Mycoplasma-induced rash and mucositis L51.-

MIRM was introduced as a disease term in a systematic review (202 cases) by Canavan et al. in 2015 (Canavan TN et al. 2015). In this review, the specific characteristics of MIRM were described with pronounced mucositis and comparatively less skin involvement than in other mucocutaneous syndromes associated with M. pneumoniae such as urticaria, erythema nodosum, erythema multiforme, SJS, TEN and DRESS (Bastuji-Garin S et al. 1993).

Mycoplasma-induced rash and mucositis is an inflammatory mucocutaneous eruption associated with infections caused by Mycoplasma pneumoniae. Originally, MIRM was described as a reactive-inflammatory (parainfectious) entity, which differs from erythema multiforme (EM) and Stevens-Johnson syndrome (SJS), as the mucous membranes are predominantly affected and the course is considered prognostically favorable. In the meantime, other pathogens that cause these inflammatory symptoms have been identified. This brings this clinical picture close to RIME, the reactive infectious mucocutaneous eruption.

Mycoplasma pneumoniae, which has been defined as the causative agent of MIRM (and is diagnosis-defining), is a common respiratory pathogen responsible for approximately 10% of all cases of community-acquired pneumonia, with rates as high as 37% in children in certain studies and geographic areas (Marchello C et al. 2016). Apart from respiratory diseases, M. pneumoniae causes extrapulmonary syndromes that affect about 25 % of patients. These syndromes include cold agglutinin-hemolytic anemia, arthritis, pericarditis, thrombosis and inflammatory mucocutaneous manifestations. The latter include"pluriorificial ectodermosis, urticaria, erythema multiforme, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reactions with eosinophilia and systemic symptoms(DRESS).

The exact incidence of MIRM is not known.

M. pneumoniae is a common respiratory pathogen responsible for about 10 % of all cases of community-acquired pneumonia. This bacterium can lead to extrapulmonary syndromes in about 25 % of patients, including cold agglutinin hemolytic anemia, arthritis, pericarditis, thrombosis and mucocutaneous manifestations (Poddighe D 2018). The hallmark of MIRM is mucosal involvement, which typically manifests in the urogenital and oral regions with ulceration, vesicles, blisters and conjunctival eye involvement, which in severe cases can lead to conjunctival ulceration and pseudomembrane formation (Gandelman JS et al. 2020).

Both M. pneumoniae and MIRM occur mainly in the winter months (Lofgren D et al. 2021). MIRM occurs mainly in children and young adolescents with an average age of 12-16 years. MIRM has now also been observed in young adults (Alcántara-Reifs CM et al. 2017). Importantly, there is currently no clear definition that distinguishes this syndrome from other mucocutaneous syndromes, which leads to its misclassification.

M. pneumoniae infections can lead to both pulmonary and extrapulmonary symptoms (Narita M 2016). Extrapulmonary symptoms include vasculitis, neurological and immunological complications, thrombotic events and mucocutaneous manifestations. Mucocutaneous manifestations occur in around 25 % of patients with M. pneumoniae infections (Meyer Sauteur PM et al. 2020).

The term MIRM was introduced in 2015 in a systematic review (202 cases) by Canavan et al. (Canavan TN et al. 2015). This review describes the specific features of MIRM with pronounced mucositis and comparatively minor skin involvement. Other skin lesions associated with M. pneumoniae are characterized as urticaria, erythema nodosum, erythema multiforme, SJS, TEN and DRESS (Bastuji-Garin S et al. 1993).

The exact pathogenesis of MIRM has not yet been clarified. It is conceivable that infection-related excessive immune activation leads to the production of polyclonal B cells and antibodies. Molecular mimicry between Mycoplasma P1 adhesion molecules and the keratinocytes of the host is also conceivable, which could lead to the known lesions via antibody formation or cytotoxic T cells (Mazori DR et al. 2020).

Mostly dominated by enanthema, blistering, erosions and ulceration, with the oral mucosa (94%), the eye region (82%) and the urogenital area (63%) being particularly affected. Infestation of the nasal introitus and anus is less common. Mucosal lesions are generally characterized as ulcerative or haemorrhagic and can cause symptoms. Involvement of the nose can manifest itself in the form of firm hemorrhagic crusts. Anal lesions may cause pain during defecation.

Non-mucosal, mostly disseminated rashes are observed in about 50% of MIRM cases. They often occur acrally (46%), less frequently on the trunk (23%). The exanthema is described as vesiculobullous in 77% of cases. Targetoid lesions are described in around 48% of cases. Less frequently, the exanthema is papular (14 %), macular (12 %) or small-spotted morbilliform (9 %) or urticarial (Canavan TN et al. 2015).

The diagnosis of MIRM includes the presence or recent onset of pulmonary infections, including pneumoniae, which can be confirmed by clinical examination and/or chest X-ray. Laboratory tests should include elevated M pneumoniae IgM antibodies, detection of M pneumoniae from oropharyngeal or polymerase chain reaction (PCR), or obtaining serum cold agglutinins (Lofgren D et al. 2021).

Histopathologically, erythema multiforme, SJS and MIRM have analogous overlapping histopathologic features, including apoptotic keratinocytes and sparse perivascular dermal infiltrates. Rzany et al. examined samples of erythema multiforme, SJS and TEN and found no significant, consistent histologic differences. Wetter and Camilleri found histopathological features in drug-induced SJS that were not present in MIRM or immunization-induced SJS in some samples examined (Rzany B et al. 1996; Wetter DA et al. 2010).

Thorough and detailed medical history. In MIRM, prodromal symptoms such as fever, cough and malaise occur in almost all patients about one week before the mucocutaneous sndrome. Patients with SJS/TEN usually have a distinct medication history (e.g. antibiotics, non-steroidal anti-inflammatory drugs, allopurinol, antiepileptic drugs and nevirapine) (Chatproedprai S et al. 2018).

Common differential diagnoses in MIRM include other diseases that can cause similar skin findings and/or mucosal manifestations:

• RIME (analogous polyetiologic, recurrent clinical picture)
• Erythema multiforme major
• SJS/TEN
• DRESS
• Staphylococcal scalded skin syndrome
• Hand-foot-and-mouth disease
• Kawasaki syndrome
• Herpetic gingivostomatitis
• Bullous systemic lupus erythematosus
• Stomatitis plasmacellularis
• SARS-CoV-2 infection
• Behçet's disease

Although 81% of patients with MIRM make a full recovery, long-term effects can occur, mainly affecting the mucous membranes. In 8.9% of patients with MIRM, ocular mucosal damage occurs, which can lead to conjunctival shrinkage, corneal ulcers, conjunctival synechiae and eyelash loss. Post-inflammatory pigmentary changes occurred in 5.6 % of patients, while oral and genital mucosal adhesions were observed in 0.8 % and 0.8 % of patients respectively.

In the acute care setting, it can be difficult for clinicians to differentiate MIRM from other mucocutaneous eruptions. Patients with MIRM require supportive care, including pain management for skin lesions and oral ulceration, mucosal care, and correction of fluid deficiencies resulting from decreased oral intake. Severe cases of MIRM with extensive skin detachment may require early referral to a burn center.

Although there are no specific treatment guidelines for MIRM, patients diagnosed with this condition often present with signs of atypical pneumonia and may therefore benefit from antibiotic treatment. Common oral antibiotic options for atypical pneumonia, such as macrolides, tetracyclines and fluoroquinolones, are usually recommended, with macrolides being the preferred choice (Bradley JS et al. 2011).

Empirical administration of corticosteroids and other immunosuppressants has been documented, especially in patients with severe MIRM. Intravenous immunoglobulin(IVIG) has also been used in cases of MIRM with severe mucositis. In a study by Canavan et al. 35 % of patients received systemic corticosteroids and 8 % intravenous immunoglobulin (IVIG).

Overall, the prognosis of MIRM is generally favorable. Only a few patients require intensive medical care and 81% of patients recover completely. The recurrence rate of MIRM is 8% (Jelić D et al. 2016). In contrast, patients with SJS/TEN require intensive medical treatment more frequently and have higher mortality rates (Jelić D et al. 2016).

Until 2015, the lack of a clear definition for MIRM led to inconsistent naming conventions in publications describing cases of M. pneumoniae infections. Examples include M. pneumoniae-associated SJS, Fuchs syndrome and pluriorificial ectodermosis (Fiessinger-Rendu) (Tay YK et al. 1996; Šternberský J 2014).

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