We illustrate a case of serologically confirmed M. pneumoniae, which manifested with predominantly extra-pulmonary symptoms. To our knowledge, this is the only reported case presenting with acute hepatitis, bicytopenia (neutropenia and thrombocytopenia), erythema multiforme, arthralgia, and vomiting. Previously reported extra-pulmonary manifestations include cardiovascular (pericarditis, endocarditis, myocarditis, cardiac thrombi), hepatic, haematological (autoimmune haemolytic anaemia, thrombocytopenic purpura, disseminated intravascular coagulation), dermatological (erythema nodosum, cutaneous vasculitis, erythema multiforme, Steven-Johnsons Syndrome), glomerulonephritis, arthritis, conjunctivitis, and neurological symptoms (encephalitis, meningitis, Guillain Barre syndrome) [1-3]. These manifestations may occur before, during or after resolution of respiratory symptoms and usually fully resolve 2-3 weeks after eradication of the respiratory disease. Respiratory symptoms may be minimal or even absent [1–3]. The exact incidence of extra-pulmonary manifestations is unknown, but some reports estimate that these occur in up to 25% of cases [1],

The mechanism behind extrapulmonary involvement remains incompletely understood. Various theories have been postulated, including:

1. direct attack from the bacterium, involving damage due to host cytokines (especially interleukin-6 and interleukin-8) and secretion of toxic molecules and proteins by the bacterium (including H2O2 and nucleases) [2–5]

2. an indirect autoimmune attack by antibodies and immune complexes [2–5]

3. vascular occlusion involving vasculitis and/or thrombosis [2–5]

4. molecular mimicry between mycoplasma cell wall components and host tissues [2-4]

5. It has also been suggested that some manifestations may be the result of post-infectious inflammation.[4]

In vitro studies have shown that M. pneumoniae can adhere to red blood cells, which may promote dissemination of the organism into other tissues [5]. Our patient developed lymphopenia (0⋅3 x 109/L) and neutropenia (0⋅5 x 109/L), which were noted on the day of admission. Whilst haemolytic anaemia has been well documented, M. pneumoniae associated neutropenia and leukopenia remain extremelyrare [1–4]. To our knowledge, there are currently only three other published case reports of this phenomenon and no such phenomenon in an otherwise healthy, young adult.

Barge and colleagues report a case of an 85-year-old male with exacerbation of COPD and positive serological test for M. Pneumonia [8]. The patient developed transient agranulocytosis. Granulocyte autoantibody testing showed positive IgG and IgM autoantibodies against neutrophils. This was found to produce significant agglutination. The agranulocytosis responded well to granulocyte colony-stimulating factor and the infection was successfully treated with azithromycin. Like our patient, L. Barge and colleagues. describe a mild thrombocytopenia relative to the neutropenia [8]. The main mechanisms postulated for the haematological manifestations is antibody cross reaction with red blood cells, platelets and white blood cells. The detection of antibodies in patients’ serum supports such autoimmune mechanism [8]. C. Chen and colleagues report a case of a four-year-old, who presented with upper respiratory tract infection symptoms [9]. Serological testing demonstrated M. pneumoniae. The patient was also found to have neutropenia, thrombocytopenia and acute hepatitis. Despite normal haemoglobin on laboratory testing, erythrocyte-bound C3d was strongly positive, as was Coomb’s test. The team also found antiplatelet and antineutrophil antibodies.

Haemolytic anaemia in M. pneumoniae is thought to be due to cold agglutinins [8]. Usually IgM antibodies, these bind to the erythrocyte cell membrane at temperatures below 5˚C. This leads to agglutination and haemolysis of the cell, precipitating anaemia. Our patient was not tested for these antibodies. Thrombocytopenia associated with M. pneumoniae is thought to be due to two main mechanisms: thrombotic thrombocytopenic purpura and direct antibody effects [9]. Chen and colleagues report a case of M. pneumoniae associated with anti-platelet antibodies and thrombocytopenia [9]. These antibodies were directly associated with platelets. The finding of increased megakaryocyte count in the patient’s bone marrow suggested increased peripheral platelet destruction and thus further supported an autoimmune mechanism. To our knowledge, this is the first report of neutropenia with a systemic manifestation of M. pneumonia infection. These findings may further our understanding of the heterogenous presentation of the infection.

Our patient also developed transient transaminitis, in keeping with an acute hepatitis picture. This has been estimated to occur in 2-21% of cases [3]. Changes in hepatic enzymes are usually transient, with complete recovery after eradication of the organism. The exact pathogenesis of M. pneumoniae-induced hepatitis is still not understood, but the major mechanisms that are thought to be implicated include molecular mimicry between mycoplasma cell components and hepatic cell surface molecules and direct invasion of the liver by the pathogen [2–4]. It has been further suggested that early-onset hepatitis may be more likely due to direct mechanisms, whereas late-onset hepatitis may be more likely due to vascular injury [5]. Skin changes may be seen in 10%-25% of cases and is thought to be due to a combination of immune complex-mediated vascular injury, cell-mediated damage, and autoimmune mechanisms[4,6]. Cutaneous manifestations are heterogeneous and can be confluent or confined to specific areas. Most common cutaneous presentations include maculopapular, vesicular, erythema multiforme and urticarial lesions [1-6]. These are generally self-limiting and associated with excellent clinical prognosis. Rarer and more serious presentations include Stevens-Johnson syndrome and toxic epidermal necrolysis [6].

The pathogenesis of cutaneous manifestations associated with M. pneumoniae is not fully understood, but some have postulated a combination of mechanisms including type III immunological hypersensitivity, immune complex deposition and immune cell infiltration, fragmentation and nuclear debris deposition [6]. Another mechanism has suggested a micro-vessel disease involving multiple thrombi and cold agglutinins [6]. M. pneumoniaehas also been isolated from the cutaneous lesions, suggesting involvement of a direct mechanism [5].bThe majority of M. pneumoniae-associated dermatological conditions respond to eradication of the bacterium and topical steroids. Commonly used antibiotics to treat M. pneumoniaeinclude erythromycin, azithromycin and co-amoxiclav. All of these have been associated with cutaneous eruptions and it can therefore be difficult to determine whether the eruptions are due to the bacterium or indeed the antibiotics. Our patient developed widespread erythema multiforme, which responded well to 0.1% topical mometasone cream, applied twice a day.