [171]; tigecycline proved therapeutic in a single case report [172].
PREVENTION — Because M. pneumoniae is spread from person to person primarily via respiratory droplets, hand and respiratory hygiene as well as isolation of hospitalized patients are important for preventing spread.
Infection control — Hospitalized patients with pneumonia caused by Mycoplasma species should be placed on droplet precautions, which should continue for the duration of the illness [173]. (See "Infection prevention: Precautions for preventing transmission of infection", section on 'Droplet precautions'.)
Reminding all patients of the importance of washing their hands with soap and water, using an alcohol-based hand sanitizer, and covering one's mouth when coughing or sneezing may also help prevent spread [52].
Postexposure prophylaxis — Antimicrobial prophylaxis is not needed for most patients who have been exposed to a person with an active M. pneumoniae infection. However, during outbreaks in close-contact settings or for selected individual patients (eg, an immunocompromised lung transplant recipient), antimicrobial prophylaxis may be warranted.
Several studies have evaluated the efficacy of azithromycin prophylaxis, either during outbreaks of M. pneumoniae pneumonia or in closed settings, such as military training facilities, in which the risk of acquisition is high [53,54,56,174]. As an example, in a randomized trial in 464 military recruits, those receiving azithromycin were less likely to develop respiratory infections than those receiving penicillin G benzathine (risk ratio 0.5, 95% CI 0.28-0.92) [56]. M. pneumoniae infections occurred in 1 of 14 patients receiving azithromycin compared with 6 of 30 receiving penicillin.
Vaccination — No vaccine is available for the prevention M. pneumoniae infection; this is due in part to the low efficacy among M. pneumoniae vaccines in development [70].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Community-acquired pneumonia in adults".)
SUMMARY AND RECOMMENDATIONS
●Background − Mycoplasma pneumoniae is among the most common bacterial causes of upper respiratory tract infection (URI), acute bronchitis, and community-acquired pneumonia (CAP) in adults and children. (See 'Introduction' above and 'Epidemiology' above.)
●Microbiology − M. pneumoniae lacks a cell wall and is one of the smallest free-living organisms. Because it lacks a cell wall, it is not visible on Gram stain and is not susceptible to antibiotics that inhibit cell wall synthesis, such as penicillins. These features designate M. pneumoniae as an "atypical" pathogen. (See 'Microbiology' above.)
●Transmission − The organism is transmitted from person to person primarily via respiratory droplets and can cause both sporadic infections and sustained outbreaks. Outbreaks most frequently occur among persons living in close quarters, such as households, schools, and military facilities, but can also spread to the community. (See 'Transmission' above and 'Outbreaks' above.)
●URI and acute bronchitis − URI and acute bronchitis are the most common manifestations of M. pneumoniae infection. Clinical features associated with URI and acute bronchitis caused by M. pneumoniae are similar to those caused by other respiratory pathogens. Because these infections are typically mild and self-limited, microbiologic diagnosis and antibiotic treatment is generally unnecessary. (See 'URI and acute bronchitis' above.)
●Community-acquired pneumonia − Pneumonia caused by M. pneumoniae is typically mild and community acquired. No clinical or radiographic features definitively distinguish M. pneumoniae pneumonia from that caused by other pathogens, although an indolent onset, concurrent URI symptoms (eg, rhinorrhea, pharyngitis, ear ache), and the presence of non-respiratory tract manifestations (eg, hemolysis) are suggestive. (See 'Pneumonia' above.)
●Extrapulmonary manifestations − Manifestations outside the respiratory tract can occur with respiratory tract infections or independently. Hemolysis is the most common, and it is typically mild and self-limited. Rarely, M. pneumoniae infection directly infects or triggers immune-mediated reactions in the central nervous system, heart, skin, and other organs. (See 'Non-respiratory tract disease' above.)
●Diagnosis in patients with CAP − For most patients with CAP, pursuing a microbiologic diagnosis of M. pneumoniae is not necessary, as results would not change management. We typically reserve M. pneumoniae testing for selected patients with suggestive clinical features or severe pneumonia in whom directing antibiotic therapy at M. pneumoniae would provide benefit or when having a specific diagnosis would provide prognostic value. (See 'Approach to diagnosis' above.)
●Microbiologic testing − When microbiologic confirmation is desired for patients with CAP, we use a nucleic acid amplification test (NAAT), such as polymerase chain reaction (PCR). These tests can be performed on most specimen types, including nasopharyngeal swabs, sputum, and bronchoalveolar lavage (BAL) fluid. Because NAATs cannot distinguish between active infection and either coinfection with other pathogens or asymptomatic carriage, clinical judgement should be used in interpreting results. Serology can be used as an alternative or adjunct to NAATs. (See 'Mycoplasma-specific assays' above.)
●Empiric treatment for patients with CAP − For most patients with CAP, the etiology is not known at the time of diagnosis, and empiric treatment for CAP is appropriate. Most recommended empiric regimens for adults in the United States include an agent that targets atypical pathogens, such as M. pneumoniae (algorithm 1 and algorithm 2). (See "Treatment of community-acquired pneumonia in adults who require hospitalization", section on 'Initial empiric therapy' and "Treatment of community-acquired pneumonia in adults in the outpatient setting", section on 'General approach'.)
●Directed treatment of M. pneumonia − For patients with microbiologically confirmed M. pneumoniae pneumonia, first-line treatment options include macrolides (eg, azithromycin), tetracyclines (eg, doxycycline), and respiratory fluoroquinolones (eg, levofloxacin or moxifloxacin). In regions where macrolide resistance is low, such as the United States, we generally use azithromycin (either 500 mg orally on day 1 followed by 250 mg orally for four additional days or 500 mg orally for three days) (Grade 2C). (See 'Pneumonia' above and 'Macrolide resistance' above.)
●Diagnosis of non-respiratory tract disease − The approach to diagnosis and treatment of manifestations that occur outside the respiratory tract is typically individualized based on the site of involvement, likelihood of antimicrobial resistance, and presence of concurrent respiratory tract infection. While antibiotic treatment is the mainstay of therapy, some non-respiratory tract manifestations may be immune mediated and adjunctive therapy with glucocorticoids or intravenous immune globulin may be beneficial. (See 'Non-respiratory tract disease' above.)
●Prevention − Key preventive measures include hand hygiene and respiratory hygiene. Postexposure prophylaxis may be indicated in rare and selected circumstances, such as outbreaks or for severely immunocompromised patients. (See 'Prevention' above.)
ACKNOWLEDGMENT — We are saddened by the death of John G Bartlett, MD, who passed away in January 2021. UpToDate gratefully acknowledges his tenure as the founding Editor-in-Chief for UpToDate in Infectious Diseases and his dedicated and longstanding involvement with the UpToDate program.
