Reactive infectious mucocutaneous eruption (RIME)

INTRODUCTION — Reactive infectious mucocutaneous eruption (RIME) refers to a severe mucocutaneous adverse reaction that occurs predominantly in children and adolescents following a bacterial or viral respiratory infection (most commonly Mycoplasma pneumoniae infection) [1-3]. RIME is characterized by prominent mucositis, usually with sparse or even absent cutaneous involvement. Compared with the Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) spectrum, RIME has a distinct pathophysiology, a milder course, and a generally good prognosis.

This topic will discuss the pathogenesis, clinical manifestations, diagnosis, and treatment of RIME. SJS/TEN and erythema multiforme (EM) are discussed separately. M. pneumoniae infection in children and adults is also discussed separately.

●(See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis".)

●(See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Management, prognosis, and long-term sequelae".)

●(See "Erythema multiforme: Pathogenesis, clinical features, and diagnosis".)

●(See "Erythema multiforme: Management".)

●(See "Mycoplasma pneumoniae infection in children".)

●(See "Mycoplasma pneumoniae infection in adults".)

TERMINOLOGY — 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 erythema multiforme (EM) [4]. Prior to that distinction, cases of Mycoplasma-induced mucocutaneous disease were referred to as SJS [5-7], atypical SJS [8], Fuchs syndrome [9,10], TEN [11], EM [12], and Mycoplasma pneumoniae-associated mucositis (MPAM) [13-15].

Based on the subsequent observation that other bacterial and viral respiratory infections can cause a mucocutaneous reaction in children, it has been proposed that MIRM should be included 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 [16-19].

The term RIME will be the preferred term used in this topic.

EPIDEMIOLOGY — RIME primarily affects children and young patients (mean age 12 years), more commonly males, with rare adult cases reported [4,20-24]. RIME most often occurs during winter [25]. Community outbreaks of RIME associated with M. pneumoniae infection have been described [26,27].

ETIOLOGY AND PATHOGENESIS — While several respiratory infections have been reported to cause RIME, M. pneumoniae, a leading cause of community-acquired pneumonia, is the most common trigger [3,28,29]. Children serve as the primary reservoir for M. pneumoniae, and transmission occurs via respiratory droplets through close personal contact (especially within households) [26,28,29]. M. pneumoniae infections are characterized by a long incubation period (up to four weeks) and asymptomatic carriage for weeks following infections [26]. M. pneumoniae is the most frequent etiologic agent of RIME in children. However, mucocutaneous eruptions indistinguishable from those described with M. pneumoniae have been reported with Chlamydia pneumoniae, human metapneumovirus, parainfluenza virus type 2, influenza B virus, rhinovirus, enteroviruses (including coxsackievirus), adenovirus, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [16,18,19,30-36].

Reports describing recurrent RIME by M. pneumoniae and other infections, familial cases, and recurrence in multiple individuals within families suggest that there may be genetic determinants of susceptibility, although none have been identified [4,34,37-41].

The exact pathogenesis of RIME is 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 [17,29]. Polyclonal B cell proliferation and antibody production can lead to skin damage via immune complex deposition and complement activation. As an example, molecular mimicry between M. pneumoniae P1-adhesion molecules and keratinocyte antigens may contribute to this pathway [42,43].

●Direct – Bacteria or other infectious agents 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 [44-46]. However, subsequent studies have not confirmed this finding [25]. Because M. pneumoniae cannot infect squamous cell epithelium, hematogenous spread from the respiratory tract to the skin would be required to cause direct infection [47]. The variable extent of mucocutaneous involvement, frequent involvement of distant sites, and expanding range of associated infections all make this mechanism unlikely.

CLINICAL MANIFESTATIONS — RIME 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 [4]. Although predominantly described in children and adolescents, RIME can also occur in adults.

Mucosal and cutaneous findings

●Mucosal findings – On average, patients have two to three mucosal sites affected [4,20]. Oral involvement is nearly universal, with hemorrhagic crusting of the lips and erosions on the tongue and buccal mucosa (picture 1A-B) [4,20]. Isolated oral erosions and ulcers can also occur [4]. The majority of patients have ocular involvement, most often characterized by a purulent bilateral conjunctivitis (picture 2). Photophobia and eyelid edema may also occur [4,48]. 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 [4]. Nasal and anal mucosa may also be involved and should be evaluated [49].

●Cutaneous findings – The morphology of skin lesions of RIME varies, but vesiculobullous lesions are most common (occurring in nearly 80 percent of cases) [4]. Targetoid (picture 3), papular, morbilliform, and transient macular or serpiginous annular eruptions (picture 4) have all been described [4,50]. 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 RIME. These include the involvement of fewer than two mucosal surfaces and extensive cutaneous involvement [4]. In addition to the typical cutaneous lesions of RIME, some patients may develop a subcorneal pustular eruption [51]. The classic, acral (palmoplantar), target lesions of erythema multiforme (EM) and the extensive epidermal detachment of toxic epidermal necrolysis (TEN) are exceedingly rare in RIME and should prompt further evaluation for other causes, such as other infections or medications. Some patients may present with only mucosal involvement (RIME "sine rash").

Laboratory findings — Patients with RIME often have elevated acute phase reactants, including C-reactive protein and erythrocyte sedimentation rate [27].

Recurrent RIME — Recurrence of RIME has been reported in 9 to 38 percent of patients in case series [3,4,34,36,41]. Most recurrent cases appear to be triggered by different viral or bacterial agents rather than re-exposure to the initial pathogen, although a triggering agent cannot be found in many cases [34,41].

PATHOLOGY — There are no histopathologic features that are pathognomonic of RIME. RIME 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 [52,53]. In one study, biopsies from cases initially diagnosed as M. pneumoniae-induced EM that were also consistent with a diagnosis of RIME were characterized by full-thickness epidermal necrosis and detachment, resembling SJS/TEN more than EM [25]. These findings indicate that the histologic differentiation of RIME, EM, and SJS/TEN is difficult or impossible. Investigators have been unable to identify M. pneumoniae in lesional skin by polymerase chain reaction (PCR) [25].

DIAGNOSIS — RIME 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 [4]. Laboratory evidence of M. pneumoniae or C. pneumoniae infection supports the diagnosis. (See "Mycoplasma pneumoniae infection in children" and "Pneumonia caused by Chlamydia pneumoniae in children".)

Diagnostic criteria — Proposed diagnostic criteria for RIME include [1,4]:

●Mucocutaneous eruption involving one or more sites with <10 percent body surface area involvement

●Presence of a few vesiculobullous lesions or scattered, atypical, targetoid lesions on skin

●Noncontributory medication history

●History of prodromal symptoms (eg, cough, fever, malaise) in the previous 7 to 10 days

●Clinical, radiographic, or laboratory evidence of an infectious trigger (most commonly M. pneumoniae, respiratory viruses, or C. pneumoniae) (see 'Imaging and laboratory tests' below)

Other authors have suggested adding young age to the diagnostic criteria, as RIME is very rare in adults [49].

The clinical diagnosis of atypical pneumonia is based on the presence of fever, cough, fatigue, and positive auscultatory findings. (See "Mycoplasma pneumoniae infection in children", section on 'Pneumonia'.)

Imaging and laboratory tests — Radiologic and laboratory investigations to confirm the diagnosis of respiratory infection include:

●Chest radiograph

●Tests for M. pneumoniae infection – 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 [54]. 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. (See "Mycoplasma pneumoniae infection in children", section on 'Laboratory tests'.)

●Tests for C. pneumoniae infection – A PCR-based assay can be used for the confirmation of C. pneumoniae infection. The test can be performed on a variety of specimens, including nasopharyngeal swabs, sputum, and bronchoalveolar lavage fluid. (See "Pneumonia caused by Chlamydia pneumoniae in children", section on 'Diagnosis'.)

●Tests for respiratory virus infections – PCR respiratory panels that include multiple respiratory viruses in addition to M. pneumoniae and C. pneumoniae are also commercially available [55]. (See "Community-acquired pneumonia in children: Clinical features and diagnosis".)

●Tests for SARS-CoV-2 infection – The diagnosis of coronavirus disease 2019 (COVID-19) is made by direct detection of SARS-CoV-2 ribonucleic acid (RNA) using real-time PCR or by detection of viral protein using an antigen test. A positive nucleic acid amplification test (NAAT) or antigen test is generally indicative of infection. (See "COVID-19: Diagnosis".)

There are rare reports of gastrointestinal pathogens causing RIME [56]. Additional testing, as indicated by a patient's history and clinical findings, may be needed.

Biopsy — A mucosal or cutaneous biopsy is not routinely performed for the diagnosis of RIME. As discussed above, histopathologic examination cannot reliably distinguish among RIME, 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 RIME includes other disorders characterized by mucositis and rash, including:

●Erythema multiforme (EM) major – EM is caused by herpes simplex virus (HSV) infection in most cases and rarely by other viral or bacterial infections or drugs. It can be clinically distinguished from RIME 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) [25]. Longer hospital stay, respiratory tract complications, and mucosal sequelae are more common in RIME than in EM associated with other triggers [25]. (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 is 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 1). (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis".)

●Herpetic gingivostomatitis – Primary herpetic gingivostomatitis is the most common manifestation of primary HSV infection during childhood [57]. 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 – Paraneoplastic pemphigus 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 [58,59]. Direct immunofluorescence and indirect immunofluorescence can confirm the diagnosis. (See "Paraneoplastic pemphigus".)

●Hand, foot, and mouth disease – Hand, foot, and mouth disease is caused by multiple coxsackievirus A and B serotypes. Hand, foot, and mouth disease 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 RIME (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 RIME, 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 RIME. Because clinicians may be unable to differentiate RIME from other severe mucocutaneous reactions in the acute care setting, the initial management of RIME is similar as the initial management 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 [60]. 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 RIME require intensive care [4]. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Management, prognosis, and long-term sequelae", section on 'Supportive care'.)

Fluids and nutrition — Oral erosions often limit intake of nutrition and fluids; therefore, 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 RIME require nutritional support, and 4 percent require intensive care [4,15].

Pain management — The amount of analgesia needed depends on the severity of the mucocutaneous lesions. Local management of oral, ocular, urogenital, and cutaneous lesions with ointments and dressings 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".)

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 another 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 the so-called "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 [61]. However, the efficacy of such preparation in reducing pain and discomfort is unproven [62]. (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 (HSV) 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 [60,63,64]. Saline rinses and multiple daily applications 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'.)

Adjunctive therapies

Antibiotics — Children with clinical, laboratory, and/or radiographic evidence of community-acquired pneumonia are initially treated empirically with antibiotics that cover M. pneumoniae, C. pneumoniae, and Streptococcus pneumoniae (macrolide, tetracycline, or fluoroquinolone antibiotics), pending results of microbiologic tests. (See "Mycoplasma pneumoniae infection in children", section on 'Empiric therapy' and "Pneumonia caused by Chlamydia pneumoniae in children", section on 'Empiric therapy for community-acquired pneumonia'.)

However, whether antibiotic treatment shortens the course of disease remains to be determined [40].

Systemic corticosteroids — Systemic corticosteroids are frequently used in patients with RIME and extensive mucosal involvement to decrease inflammation and pain. In a review of 202 patients with RIME associated with M. pneumoniae, 35 percent received systemic corticosteroids [4]. Although evidence to support this approach is weak, we suggest a short course (5 to 10 days) of prednisone 1 mg/kg/day with no taper in patients with extensive mucosal involvement and severe symptoms.

Other immunomodulatory therapies — Other immunomodulatory treatments that have been reported in cases of RIME with severe mucosal involvement include cyclosporine [65], intravenous immune globulin (IVIG) [66], and anti-tumor necrosis factor (TNF) agents [67,68].

In a retrospective series of six patients with RIME and evidence of disease progression (age 5 to 13 years), a single dose of subcutaneous etanercept, 0.6 to 0.8 mg/kg or 50 mg for those who weighed >60 kg, induced clinical improvement in five of six patients within two days of administration [67].

Cyclosporine has been reported to be effective in a small case series of pediatric patients with RIME [65]. Patients were treated with cyclosporine 3 to 5 mg/kg/day in two divided doses for 7 to 10 days.

PROGNOSIS — The prognosis of RIME is generally good, with most patients making a full recovery. Recurrence has been reported in at least 8 percent of cases [4,40,41].

In contrast with Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), RIME 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 [4]. C. pneumoniae-induced rash and mucositis has a similarly good prognosis and presentation in school-age children.

Mucocutaneous sequelae occur in approximately 10 percent of patients and include postinflammatory pigmentary alteration and genital and ocular complications, such as scarring and synechiae [4]. Ocular sequelae, including conjunctival shrinkage, corneal ulcerations, blindness, synechiae, dry eyes, and loss of eyelashes, have been reported in 9 percent of cases [4,64].

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

●Terminology – The term "Mycoplasma pneumoniae-induced rash and mucositis" (MIRM) was coined in 2015 to distinguish the mucocutaneous disease associated with Mycoplasma pneumoniae in children and adolescents from the Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) spectrum and erythema multiforme (EM). Based on the subsequent observation that other respiratory infections can trigger a mucocutaneous reaction in children indistinguishable from MIRM, the broader term "reactive infectious mucocutaneous eruption" (RIME) has been proposed. (See 'Terminology' above and 'Epidemiology' above.)

●Clinical manifestations – RIME is characterized by severe mucositis and variable, but generally limited, 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 – Proposed diagnostic criteria for RIME include (see 'Diagnosis' above):

•Mucocutaneous eruption involving one or more sites with <10 percent body surface area involvement

•Presence of a few vesiculobullous lesions or scattered, atypical, targetoid lesions on skin

•Noncontributory medication history

•History of prodromal symptoms (eg, cough, fever, malaise) in the previous 7 to 10 days

•Clinical, radiographic, or laboratory evidence of an infectious trigger (most commonly M. pneumoniae, respiratory viruses, or Chlamydia pneumoniae)

●Management:

•Initial management and supportive care – The initial management of RIME is similar to the initial management for 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 and "Stevens-Johnson syndrome and toxic epidermal necrolysis: Management, prognosis, and long-term sequelae", section on 'Supportive care'.)

•Adjunctive therapies:

-Empiric antibiotic therapy – Patients with clinical, laboratory, and/or radiographic evidence of community-acquired pneumonia are initially treated empirically with antibiotics that cover M. pneumoniae, C. pneumoniae, and Streptococcus pneumoniae. (See "Mycoplasma pneumoniae infection in children", section on 'Empiric therapy' and "Pneumonia caused by Chlamydia pneumoniae in children", section on 'Empiric therapy for community-acquired pneumonia'.)

-Immunomodulatory therapies – For patients with extensive mucosal involvement or high burden of symptoms, we suggest a short course of systemic corticosteroids rather than intravenous immune globulin (IVIG) (Grade 2C). A reasonable regimen is prednisone 1 mg/kg/day for 5 to 10 days. Cyclosporine (at a dose of 3 to 5 mg/kg/day for 7 to 10 days) or a single dose of etanercept may be an alternative to systemic corticosteroids. (See 'Systemic corticosteroids' above and 'Other immunomodulatory therapies' above.)