INTRODUCTION — Mycoplasma pneumoniae, a leading cause of community-acquired pneumonia, may cause a number of extrapulmonary manifestations, including mucocutaneous eruptions, which have been reported in approximately 25 percent of pediatric patients [1]. The term "Mycoplasma pneumoniae-induced rash and mucositis" (MIRM) was coined in 2015 to distinguish the mucocutaneous disease associated with Mycoplasma from the Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) spectrum and from erythema multiforme (EM) [2]. Prior to that distinction, cases of mycoplasma-induced mucocutaneous disease were referred to as SJS [3-5], atypical SJS [6], Fuchs syndrome [7,8], TEN [9], EM [10], and Mycoplasma pneumoniae-associated mucositis (MPAM) [11-13].
It has been proposed to include MIRM in a broader category called "reactive infectious mucocutaneous eruption" (RIME). RIME describes mucocutaneous eruptions resulting from a variety of infectious triggers and differentiates infectious triggers, which are far more likely in children and adolescents, from drug triggers [14,15].
MIRM is characterized by prominent mucositis, usually with sparse or even absent cutaneous involvement. Compared with SJS/TEN, MIRM has a distinct pathophysiology, a milder course, and a generally good prognosis.
This topic will discuss the pathogenesis, clinical manifestations, diagnosis, and treatment of MIRM. SJS/TEN and EM are discussed separately. M. pneumoniae infection in children and in adults are also discussed separately.
●(See "Erythema multiforme: Pathogenesis, clinical features, and diagnosis".)
●(See "Erythema multiforme: Management".)
●(See "Mycoplasma pneumoniae infection in children".)
●(See "Mycoplasma pneumoniae infection in adults".)
EPIDEMIOLOGY — MIRM primarily affects children and young patients (mean age 12 years), more commonly males, with rare adult cases reported [2,16-20]. MIRM occurs most often during winter [21]. Children serve as the primary reservoir for M. pneumoniae, and transmission occurs via respiratory droplets through close personal contact, especially within households [22]. M. pneumoniae infections are characterized by a long incubation period (up to four weeks) and asymptomatic carriage for weeks following infections [22]. While only approximately 25 percent of patients with M. pneumoniae infections present with a mucocutaneous eruption [23], community outbreaks of MIRM have been described [22,24].
ETIOLOGY AND PATHOGENESIS — A minority of patients with M. pneumoniae infection develop mucocutaneous lesions, suggesting a variability in susceptibility determined by host factors, microbial factors, or both [23,25]. The exact pathogenesis of M. pneumoniae-induced mucocutaneous eruptions remains unknown. Two primary mechanisms have been proposed:
●Indirect – In this mechanism, which is the most commonly accepted, an immune response is triggered by a distant infection leading to tissue damage [15,25]. Polyclonal B cell proliferation and antibody production can lead to skin damage via immune complex deposition and complement activation. Molecular mimicry between M. pneumoniae P1-adhesion molecules and keratinocyte antigens may contribute to this pathway [26,27].
●Direct – Bacteria present at mucocutaneous sites induce local release of inflammatory cytokines and tissue damage. This mechanism is supported by early studies reporting isolation of M. pneumoniae from skin blister fluid [28-30]. However, subsequent studies have not confirmed this finding [21]. Because M. pneumoniae cannot infect squamous cell epithelium, hematogenous spread from the respiratory tract to the skin would be required to cause direct infection [31]. Additionally, the variable extent of mucocutaneous involvement and frequent involvement of distant sites make this mechanism unlikely.
Reports describing recurrent MIRM, familial cases, and recurrence in multiple individuals within families suggest that there may be genetic determinants of susceptibility, although none have been identified [2,32-36]. Whether certain strains of M. pneumoniae may be more likely to cause MIRM than others has not been proven [22,37].
CLINICAL MANIFESTATIONS — Classic MIRM is characterized by severe mucositis and variable, but generally sparse, cutaneous lesions. Most patients experience a prodrome of cough, malaise, and fever for approximately one week prior to the onset of their mucocutaneous eruption [2]:
●Mucosal findings – On average, patients have two to three mucosal sites affected [2,16]. Oral involvement is nearly universal, with hemorrhagic crusting of the lips and erosions on the tongue and buccal mucosa (picture 1A-B) [2,16]. Isolated oral erosions and ulcers can also occur [2]. The majority of patients have ocular involvement, most often characterized by a purulent bilateral conjunctivitis (picture 2); photophobia and eyelid edema may also occur [2,38]. Urogenital lesions occur in approximately 60 percent of patients and can affect the vulva, vagina, any part of the penis (including the urethral meatus), and scrotum [2]. Nasal and anal mucosa may also be involved and should be evaluated [39].
●Cutaneous findings – The morphology of skin lesions of MIRM varies, but vesiculobullous lesions are most common, occurring in nearly 80 percent of cases [2]. Targetoid (picture 3), papular, morbilliform, and transient macular or serpiginous annular eruptions (picture 4) have all been described [2,40]. Lesions are usually sparsely scattered on the extremities and trunk, with occasional involvement of the face.
●Clinical variants – Rarely, patients may present with clinical variants of MIRM. These include the involvement of fewer than two mucosal surfaces and extensive cutaneous involvement [2]. In addition to the typical cutaneous lesions of MIRM, some patients may develop a subcorneal pustular eruption [41]. The classic acral (palmoplantar) target lesions of erythema multiforme (EM) and the extensive epidermal detachment of toxic epidermal necrolysis (TEN) are exceedingly rare in MIRM and should prompt further evaluation for other causes, such as other infections or medications. Some patients may present with only mucosal involvement (MIRM "sine rash").
●Laboratory findings – Patients with MIRM often have elevated acute phase reactants, including C-reactive protein and erythrocyte sedimentation rate [24].
PATHOLOGY — There are no histopathologic features that are pathognomonic of MIRM. MIRM shares features of both erythema multiforme (EM) major and Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), including apoptotic keratinocytes and a sparse, perivascular, dermal infiltrate [42,43]. In one study, biopsies from cases initially diagnosed as M. pneumoniae-induced EM that were also consistent with a diagnosis of MIRM were characterized by full-thickness epidermal necrosis and detachment, resembling more SJS/TEN than EM [21]. These findings indicate that the histologic differentiation of MIRM, EM, and SJS/TEN is difficult or impossible. Investigators have been unable to identify M. pneumoniae in lesional skin by polymerase chain reaction (PCR) [21].
DIAGNOSIS — MIRM should be suspected in a child or young patient presenting with a mucosal or mucocutaneous eruption and a history of prodromal symptoms, including cough, malaise, and fever preceding the eruption by approximately one week [2]. Laboratory evidence of M. pneumoniae infection supports the diagnosis. (See "Pneumonia caused by Chlamydia pneumoniae in children", section on 'Clinical features'.)
Diagnostic criteria — Proposed diagnostic criteria for classic cases of MIRM include (table 1A) [2]:
●Mucocutaneous eruption with <10 percent body surface area involvement
●Involvement of two or more mucosal sites
●Presence of a few vesiculobullous lesions or scattered, atypical, targetoid lesions
●Clinical and laboratory evidence of M. pneumoniae infection (see 'Laboratory tests' below)
Other authors have suggested adding young age to the diagnostic criteria, as MIRM is very rare in adults [39].
The clinical diagnosis of atypical pneumonia is based on the presence of fever, cough, fatigue, and positive auscultatory findings. A chest radiograph can be obtained to confirm this diagnosis. (See "Mycoplasma pneumoniae infection in children", section on 'Pneumonia'.)
Laboratory tests — Confirmatory laboratory tests for M. pneumoniae include polymerase chain reaction (PCR) of pharyngeal swab and measurement of serum-specific immunoglobulin G (IgG), immunoglobulin M (IgM), and immunoglobulin A (IgA) titers [44]. Although PCR is highly sensitive and specific, it can remain positive for up to four months after infection, making it difficult to distinguish acute from past infection. IgM titers start to increase approximately seven to nine days after infection, peak at three to six weeks, and persist for months; IgG titers begin to rise and peak approximately two weeks after IgM titers and persist for years. Thus, as both IgM and IgG may be normal in the acute phase, documentation of titer increase in paired sera is needed for accurate serologic diagnosis.
M. pneumoniae-specific, IgM antibody-secreting cells have been shown to be highly specific for active M. pneumoniae infection, but this test is not widely available [25]. (See "Mycoplasma pneumoniae infection in children", section on 'Laboratory tests'.)
Biopsy — A mucosal or cutaneous biopsy is not routinely performed for the diagnosis of MIRM. As discussed above, histopathologic examination cannot reliably distinguish among MIRM, erythema multiforme (EM), or Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) (see 'Pathology' above). However, a skin biopsy including direct immunofluorescence should be performed if an autoimmune blistering disorder is being considered in the differential diagnosis. (See 'Differential diagnosis' below.)
DIFFERENTIAL DIAGNOSIS — The differential diagnosis of MIRM includes other disorders characterized by mucositis and rash, including:
●Erythema multiforme (EM) major – EM is in most cases caused by herpes simplex virus (HSV) infection and rarely by other viral or bacterial infections or drugs. It can be clinically distinguished from MIRM by the lesional morphology and distribution. EM presents with acute onset of acrally distributed, classic, target lesions, which can become bullous centrally (picture 5). In EM minor, the lips can be involved, but multiple mucosal surfaces are not involved (picture 6). In EM major, severe mucosal lesions occur in association with cutaneous lesions but rarely involve more than one site (picture 7) [21]. Longer hospital stay, respiratory tract complications, and mucosal sequelae are more common in MIRM than in EM associated with other triggers [21]. (See "Erythema multiforme: Pathogenesis, clinical features, and diagnosis".)
●Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) – SJS/TEN is a severe mucocutaneous reaction most commonly triggered by medications in both adults and children and characterized by extensive necrosis and detachment of the epidermis (picture 8). Mucosal involvement occurs in approximately 90 percent of cases (picture 9). Constitutional symptoms, such as fever, are common and may precede the onset of the disease. A history of antecedent exposure to drugs known to cause SJS/TEN is a key diagnostic clue (table 2). (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis".)
●Reactive infectious mucocutaneous eruptions (RIME) – Other bacterial and viral infections that have been associated with mucocutaneous eruptions include Chlamydia pneumoniae [45,46], human metapneumovirus, parainfluenza virus type 2, influenza B virus [47], rhinovirus, enteroviruses (including coxsackievirus) [48], adenovirus [49], and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [50]. C. pneumoniae-induced rash and mucositis has a similarly good prognosis and presentation in school-age children.
●Herpetic gingivostomatitis – Primary herpetic gingivostomatitis is the most common manifestation of primary HSV infection during childhood [51]. It is characterized by ulcerative lesions of the gingiva and oral mucosa (picture 10), fever, malaise, anorexia, and lymphadenopathy. Viral culture and polymerase chain reaction (PCR) can confirm the diagnosis. (See "Herpetic gingivostomatitis in young children".)
●Paraneoplastic pemphigus (PNP) – PNP is a rare, autoimmune, blistering disorder linked to an underlying lymphoproliferative disorder that presents with severe, erosive stomatitis and a polymorphous, cutaneous eruption (picture 11). In children, the most common underlying neoplasm is Castleman disease [52,53]. Direct immunofluorescence and indirect immunofluorescence can confirm the diagnosis. (See "Paraneoplastic pemphigus".)
●Hand, foot, and mouth disease (HFMD) – HFMD is caused by a number of coxsackievirus A and B serotypes. HFMD presents with vesicular, cutaneous lesions (picture 12) and mucosal erosions. The latter are usually well-circumscribed and discrete, as opposed to the larger erosions and bullae of MIRM (picture 13). (See "Hand, foot, and mouth disease and herpangina".)
●Aphthous ulcers – Aphthae are painful mucosal ulcerations that can be recurrent in the oral and genital mucosae. In contrast with MIRM, aphthous lesions are well demarcated and are typically limited to the nonkeratinized mucosal surfaces (picture 14), without involvement of the vermillion lips. (See "Recurrent aphthous stomatitis".)
●Multifocal fixed drug eruption – Multifocal fixed drug eruption can have mucosal involvement but has a distinct cutaneous morphology and histopathology. (See "Fixed drug eruption".)
MANAGEMENT
General considerations — There is no evidence-based, established treatment for MIRM. Because in the acute care setting clinicians may be unable to differentiate MIRM from other severe mucocutaneous reactions, the initial management of MIRM is similar as for patients with suspected Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). It involves immediate in-hospital evaluation for diagnosis confirmation, evaluation of severity, consultation with dermatology and infectious diseases, and initiation of supportive treatment. Based on symptom severity, referral to the most appropriate health care setting should also be considered. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Management, prognosis, and long-term sequelae".)
Supportive care — Supportive care includes mucosal and skin care, eye care, fluids and nutrition, and pain management. Approximately 4 percent of patients with MIRM require intensive care [2]. Empirical antibiotic therapy for M. pneumoniae and immunosuppressive agents are adjunctive treatments for MIRM [2,13].
Pain management — The amount of analgesia needed depends on the severity of the mucocutaneous lesions. Local management of mucosal, urogenital, and cutaneous lesions is essential because covered erosions are less painful than those left open to the air. Systemic analgesia may be necessary and should be carefully selected, based on the severity of symptoms. (See "Pain in children: Approach to pain assessment and overview of management principles".)
It is important to exclude previous use of analgesics as potential triggers of the mucocutaneous eruption (SJS/TEN) prior to starting systemic therapy. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis", section on 'Patient evaluation and diagnosis'.)
Mouth care — Oral erosions can be a cause of significant pain and morbidity. Care should be taken to avoid accumulation of a thick crust on the lips. Lips can be soaked with saline-soaked gauze several times a day. Petrolatum or other ointment should be applied liberally many times a day. In patients with severe erosions at the angles of the mouth, petrolatum-soaked gauze can be rolled into small cylinders and placed in the corners of the mouth to prevent scarring.
Intraoral erosions can be managed with "magic mouthwash" (a variable combination of topical anesthetics, topical corticosteroids, antibiotics, and antacids) several times a day, as long as the patient is old enough to know how to swish and spit. However, the efficacy of such preparation in reducing pain and discomfort is unproven [54]. (See "Herpetic gingivostomatitis in young children", section on '"Magic mouthwash" and other topical therapies'.)
In severe cases, dexamethasone swish and spit can be used as a topical treatment. Thrush or herpes simplex virus reactivation should be treated if present.
Eye care — Ophthalmology should be consulted early when there is ocular involvement, and ocular care should be promptly initiated [55,56]. Saline rinses and multiple daily application of ocular lubricants are indicated for patients with mild conjunctivitis. Amniotic membrane grafting may be required in severe cases with extensive sloughing of the bulbar conjunctiva. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Management, prognosis, and long-term sequelae", section on 'Management of ocular involvement'.)
Urogenital lesions — Urogenital lesions can be painful and affect normal voiding. Erosions can be treated with liberal application of petrolatum. Topical corticosteroids (eg, triamcinolone 0.1% ointment) can help with pain, erythema, and edema. If pain is mild and voiding is normal, then a Foley catheter is not needed. If normal voiding is not possible, then a Foley catheter may be required, and urology input may be helpful.
Skin care — In cases with limited skin involvement, denuded areas should be gently cleaned and covered with petrolatum or another bland emollient and a nonstick dressing. In general, debridement is not necessary. Management in a burn center or intensive care unit may be more appropriate for cases with extensive cutaneous involvement. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Management, prognosis, and long-term sequelae", section on 'Wound care'.)
Fluids and nutrition — Oral erosions often limit intake of nutrition and fluids, and as such, fluids, electrolytes, and nutrition should be managed actively. Patients who are unable to ingest foods should be offered a nasogastric tube for nutrition. Approximately one-quarter of patients with MIRM require nutritional support, and 4 percent require intensive care [2,13].
Adjunctive therapies
Antibiotics — In patients with clinical, laboratory, and/or radiographic evidence of atypical pneumonia, empiric antibiotic therapy targeted to M. pneumoniae should be initiated (macrolide, tetracycline, or fluoroquinolone antibiotics). In children, fluoroquinolones can be used if there is no safe or effective alternative. (See "Mycoplasma pneumoniae infection in children", section on 'Management' and "Mycoplasma pneumoniae infection in adults", section on 'Treatment'.)
In a review of 202 reported cases of MIRM, 80 percent of patients were treated with antibiotics active against M. pneumoniae [2,13]. However, whether antibiotic treatment shortens the course of disease remains to be determined [35].
Systemic corticosteroids — Systemic corticosteroids are frequently used in patients with MIRM and extensive mucosal involvement in an attempt to decrease inflammation and pain. In a review of 202 patients with MIRM, 35 percent received systemic corticosteroids [2]. However, evidence to support this approach is lacking.
If a decision is made to use systemic corticosteroids, we suggest a short course (five to seven days) of prednisone 1 mg/kg/day with no taper in order to limit adverse effects. (See "Major side effects of systemic glucocorticoids".)
Other — Other reported treatments include intravenous immune globulin (IVIG), cyclosporine, and plasmapheresis [2,57].
PROGNOSIS — The prognosis of MIRM is generally good, with most patients making a full recovery. Recurrence has been reported in at least 8 percent of cases [2,35,36].
In contrast with Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), MIRM is associated with a very low mortality rate. In a review of 202 published cases from 1922 to 2013, the mortality rate was 3 percent, and all deaths occurred in the 1940s [2].
Mucocutaneous sequelae occur in approximately 10 percent of patients and include postinflammatory pigmentary alteration and genital and ocular complications, such as scarring and synechiae [2]. Ocular sequelae, including conjunctival shrinkage, corneal ulcerations, blindness, synechiae, dry eyes, and loss of eyelashes, have been reported in 9 percent of cases [2,56].
Rare complications include restrictive lung disease or chronic obliterative bronchitis, persistent cutaneous lesions, and B cell lymphopenia.
FOLLOW-UP — After recovery from the initial episode, patients should be followed based on their specific sequelae (mouth scarring, pulmonary complications, etc). Patients with cutaneous sequelae (eg, scarring, dyspigmentation) should be reassured about the slow improvement of pigmentary alteration and scarring over time and educated about the importance of sun protection. Patients and families should be counseled on the low, but real, risk of recurrence and instructed to present to care early in the course of disease if recurrence is suspected.
SUMMARY AND RECOMMENDATIONS
●Definition – The term "Mycoplasma pneumoniae-induced rash and mucositis" (MIRM) was coined in 2015 to distinguish the mucocutaneous disease associated with Mycoplasma from the Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) spectrum and from erythema multiforme (EM). MIRM primarily affects children and young patients and is more common in males. Other infections have been reported to cause similar mucocutaneous disease. The term "reactive infectious mucocutaneous eruption" (RIME) has been proposed to include these other infectious triggers. (See 'Introduction' above and 'Epidemiology' above.)
●Clinical manifestations – MIRM is characterized by severe mucositis and variable, but generally sparse, cutaneous lesions. Most patients experience a prodrome of cough, malaise, and fever for approximately one week prior to the onset of their mucocutaneous eruption. Oral involvement is nearly universal, with hemorrhagic crusting of the lips and erosions on the tongue and buccal mucosa (picture 1A-B). Most patients also have ocular and urogenital involvement (picture 2). (See 'Clinical manifestations' above.)
●Diagnosis – The diagnosis of MIRM is made in a patient presenting with a mucocutaneous eruption involving at least two mucosal sites and clinical and laboratory evidence of Mycoplasma pneumoniae infection (table 1A-B). Confirmatory laboratory tests for M. pneumoniae include polymerase chain reaction (PCR) of pharyngeal swab and measurement of serum-specific immunoglobulin G (IgG), immunoglobulin M (IgM), and immunoglobulin A (IgA) titers. (See 'Diagnosis' above and "Mycoplasma pneumoniae infection in children", section on 'Laboratory tests'.)
●Initial management and supportive care – The initial management is similar as for patients with suspected SJS/TEN and involves immediate in-hospital evaluation for diagnosis confirmation, evaluation of severity, consultation with dermatology and infectious diseases, and initiation of supportive treatment, including mucosal and skin care, eye care, fluids and nutrition, and pain management. (See 'Supportive care' above.)
●Adjunctive therapies – Patients with clinical and laboratory evidence of M. pneumoniae infection are treated with empiric antibiotic therapy targeted to M. pneumoniae (macrolide, tetracycline, or fluoroquinolone antibiotics). (See 'Antibiotics' above and "Mycoplasma pneumoniae infection in children", section on 'Management'.)
Systemic corticosteroids are frequently used in patients with MIRM and extensive mucosal involvement in the attempt to decrease inflammation and pain, although evidence to support their use is lacking. If a decision is made to use systemic corticosteroids, we suggest a short course (five to seven days) of prednisone 1 mg/kg/day with no taper (Grade 2C). (See 'Systemic corticosteroids' above.)
