Reactive infectious mucocutaneous eruption (RIME)

What is reactive infectious mucocutaneous eruption?

Reactive infectious mucocutaneous eruption (RIME) is a mucocutaneous disease characterised by predominantly mucosal involvement. It commonly follows a bacterial or viral respiratory tract infection and is mostly observed in children and adolescents, although it can occur in adults.

In 2015, the term “mycoplasma pneumoniae-induced rash and mucositis” (MIRM) was introduced to differentiate specific mucocutaneous eruptions from erythema multiforme, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). The MIRM classification, as originally proposed by Ramien et al. in 2020, has subsequently been modified to “reactive infectious mucocutaneous eruption” (RIME), a broader term that includes non-mycoplasma pneumoniae pathogens capable of causing a clinically similar presentation.

Key characteristics of RIME include:

• Association with young patients
• Mucosal involvement
• Relatively sparse cutaneous manifestations
• Favourable prognosis.

The clinical course of RIME characteristically begins with respiratory symptoms approximately one week prior to the onset of mucocutaneous eruption. Mucositis can affect the mouth, eyes, urogenital organs, and gastrointestinal tract, with lesions tending to be primarily vesiculobullous or targetoid. Cutaneous lesions typically affect the extremities, including acral areas.

Haemorrhagic erosions and crusts in RIME (RIME-patient1)

Severe oral and labial erosions in RIME (RIME-patient2)

Severe conjunctival lesions in RIME (RIME-patient2)

Vesicobullous targetoid skin lesions in RIME (RIME-patient1)

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Who gets reactive infectious mucocutaneous eruption?

RIME typically affects children and adolescents (median age of 12 years) with a slight male predominance; however, rare cases have been reported in adults. A 2019 prospective cohort study showed that 22.7% of children with MP-associated community-acquired pneumonia developed mucocutaneous lesions, with 6.8% developing RIME.

Genetic susceptibility has been suspected following reports of recurrent RIME among affected families. However, specific genetic determinants have not been identified.

There appears to be no association with race or ethnicity.

What causes reactive infectious mucocutaneous eruption?

Although the pathophysiology of RIME is not known, it is hypothesised to involve pathogenic factors and inflammatory response mechanisms. Respiratory infections have been identified to cause RIME, with Mycoplasma pneumoniae being the most frequently associated pathogen.

In addition to M. pneumoniae, other associated pathogens include:

• Chlamydia pneumoniae
• Human metapneumovirus
• Parainfluenza virus type 2
• Influenza B virus
• Rhinovirus
• Enteroviruses (eg, coxsackievirus)
• Adenovirus
• SARS-CoV-2 (COVID-19).

What are the clinical features of reactive infectious mucocutaneous eruption?

RIME is characterised by severe mucositis and generally sparse, variable cutaneous involvement. Some patients may present with only mucosal involvement, termed RIME “sine rash” (without rash).

Antecedent symptoms, such as fever, malaise, and cough, typically occur one week prior to the onset of mucocutaneous eruption and likely reflect the precipitating infection rather than a true prodromal phase of RIME.

Mucosal features

RIME predominantly affects mucous membranes:

• Oral (94%-100% of cases)
  • Includes isolated erosions, ulcers, hemorrhagic crusts, and vesiculobullous lesions; involvement may be isolated or may be so extensive as to affect the entirety of the buccal mucosa with significant denudation
• Ocular (82%-92% of cases)
  • Includes bilateral conjunctivitis, photophobia, and eyelid edema
• Urogenital (63%-78% of cases)
  • Includes vesiculobullous, erosions, and ulcerations of the glans, urethral meatus, penile shaft, scrotum, vulva, and vagina
• Nasal, esophageal, and anal membranes can also be affected.

Cutaneous features

• Cutaneous involvement is frequently absent (34%) or sparse (47%) in RIME. However, in rare cases, cutaneous findings may be extensive.
• Lesion morphology in order of reported frequency is as follows: vesiculobullous (77%), targetoid (48%), papular (14%), macular (12%), and morbilliform/maculopapular (9%; which may be faint and/or transient)
• The most common distribution is acral or extremity (46%), followed by generalised (31%) and truncal patterns (23%).

What are the complications of reactive infectious mucocutaneous eruption?

Mucocutaneous complications occur in about 10% of patients, with ocular complications being the most serious. These include:

• Dry eye
• Loss of eyelashes
• Conjunctival shrinkage
• Synechiae
• Corneal ulceration
• Blindness.

Cutaneous complications include post-inflammatory pigmentary alteration (eg, hyperpigmentation) and scarring.

Systemic complications are exceedingly rare and include restrictive lung disease, chronic obliterative bronchitis, and B-cell lymphopenia.

How is reactive infectious mucocutaneous eruption diagnosed?

Diagnosis is made clinically based on history and physical examination. RIME should be suspected in children or young adults with mucocutaneous eruption that appears about one week following flu-like symptoms, such as fever, malaise, and cough.

Clinical, radiographic, and laboratory evidence of an infectious trigger supports the diagnosis and may include:

• Chest x-ray
• Tests for Mycoplasma pneumoniae:
  • Polymerase chain reaction (PCR) of a pharyngeal/throat swab; note that PCR tests can remain positive for months following infection
  • IgM and IgG serologies may be useful; however, these may be negative during the early stage of disease, and paired acute/convalescent sera four weeks apart is required.
• PCR respiratory panels for Chlamydia pneumoniae and multiple respiratory viral infections
• Rapid antigen test (RAT) or nucleic acid amplification test (NAAT) for COVID-19 infection

Histologic features include apoptotic keratinocytes and sparse perivascular dermal infiltrates. However, biopsy is not routinely performed as histology does not reliably distinguish RIME from other similar mucocutaneous diseases, such as erythema multiforme or SJS/TEN.

What is the differential diagnosis for reactive infectious mucocutaneous eruption?

• Erythema multiforme (EM) major:
  • Typically lacks antecedent respiratory symptoms seen in RIME.
  • Presents with classic target lesions versus sparse skin involvement and atypical, targetoid lesions in RIME.
• Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN):
  • Severe and life-threatening
  • Rare medication reaction often with a recent history (2 months) of exposure to the causative medication
  • Causes extensive sheet-like skin and mucosal detachment with a positive Nikolsky’s sign.
• Kawasaki disease
• Pemphigus vulgaris
• Autoinflammatory disease
• Severe hand, foot, and mouth disease

What is the treatment for reactive infectious mucocutaneous eruption?

There are no established treatment guidelines. However, a comprehensive approach includes supportive measures, early consultation with appropriate specialty departments, and antimicrobial and immunomodulatory therapies as indicated.

Approximately 4% of patients with RIME require admission to intensive care, however this is primarily due to airway complications of M. pneumoniae infection rather than mucocutaneous complications. Ophthalmologic consultation should be sought if any ocular involvement is identified given the risk for serious sequelae.

General measures

• Fluids and nutrition – consider nasogastric tube placement in patients unable to tolerate oral intake
• Skin care and pain management – emollients and non-adhesive dressings; systemic analgesia may be necessary
• Lip care – frequent application of saline-soaked gauze as well as liberal use of petroleum jelly or other barrier protectants
• Intraoral lesions – medicated mouthwash mixtures (eg, 'magic mouthwash”)

Specific measures

Antimicrobials:

• Mucocutaneous involvement: It is unclear whether antimicrobial treatment reduces the incidence, severity, or duration of mucocutaneous eruption. However, identified infections should be treated with antimicrobial therapy as per local guidelines.
• Cutaneous involvement: Antimicrobials are recommended if the skin is involved, although evidence for this remains lacking. Macrolides are commonly used. Patients with macrolide-resistant MP may require prolonged antibiotic therapy. Alternative antibiotics include tetracyclines or fluoroquinolones.
• Respiratory: treatment of uncomplicated upper respiratory tract infections or bronchitis with antimicrobial therapy is not recommended. However, pneumonia should be treated according to local guidelines.

Immunomodulatory agents:

Systemic corticosteroids and other therapies have been used in the treatment of RIME, often where there is extensive mucosal involvement or high symptom burden. However, high-quality evidence and standard dosing recommendations are currently lacking.

• Systemic corticosteroids. Example regimens include:

  • Prednisone: 0.5-1 mg/kg/day for 7-10 days
  • Methylprednisolone: 15-30 mg/kg/day IV (max 1g) for 3 days
  • Dexamethasone: 1.5mg/kg/day IV for 3 days

• Steroid-sparing agents. Example regimens include:

  • Intravenous immunoglobulin (IVIG): 0.5g/kg/day for 4 days or 1g/kg/day for 2-3 days, either alone or in combination with IV methylprednisolone
  • Ciclosporin: 3-5mg/kg/day divided twice daily for 7 days, then 50% dose for 7 days; a small case series reported a reduction in time-to-resolution
  • Etanercept (TNF-alpha inhibitor): 3-5 mg/kg/day in two divided doses for 7-10 days; etanercept may be considered in severe cases.

Considerations for specific organ involvement:

• Eyes – ophthalmology consultation should be sought promptly for any ocular involvement. Case reports of early treatment with a combination of topical corticosteroids and antibiotic eye drops for conjunctivitis have been reported to produce favourable outcomes. Amniotic membrane grafting may be required in severe cases.
• Urogenital area – erosions can be managed with petroleum jelly. Topical corticosteroids (eg, 0.1% triamcinolone ointment) may be used to mitigate inflammation and reduce pain, oedema, and other symptoms.

What is the outcome for reactive infectious mucocutaneous eruption?

RIME is associated with a low mortality rate (2-3%) and most patients achieve full recovery. Mucosal synechiae and pigmentary changes are the most common sequelae. Recurrence has been reported in approximately 8% of cases.

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