Mycoplasma pneumoniae infections

Mycoplasma pneumoniae infections

• Mycoplasma pneumoniae is a common bacterial pathogen causing respiratory tract infections in both children and adults 
• Typical presentation includes persistent cough, fever, and upper respiratory tract symptoms (eg, coryza, sore throat)
• Diagnostic testing for Mycoplasma pneumoniae infections involves primarily serology and/or molecular assays
  • Quantitative polymerase chain reaction assay for Mycoplasma pneumoniae and other relevant organisms provides rapid results; samples can be sent to CDC for these tests, which are not generally available otherwise
• Symptoms can be mild and self-resolving, but antibiotics are prescribed in cases of pneumonia or severe infection
  • Macrolides are commonly used as first line therapy, but tetracyclines and fluoroquinolones may be viable options for patients with macrolide-resistant strains of bacteria
• There is a wide spectrum of possible complications, including severe pneumonia, exacerbation of asthma, encephalitis, hemolytic anemia, and skin and mucosal manifestations
  • Because of the common occurrence of Mycoplasma pneumoniae colonization and infection, many so-called complications may be coincidental rather than causatively related
• Disease may last for weeks or months; both symptoms and transmissibility of infection may persist for several weeks even after antibiotic treatment is completed 

Pitfalls

• Strains of macrolide-resistant Mycoplasma pneumoniae are increasingly common, prompting use of second line antibiotics 
• Laboratory diagnosis of Mycoplasma pneumoniae infection using culture has limitations: the organism can be grown in cell-free artificial media but has complex growth requirements and grows slowly, so time to results is not optimal for making treatment decisions
• Occasionally, with polymerase chain reaction testing, Mycoplasma pneumoniae nucleic acids are detected in clinical specimens from asymptomatic persons; therefore, in symptomatic persons, recovery of these nucleic acids does not necessarily prove Mycoplasma pneumoniae to be the cause of the symptoms that prompted the test

Mycoplasma pneumoniae is a common bacterial pathogen causing respiratory tract infections in both children and adults 

Mycoplasma pneumoniaecommonly causes mild, prolonged symptoms of upper respiratory tract infection or acute bronchitis 

Tracheobronchitis is the most common illness among children infected with Mycoplasma pneumoniae 

Pneumonia due to Mycoplasma pneumoniae most often occurs in adults; it is the most common form of atypical pneumonia

Terminology of typical and atypical pneumonias reflects a historical distinction from decades ago; it remains in use despite being broad rather than precise 

With pneumococcal lobar pneumonia being the reference point of typical, atypical pneumonias are thus characterized by different antibiotic response and a different pattern of clinical features

Atypical pneumonia does not respond to β-lactam antibiotics (eg, penicillin) or sulfonamides

It tends to feature dry cough, patchy lung involvement, and overlap with upper respiratory tract infection symptoms

Rarely nonrespiratory manifestations may accompany respiratory disease or occur without obvious respiratory disease

Nonrespiratory manifestations include mucositis, hemolytic anemia, and carditis

Clinical Presentation

History

• Many cases are asymptomatic
• May be history of ill contact (local outbreaks and epidemics occur every few years) 
• Timing of symptoms
  • Onset of disease is often gradual and subacute 
    • Incubation period is generally 1 to 4 weeks 
  • In some cases symptoms may persist for weeks and cough may linger for months 
• Common symptoms include: 
  • Cough, which may be productive or dry
  • Fever
  • Coryza
  • Pharyngitis
  • Malaise
  • Headache
  • Chest pain from coughing
• Most common symptoms in children younger than 5 years 
  • Nasal congestion, coryza, and wheezing, sometimes without fever
  • Diarrhea and vomiting

Physical examination

• Most common findings
  • Fever, usually low grade 
  • Oropharyngeal erythema may be seen but exudates and cervical lymphadenopathy are rare
  • On chest auscultation, scattered or localized rhonchi or coarse patches of rales may be heard, but they are often absent or heard inconsistently 
  • Fine inspiratory rales and dullness at lung bases if pneumonia has developed 
• Dermatologic findings (common in children but uncommon in adults)
  • Oral eruptions seen as crusted lips or tongue or buccal erosions (mucositis) 
  • Ocular eruptions seen as conjunctival erythema, eyelid edema, and photophobia 
  • A variety of transient exanthems can be present; they may be macular, maculopapular, vesicular, bullous, or targetoid 
• Vascular findings
  • Blanching of fingers and toes on exposure to cold
  • Gangrenous digits may occur in patients with sickle cell disease who have high titer of cold agglutinin

Causes

• Mycoplasma is a genus of bacteria without cell walls; Mycoplasma pneumoniae is one of the species with highest clinical relevance because of the respiratory tract infections it can cause
  • Mycoplasma pneumoniae produces a virulence factor known as the CARDS toxin (community-acquired respiratory distress syndrome toxin) 
    • This toxin aids in bacterial colonization and leads to inflammation and airway dysfunction
  • Bacterial transmission from person to person by airborne droplets occurs through close contact (from coughing, sneezing, and speech)
  • Patients may remain infectious for prolonged periods after many of the symptoms other than cough have resolved 

Risk factors and/or associations

Age

• Infection occurs in humans of 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 
• In children younger than 3 years, upper respiratory tract infections are predominant and progression to pneumonia is uncommon 
• Children, adolescents, and young adults aged 5 to 20 years tend to develop bronchitis and pneumonia (Related: Community-acquired pneumonia in children (aged older than 3 months))
• In adults older than 20 years, pneumonia is the most common manifestation (Related: Community-acquired pneumonia in adults)
  • Mycoplasma pneumoniae is the second most common pathogen implicated in community-acquired pneumonia in elderly adults, after Streptococcus pneumoniae 
    • Mycoplasma pneumoniae infection accounts for 1 to 10 of every 50 cases of community-acquired pneumonia 

Sex

• Studies show no significant difference in susceptibility between sexes 

Other risk factors/associations

• Living communally or being in close quarters is a risk factor for infection 
  • Closed and semiclosed populations, in settings where people live or work closely together (eg, schools, college dormitories, military barracks, nursing homes, hospitals) 
• People with sickle cell disease, Down syndrome, cystic fibrosis, therapeutic immunosuppression, or other immunodeficiency are predisposed to severe disease 
• There are minor, if any, effects of climate on the incidence of disease 

Diagnostic Procedures

Primary diagnostic tools

• Diagnosis should be considered as a possibility for respiratory illness in any child or young adult presenting with symptoms of upper respiratory tract infection 
  • Other situations that should prompt consideration include:
    • Older adults who have had no response to β-lactam antibiotics
    • Adults of any age with community-acquired pneumonia of mild to moderate severity with persistent intractable cough
    • Any patient with severe pneumonia that is not lobar or consolidating in its radiologic appearance, as typical pneumonia would usually be
• Most cases of upper respiratory tract infections or atypical pneumonia are diagnosed clinically, without the need for laboratory testing to identify a specific pathogen 
  • Testing for the causative agent (using sputum culture and/or various laboratory tests) is indicated in the following situations: 
    • Severe community-acquired pneumonia, especially in cases requiring intubation
    • Previous infection with MRSA or Pseudomonas aeruginosa, especially prior respiratory tract infection
    • Hospitalization during which parenteral antibiotics were received in the past 90 days
    • Legionella outbreak or recent travel to an area of outbreak (use Legionella urinary antigen test)
    • Testing for influenza with a rapid influenza molecular assay (eg, influenza nucleic acid amplification test)
  • Other situations in which identifying the causative pathogen may be important include:
    • Adjusting antibiotic therapy to a different agent or narrowing the antibiotic regimen
    • Documenting an outbreak
    • Treating patients with very unusual coexisting manifestations (eg, hemolysis)
  • For most adults with routine community-acquired pneumonia treated as outpatients, neither sputum Gram stain and culture nor blood cultures are recommended by the guideline on community-acquired pneumonia from the American Thoracic Society and the Infectious Diseases Society of America 
• Testing for Mycoplasma pneumoniae infection relies mostly on molecular assays and serology 
  • Molecular assays using nucleic acid amplification are the preferred method for laboratory diagnosis, where available (either single reaction for Mycoplasma pneumoniaeor as part of a multiplex reaction to detect several pathogens)
    • For acute infection, polymerase chain reaction assay has been found to be superior to IgM serologic testing 
  • Serology using enzyme immunoassays of paired acute and convalescent sera may be used instead of, or in addition to, molecular techniques
  • Bacterial cultures are definitive but are seldom used; they are impractical owing to specialized media requirements and long turnaround times
  • Caveats in interpretation of results from laboratory tests:
    • Molecular tests and cultures yield more definitive results if samples are collected before antibiotic therapy is started
    • Growth of organism or detection of its DNA is not absolute confirmation of causative role in illness, because coincident colonization is possible, but such results are supportive
  • Serum cold agglutinin levels, if elevated, can provide supportive information
• Local or state public health laboratories can provide diagnostic support, or patient samples may be sent to CDC if additional or specialized testing is required 
  • CDC uses molecular testing with multiplex quantitative polymerase chain reaction as the primary laboratory procedure for Mycoplasma pneumoniae identification
  • Culture and serologic testing are not used as routine diagnostic tools in CDC laboratory; they are mainly performed in local or reference laboratories
  • State public health laboratories and other federal agencies can send specimens directly to CDC for analysis
• For cases with suspected pneumonia, obtain chest radiograph

Laboratory

• Molecular testing
  • Specimen sources are usually nasal or oropharyngeal secretions, but many other types of samples may be collected and submitted as well, including sputum, bronchial lavage fluid, bronchial washings, or cerebrospinal fluid 
  • Single or multiplex nucleic acid amplification tests are commercially available; single assays detect only Mycoplasma pneumoniae, whereas multiplex assays detect several pathogens at once
  • Commercially available kits are sufficiently sensitive and specific, and the methods are fast enough to produce results that can guide treatment decisions; they provide direct detection of Mycoplasma pneumoniae DNA in respiratory specimens 
    • FDA-approved test options include:
      • Biofire FilmArray Respiratory Panel, a multiplex system using polymerase chain reaction for detection of 22 of the most common viral and bacterial respiratory pathogens, including Mycoplasma pneumoniae 
      • Illumigene Mycoplasma Direct DNA amplification assay, an in vitro test using LAMP technology (loop-mediated isothermal amplification) rather than polymerase chain reaction 
• Serology
  • Sera are provided to a clinical laboratory testing service for enzyme immunoassay testing
  • 4-fold rise in titer in paired acute and convalescent sera separated by 4 weeks is indicative of infection 
  • Disadvantages of serology include delayed results due to need to acquire convalescent sample
    • A single titer is insufficient for a formal serologic diagnosis; both IgM and IgG antibodies can be negative in the first week, and a single positive IgG may reflect infection in the remote past
    • Serology may not be able to discern active infection from asymptomatic carriage 
• Culture
  • Most clinical microbiology laboratories do not perform cultures for Mycoplasma pneumoniae
    • CDC accepts specimens from state public health laboratories and other federal agencies for analysis 
  • Mycoplasma pneumoniaehas no cell wall, so it does not appear on Gram stain
  • As an agent of intracellular infection, it is fastidious; culturing it requires specialized media and technician skill, and time to results is lengthy (3-4 weeks)
  • One major use of cultures is to obtain isolates for antimicrobial susceptibility testing and/or typing 
• Cold agglutinins
  • IgM antibodies that cross react with I antigen on human erythrocytes are increased in 50% to 70% of patients with Mycoplasma pneumoniae infection 

Imaging

• Chest radiograph
  • Radiographic findings can be variable in Mycoplasma pneumoniaeinfection 
    • Diffuse, reticular infiltrates of bronchopneumonia
    • Focal consolidation can occur in a quarter of cases
  • Pleural effusion may be observed in severe cases (up to 25% of cases) 
  • Bilateral disease may occur in about 20% of cases 

Differential Diagnosis

Most common

Clinical presentation of  respiratory tract disease is similar to that seen with other atypical pathogens, including  (),  species, and various respiratory viruses; it also overlaps in features with respiratory tract disease from typical pathogens (eg, pneumococcus)

• Pneumococcal pneumonia
• Chlamydia Pneumoniae Infection
• Viral illnesses that affect the respiratory tract
• Legionnaires disease

Treatment Goals

• Eradicate infection
• Relieve symptoms and provide supportive care as needed
• Prevent complications

Admission criteria

Most cases of Mycoplasma pneumoniae infection can be managed with outpatient care. Use severity of illness scores in combination with clinical judgment to determine whether the patient should be admitted; 2019 guidelines recommend Pneumonia Severity Index preferentially over the CURB-65 criteria 

• Pneumonia Severity Index 
  • Uses a point system of several variables including patient age, vital signs, mental status, and the presence of comorbid conditions (eg, neoplastic disease, liver disease, chronic heart failure, cerebrovascular disease, renal disease)
  • Classifies patients into a mortality risk level
    • Class I and II patients (fewer than 70 points) may be treated as outpatients
    • Class III patients should be treated in an observation unit or briefly hospitalized (71-90 points)
    • Class IV patients (91-130 points) and class V patients (more than 130 points) should be treated as inpatients
• CURB-65 criteria 
  • Patients receive 1 point for each of the following indicators:
    • Confusion (compared with baseline)
    • High BUN level: more than 20 mg/dL
    • High respiratory rate: 30 breaths per minute or more
    • Hypotension: systolic blood pressure less than 90 mm Hg or diastolic blood pressure of 60 mm Hg or less
    • Older age: 65 years or older
  • Admission is recommended for patients with a score of 2 or more

Children require hospitalization for severe pneumonia 

• Admit patients who have respiratory distress; radiography will show pleural effusion and infiltrates in lungs

Criteria for ICU admission

• Very few cases of Mycoplasma pneumoniae–associated community-acquired pneumonia require intensive care 
  • Acute respiratory failure is the main cause for ICU admission

Recommendations for specialist referral

• Refer to infectious disease specialist for patients requiring laboratory confirmation of disease
  • Referral allows facilitation of tests, with specimens to be sent to local or state public health laboratories, who can then forward them to CDC if necessary 
• Consider consultation with infectious disease specialist and/or intensivist/pulmonologist for patients with severe disease and for patients with significant comorbidities (for escalated medical management options)
• Refer to pulmonologist for pneumonia worsening despite appropriate antibiotic therapy (for a possible bronchoscopy)

Treatment Options

Most Mycoplasma pneumoniaeinfections are self-limiting; however, most clinicians routinely treat pneumonia caused by Mycoplasma pneumoniaewith antibiotics

• Initial treatment is empirically based because the causative pathogen is unknown (or not definitively known) at time of diagnosis
• Treatment for confirmed Mycoplasma pneumoniae with antibiotic therapy shortens duration of symptoms 

Empiric antibiotic therapy for community-acquired pneumonia

• Antibiotic recommendations for the empiric treatment of community-acquired pneumonia are based on selecting agents effective against the major treatable bacterial causes
  • Major treatable bacterial pathogens include Streptococcus pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae, Staphylococcus aureus, Legionella species, Chlamydia pneumoniae, and Moraxella catarrhalis
  • If Mycoplasma pneumoniae is suspected and considered likely, a regimen containing a macrolide, tetracycline, or fluoroquinolone should be selected
• Antibiotics for empiric treatment of community-acquired pneumonia in adult outpatients include amoxicillin, doxycycline, or a macrolide 
• Antibiotics for empiric treatment of community-acquired pneumonia in adult outpatients with comorbidities and inpatients with nonsevere pneumonia and without risk factors for MRSA or resistant gram-negative organisms 
  • Combination therapy with amoxicillin-clavulanate and a macrolide or doxycycline or 
  • Monotherapy with a respiratory fluoroquinolone 
• Antibiotics for empiric treatment of community-acquired pneumonia in pediatric outpatients 
  • Amoxicillin is first line therapy for appropriately immunized infants, preschool- and school-aged children, and adolescents with suspected typical bacterial community-acquired pneumonia 
    • 2011 guideline by Pediatric Infectious Diseases Society and Infectious Diseases Society of America is archived but not yet replaced
  • Macrolide antibiotics are first line therapy for children with community-acquired pneumonia suspected to be caused by atypical organisms, including Mycoplasma 

Antibiotic therapy specific to Mycoplasma pneumoniae

• Selection of optimal antibiotic involves considerations of local prevalence of macrolide resistance, patient age, potential drug interactions, risk of photosensitivity, presence of liver or renal disease, and pregnancy 
  • All Mycoplasma species have no cell wall, and therefore all are inherently resistant to β-lactam antibiotics (eg, penicillins, cephalosporins)
• Second-generation macrolides are generally considered the treatment of choice for healthy children and adults 
  • Azithromycin is first line treatment in areas where macrolide-resistant bacterial strains have low prevalence 
    • Rates of resistance are low in the United States and Europe (up to 18%) but are high in Japan and China (53% to 90%) 
  • Optimum duration of therapy is uncertain; successful therapy has been reported with 3 and 5 days of azithromycin therapy, but short courses of therapy have been associated with relapse 
• Tetracyclines or fluoroquinolones are alternatives that may be used in areas where macrolide-resistant strains of Mycoplasma pneumoniaeare prevalent 

Drug therapy

• Macrolides
  • Azithromycin 
    • Azithromycin Oral suspension; Infants 3 to 5 months†: 10 mg/kg/dose PO for 1 day, followed by 5 mg/kg/dose PO once daily for 4 days.
    • Azithromycin Oral suspension; Infants and Children 6 months to 12 years: 10 mg/kg/dose (Max: 500 mg/dose) PO for 1 day, followed by 5 mg/kg/dose (Max: 250 mg/dose) PO once daily for 4 days.
    • Azithromycin Oral tablet; Infants and Children 6 months to 12 years: 10 mg/kg/dose (Max: 500 mg/dose) PO for 1 day, followed by 5 mg/kg/dose (Max: 250 mg/dose) PO once daily for 4 days.
    • Azithromycin Oral tablet; Adolescents: 10 mg/kg/dose (Max: 500 mg/dose) PO for 1 day, followed by 5 mg/kg/dose (Max: 250 mg/dose) PO once daily for 4 days.
    • Azithromycin Oral tablet; Outpatient Adults: 500 mg PO on day 1, followed by 250 mg PO once daily for at least 5 days.
• Tetracyclines
  • Doxycycline 
    • Doxycycline Monohydrate Oral suspension; Children 8 to 12 years: 2 to 4 mg/kg/day PO in 1 to 2 divided doses (Max: 200 mg/day) for 10 days.
    • Doxycycline Hyclate Oral tablet; Children 8 to 12 years: 2 to 4 mg/kg/day PO in 1 to 2 divided doses (Max: 200 mg/day) for 10 days.
    • Doxycycline Hyclate Oral tablet; Adolescents: 2 to 4 mg/kg/day PO in 1 to 2 divided doses (Max: 200 mg/day) for 5 to 10 days.
    • Doxycycline Hyclate Oral tablet; Adults: 100 mg PO every 12 hours for at least 5 days.
• Fluoroquinolones
  • Levofloxacin 
    • Levofloxacin Oral tablet; Adults: 750 mg PO every 24 hours for at least 5 days.

Nondrug and supportive care

• Administer antitussives and antipyretics (acetaminophen or NSAIDs) where indicated
• Supplemental oxygen
  • Usually reserved for severe cases or for those with underlying lung disease
  • Maintain oxygen saturation within range of 94% to 98% in patients with hypoxemia 

Comorbidities

• Comorbidities that alter the selection of initial empiric antibiotic therapy for adult outpatients with community-acquired pneumonia include: 
  • Chronic heart, lung, liver, or renal disease; diabetes mellitus; alcoholism; malignancy; or asplenia
• Options include:
  • Combination therapy with amoxicillin-clavulanate and a macrolide or doxycycline
  • Monotherapy with a respiratory fluoroquinolone

Special populations

• People with sickle cell disease, Down syndrome, cystic fibrosis, therapeutic immunosuppression, or other immunodeficiency are predisposed to severe disease 
  • Consider administering prophylactic antibiotics in these patients during community outbreaks 

Complications

• Encephalitis
  •  is a major cause of encephalitis in children (Related: Encephalitis in children)Mycoplasma pneumoniae
    • Attributable in about 5% to 10% of all encephalitis cases 
• Other neurologic complications (which usually arise 1 to 2 weeks after onset of respiratory signs, and which usually resolve completely) 
  • Central nervous system complications
    • Cerebellar syndrome and polyradiculitis
    • Cranial nerve palsies
    • Optic neuritis
    • Coma
    • Mental confusion
    • Stroke
  • Motor deficiencies
    • Brachial plexus neuropathy
    • Ataxia
    • Choreoathetosis
    • Guillain-Barre syndrome
    • Transverse myelitis
• Carditis
  • Pericarditis
    • Carditis occurs primarily in older patients (Related: Myocarditis)
  • Long-term sequelae may include heart failure or persistent rhythm disturbances 
  • Manifested by abnormal ECG findings (eg, ST-T wave changes, atrioventricular block, ventricular ectopic beats, atrial fibrillation) 
• Hematologic complications 
  • Hemolytic anemia
  • Aplastic anemia
  • Thrombotic thrombocytopenic purpura
  • Disseminated intravascular coagulation (Related: Sickle cell disease)
  • Sickle crisis, in those with sickle cell disease (Related: Sickle cell disease)
• Renal dysfunction
  • Glomerulonephritis
  • Tubulointerstitial nephritis
  • IgA nephropathy
• Gastrointestinal disease
  • Cholestatic hepatitis 
  • Pancreatitis
• Dermatologic complications 
  • Erythema multiforme
    • Raised red mucocutaneous eruptions
    • Occurs in about 25% of patients and is often self-limiting 
  • Stevens-Johnson syndrome (Related: Stevens-Johnson syndrome and toxic epidermal necrolysis)
    • Toxins released from Mycoplasma pneumoniae can cause immune-mediated destruction of epidermis (epidermal detachment)
      • Lesions resemble scalding
      • Epidermal detachment of less than 10% of body surface area 
    • May affect about 5% of infected patients 
  • Toxic epidermal necrolysis (Related: Stevens-Johnson syndrome and toxic epidermal necrolysis)
    • A more severe disorder on the same spectrum with Stevens-Johnson syndrome
    • Epidermal detachment of more than 30% of body surface area corresponds to toxic epidermal necrolysis; between 10% and 30% corresponds to overlap of the 2 entities 
      • Toxic epidermal necrolysis occurs less frequently than Stevens-Johnson syndrome
• Exacerbation of asthma
  •  infection can precipitate exacerbations of childhood asthma (Related: Asthma in children)Mycoplasma pneumoniae
  • Role of Mycoplasma pneumoniae infection as an initiator of childhood asthma is controversial
• Because of the common occurrence of Mycoplasma pneumoniae colonization and infection, many so-called complications may be coincidental rather than causatively related

Prognosis

• Disease may persist for weeks or months, but it is typically mild and self-resolving 
  • Infection in immunocompromised patients may not resolve without antibiotic therapy 
  • Natural history of pneumonia due to Mycoplasma is one of extended illness, with fever and cough lasting well into the third week of illness, and then followed by gradual recovery 
• Mortality rate for Mycoplasma pneumoniae infection is approximately 1.4% 
  • In general, patients older than 50 years with community-acquired pneumonia are at increased risk of mortality 
    • Having any or all of the following increases mortality: neoplasia, liver disease, renal disease, elevated BUN level, or abnormal vital signs

Prevention

• Proper handwashing and use of alcohol-based gels can limit household transmission of lower respiratory tract illnesses 
• Prophylactic antibiotics are not routinely recommended for people who live or work in a community that experiences an infectious outbreak 
  • Appropriate only for patients with especially high risk of developing severe illness from Mycoplasma pneumoniae
    • People with sickle cell disease, Down syndrome, cystic fibrosis, therapeutic immunosuppression, or other immunodeficiency are candidates 
      • Azithromycin or doxycycline may be prescribed 
• Institute droplet precautions for inpatients with confirmed Mycoplasma pneumoniae infections for the duration of illness 
• Smoking cessation efforts help to prevent pneumonias or forestall severity by preserving the histologic and immunologic health of lung tissue

Sources

CDC: Mycoplasma pneumoniae Infections: For Clinicians and Laboratorians: Clinical Features and Complications. CDC website. Updated April 13, 2018. Reviewed April 13, 2018. Accessed July 29, 2020. https://www.cdc.gov/pneumonia/atypical/mycoplasma/hcp/clinical-features-complications.html Reference