The mire of mycoplasma

After a busy ED shift filled with innumerable toddlers with viral-induced wheezes, your last patient of the day is a little older than most of the others you’ve seen presenting with respiratory distress. A 7-year-old child wearing their school uniform lies in bay 2, having been sent home from school seeming a little ‘flat and breathless.’ 

You check her triage stats and note a temperature of 38.2℃. From the end of the bed, she looks comfortable yet a little tachypnoeic, and the oxygen monitor is hovering around the high 80s. She has some crackles on auscultation, so you decide to do a CXR, which reveals bilateral peribronchial shadowing. You piece her age and clinical picture together and pat yourself on the back for nailing a diagnosis of pneumonia secondary to Mycoplasma pneumoniae.

What exactly are “Mycoplasma”?

Over 120 Mycoplasma species have been isolated from humans, yet the vast majority exist as commensals with little pathogenic potential. Of those which can cause disease, the most well-established is Mycoplasma pneumoniae, although a couple of other species (such as Mycoplasma hominis and Mycoplasma genitalium) are capable of causing a genitourinary infection which may, in turn, affect (particularly premature) neonates via vertical transmission.

Mycoplasma are distinguished from other bacteria by their lack of a cell wall, which has implications for their treatment – as most antibiotic classes, which act on the cell wall, will be ineffective in treating Mycoplasma species. Notoriously difficult to culture, isolation is not usually performed in clinical laboratories due to their fastidious growth requirements, so diagnosis is also challenging.

There are many ways Mycoplasmas produce infection and disease: via direct bacterial effects, via indirect immune-mediated effects, or via chemokine-induced vasculitic and thrombotic processes. The adherence proteins of M. pneumoniae have a particular affinity for respiratory tract epithelium, where they produce hydrogen peroxide and superoxide once attached, causing injury to the cilia. 

M. pneumoniae is transmitted via infected respiratory droplets during close contact, with a long incubation period of up to 23 days causing very high (90%) cumulative attack rates in families. After acute infection, prolonged (asymptomatic) carriage may be mediated by intracellular invasion and can persist for weeks to months, even in patients treated with antimicrobial therapy.

Clinical Manifestations of acute M. pneumoniae infection

M. pneumoniae infection can occur in children of all ages. Yet, the proportion of children with community-acquired pneumonia (CAP) due to M. pneumoniae increases during the school years (despite an overall decline in the prevalence of CAP in this age group), with a median age of hospitalization with CAP due to M. pneumoniae of 7 years. However, the codetection of viral pathogens (in 1/3 of children hospitalized with M. pneumoniae infection) is common.

M. pneumoniae causes a wide spectrum of illnesses, with the majority of infections being asymptomatic. Of the symptomatic infections, manifestations are divided into (i) respiratory tract symptoms (most common); and (ii) extrapulmonary manifestations (less common). The manifestations of infection due to M. pneumoniae are dictated by the host’s immune competence and immune response, with many extra-pulmonary manifestations being immune-mediated.

Pneumonia is the most common clinical manifestation and is typically preceded by a few days of malaise, headache and low-grade fever; a non-productive cough follows and may persist for weeks to months. Historically referred to as the ‘walking pneumonia’, when mild-moderate, M. pneumoniae typically causes a mild illness in most patients. When severe, M. pneumoniae CAP can cause pleural effusions and (rarely) empyema. The CXR findings are variable and nonspecific and may include bilateral diffuse interstitial infiltrates, focal consolidation, or pleural effusion.

Laboratory findings are also non-specific. The total WBC (including neutrophil count) may be slightly elevated; mild thrombocytosis may be evident, and the CRP may be raised (yet is typically <100mg/L). Some patients will exhibit (usually subclinical) evidence of haemolytic anaemia (with an elevated reticulocyte count or positive Coombs test).

Extrapulmonary manifestations of mycoplasma

While the pulmonary manifestations of Mycoplasma are common, considering this fastidious organism in a child presenting with less common signs – such as erythema nodosum or meningoencephalitis – is important (and deserves an extra-large pat on the back when the diagnosis is nailed).

Extrapulmonary manifestations may occur concurrently with respiratory manifestations or independently. When present, they help to support a suspected clinical diagnosis of M. pneumoniae infection. Direct local effects of M. pneumoniae or indirect immune-mediated effects cause extrapulmonary manifestations. They can affect almost every organ – including the skin, nervous system, haematological, cardiovascular, and musculoskeletal systems.

Skin manifestations are the most common extrapulmonary manifestation, occurring in up to ¼ of all infections. These may range from mild maculopapular rashes to bullous papular purpuric glove and stocking syndrome, mucositis, or fulminant Stevens-Johnson Syndrome (SJS).

M. pneumoniae-induced haemolysis is the next most common extrapulmonary manifestation and is usually mild, occurring due to Mycoplasma-specific IgM antibodies producing a cold agglutinin response. Transfusion is usually only required in children with underlying risk factors (such as those who are immunocompromised or with sickle cell anaemia).

While uncommon, CNS involvement is important to recognise due to its significant morbidity and mortality. These occur in 0.1 – 6% of all patients with M. pneumoniae and most commonly present as meningoencephalitis or Guillain Barre Syndrome, although ADEM, transverse myelitis, cerebellar ataxia and cranial nerve palsies have been reported. The CSF in these cases will typically reveal a lymphocytic pleocytosis, mildly elevated protein, and normal glucose. Most clinical laboratories will not perform M. pneumoniae PCR analysis on CSF, as this investigation has not been validated.

The challenges of microbiological diagnosis

Investigations are usually warranted in children sick enough to require hospitalisation due to clinical features consistent with M. pneumoniae infection, particularly in those presenting with extrapulmonary manifestations or those who do not improve with β-lactam antibiotic therapy for presumed bacterial pneumonia. However, due to limitations in the currently available diagnostic tools, infection due to M. pneumoniae almost always requires a clinical diagnosis.

With a high pre-test probability in a child presenting with compatible clinical signs, confirmation may be sought by detection of M. pneumoniae by PCR on a viral pharyngeal swab or by antibody response to M. pneumoniae. Remember that up to 1/3 of children may have a concurrent viral diagnosis, too. Often, the diagnosis is confirmed retrospectively (with convalescent serology or clinical improvement with M. pneumoniae-specific therapy).

Of the investigative tools available, a polymerase chain reaction (PCR) respiratory specimen (nasopharyngeal or throat swab) is the current ‘gold standard’, with the highest sensitivity and specificity (>90% combined) of the available tests. Serology (M. pneumoniae IgM and IgG enzyme immunoassay, EIA) may be used as an adjunct to PCR-based tests or as an alternative to PCR-based tests if they are not available but have only moderate sensitivity and specificity.

When you see a positive M. pneumoniae result, it’s important to step back and re-evaluate the clinical picture, as positive PCR swabs can be due to prolonged asymptomatic carriage or responsible for the current acute presentation, and many observational studies have found high rates of M. pneumoniae PCR-positive pharyngeal swabs in children without any clinical symptoms suggestive of illness: in fact, one prospective cross-sectional observational study found a higher rate of PCR positive M. pneumoniae swabs in well children presenting for elective surgery than was evident in children presenting to the Emergency Department with respiratory symptoms.

IgM antibody titres rise 7-9 days after infection and peak at 3-6 weeks, then persist for months. IgG titres rise and peak two weeks after IgM and persist for years. It’s important to note that falsely negative IgM tires earlier in the course of illness are, therefore, common. Many laboratories will also report a quantitative antibody titre, and while these are non-specific tests for M. pneumoniae infection, very elevated titres may support a diagnosis of M. pneumoniae in patients with clinical features suggestive of infection. The sensitivity of serology tests can be improved by collecting paired samples ≥ two weeks apart to assess for seroconversion and/or a ≥ 4-fold antibody titre increase.

Treatment of Community-Acquired Pneumonia due to M. pneumoniae

Due to these significant limitations in laboratory diagnosis, empirical treatment for CAP due to suspected M. pneumoniae infection is typically driven by clinical suspicion. As M. pneumoniae is intrinsically resistant to antibiotics that inhibit cell wall synthesis (including β-lactams and glycopeptides), macrolides, fluoroquinolones and tetracycline antibiotics are prescribed in most settings – although there are increasing reports of macrolide-resistance emerging in Asia and the Middle East.

Azithromycin is the first-line antibiotic recommenced by the Therapeutic Guidelines (Australia) and the British Thoracic Guidelines. Azithromycin has a long half-life, which allows once-daily dosing, and is generally better tolerated than alternative macrolide antibiotics in children. Clarithromycin and doxycycline provide alternative treatment options, and as second-line options, these agents are preferred over erythromycin due to erythromycin’s cumbersome (four times daily) dosing regimen and increased propensity to cause gastrointestinal side effects.

Fluoroquinolones are prescribed when the patient has failed treatment with a macrolide antibiotic, particularly if there is a risk of exposure in a region with known documented high levels of macrolide resistance (such as China). There is some evidence that high-dose steroids may be helpful in severe M. pneumoniae infections, but a decision to commence these should be made with subspecialist advice.

What about treating extra-pulmonary manifestations?

If there are no concurrent respiratory symptoms, as the pathogenicity of extra-pulmonary manifestations is likely immune-mediated, there is no strong evidence that mucocutaneous disease and CNS disease will respond to treatment with antimicrobials. Supportive therapy (which may include IVIg and systemic glucocorticoids) provides the most benefit, and once again, the decision to initiate this management should involve subspecialist support.

The Bottom Line

Although the prevalence of community-acquired pneumonia decreases with age, the proportion of cases that are due to Mycoplasma pneumoniae increases with age; so this atypical organism causes a large proportion of pneumonia in school-age children.

M. pneumoniae can cause both pulmonary and extra-pulmonary manifestations, which may affect any organ system of the body – including the skin, haematological (haemolytic anaemia), cardiac (myocarditis, pericardial effusion), rheumatological (arthritis or arthralgia), gastrointestinal (abdominal pain, nausea and vomiting) and renal systems.

Mycoplasma spp. lack a cell wall, so are intrinsically resistant to a number of our most common antibiotic classes (including β-lactams)

Azithromycin should be the first-line antibiotic prescribed when a clinical diagnosis of M. pneumoniae pneumonia is made. Antibiotic therapy is generally only indicated for pulmonary disease, as extra-pulmonary manifestations tend to be immune-mediated.

Supportive microbiological investigations are imperfect in assisting in the diagnosis of M. pneumoniae infection, as false-positive PCR-based tests can occur due to asymptomatic carriage and serology has only modest sensitivity and specificity. However, combined with a high pre-test probability in a child presenting with features suggestive of M. pneumoniae pneumonia when positive, these investigations may assist in supporting the diagnosis.

References

Narita, M. 2016. Classification of extrapulmonary manifestations due to Mycoplasma pneumoniae infection on the basis of possible pathogenesis. Front Microbiol; 7:23.

Riordan, A. 2014. In children with respiratory symptoms are Mycoplasma pneumoniae PCR and serology clinically significant? BMJ Archives of Disease in Childhood; 99:157.

Roy Chowdhury, S. Mycoplasma pneumoniae-induced rash and mucositis is a distinct entity that needs more recognition. J Paediatr Child Health; doi: 10.1111/jpc.14625.

Sauteur, P. et al. 2016. Infection with and carriage of Mycoplasma pneumoniae in children. Front Microbiol; 7; 329.

Shah, S. 2019. Mycoplasma pneumoniae as a cause of community-acquired pneumonia in children. CID; 68:13.

Sauteur, P. et al. 2018. The art and science of diagnosis Mycoplasma pneumoniae infection. PIDJ; 37,11, 1192-4.

Speusens, E. et al. 2013. Carriage of Mycoplasma pneumoniae in the upper respiratory tract of symptomatic and asymptomatic dhildren: an observational study. PLoS Med, 10(5); e1001444.

National Institute for Health and Care Excellence. Pneumonia (community-acquired): antimicrobial prescribing NICE guideline [NG138]. Published Sept 2019. [Online], Available: https://www.nice.org.uk/guidance/ng138/chapter/Recommendations

Therapeutic Guidelines (Australia). Community-acquired pneumonia in children. Published April 2019. [Online], Available: https://tgldcdp.tg.org.au.acs.hcn.com.au/viewTopic?topicfile=community-acquired-pneumonia-children&guidelineName=Antibiotic#toc_d1e966