Mycoplasma-Induced Rash and Mucositis

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Descriptive article of the ophthalmic manifestations of Mycoplasma-Induced Rash and Mucositis

Disease Entity

Mycoplasma-Induced Rash and Mucositis (MIRM) is recognized by the following codes as per the International

Classification of Diseases (ICD) nomenclature:

ICD 9

  • ICD-9-CM
    • 041.81 Other specified bacterial infections in conditions classified elsewhere and of unspecified site, mycoplasma

ICD 10

  • ICD-10-CM
    • B96.0 – Mycoplasma pneumonia as the cause of diseases elsewhere[1]


Disease

Mycoplasma-Induced Rash and Mucositis (MIRM), also known as Mycoplasma pneumoniae-associated mucositis (MPAM) is an extrapulmonary manifestation of Mycoplasma pneumoniae (M. pneumoniae) that has recently been distinguished from Erythema Multiforme (EM), Stevens-Johnson Syndrome (SJS), and Toxic Epidermal Necrolysis (TEN).[2][3][4][5]This disease is characterized by a severe mucositis that predominantly affects the oral mucosa, but can involve the conjunctiva and genital mucosa as well.[2] Ocular involvement is varied, but it generally includes a bilateral conjunctivitis without chemosis or corneal involvement. Other ophthalmic features can include mucoid discharge, conjunctival epithelial defects, eyelid margin hyperemia and staining, and/or pseudomembranes.[4] While there is limited data published for ocular manifestations of MIRM the current data demonstrates MIRM typically has a more limited ocular course and a more favorable ocular prognosis compared to SJS/TEN.[4]

Definitions

Previously, M. pneumoniae associated mucocutaneous eruptions were labeled with different designations along the spectrum of erythema multiforme (EM), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) based on the varied presentations of these cases.[2][5][6][7][8] However, recent studies have separated MIRM as a distinct entity, including a large systematic review by Canavan et al.[2][3][4][5] Some distinguishing features include its predilection for young patients, predominant mucosal involvement, sparse vesiculobullous and/or targetoid cutaneous eruption, and great overall prognosis.[2] More distinguishing traits are summarized in Table 1 and in the respective sections below.

Table 1: Distinguishing characteristics comparing Mycoplasma-induced rash and mucositis (MIRM), erythema multiforme (EM), and Stevens-Johnson syndrome (SJS) / Toxic Epidermal Necrolysis (TEN).[9]
MIRM EM SJS/TEN
Trigger M. Pneumonia HSV Drug induced
Patient Demographics Younger males Younger males Adults
Rash Characteristics Prominent mucositis, limited cutaneous vesiculobullous lesions +/- targetoid eruption Classic acral target lesions Extensive and central target lesions with potential for extensive detachment (TEN)
Frequency of Ocular Disease 82% 5-23% 50-88%
Mortality 3-4% 0-6% 25-30%

Epidemiology

Mycoplasma pneumoniae (M. pneumoniae) is a common cause of skin and respiratory infections, pneumonitis, bronchitis, and febrile upper respiratory infections.[10] M. pneumoniae is also an important cause of community-acquired pneumonia in children, which often has extra-pulmonary manifestations in up to 25% of patients, most commonly mucocutaneous involvement as in MIRM.[11][12] MIRM typically affects younger patients and has less severe cutaneous findings and a more favorable prognosis compared to SJS/TEN.[2][3] MIRM commonly involves more than one mucous membrane, most prominently the oral mucosa with vesiculobullous lesions and extensive oral erosions.[13] A systematic review of patients with MIRM found that most patients were young males (66%), with a mean age of 11.9 years old, and ocular findings were present in 82% of these patients.[2]

Pathophysiology

The precise pathophysiology of MIRM is not completely understood. One proposed mechanism is polyclonal B-cell proliferation and antibody production with subsequent immune complex deposition and complement activation that could cause skin damage. Another possibility is molecular mimicry between Mycoplasma P1-adhesion molecules and a hosts keratinocytes.[2] Conversely, erythema multiforme type diseases likely involve cytotoxicity mediated through a perforin/granzyme pathway with Fas ligand and granulysin and a type IV delayed-type hypersensitivity reaction.[2]

Diagnosis

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History

MIRM typically affects younger patients with a slight male predominance. Patients generally have a prodrome of fever, malaise, and cough approximately one week prior to the onset of mucocutaneous eruption.[2][4] Mortality is low, most patients have a full recovery from their disease, and recurrence is uncommon (8%).[2] Prominent involvement of the mucosal membranes with limited cutaneous involvement is the common presentation; however, there are forms with no cutaneous involvement, which can be classified as MIRM sine rash .[2][14][15]

Physical examination

Most patients are seen in the inpatient setting; therefore, the exam can be performed with an indirect ophthalmoscope, 20 diopter lens, fluorescein stain, and cobalt blue light source to evaluate the anterior segment. A thorough evaluation of the cornea, conjunctiva (bulbar and palpebral), and eyelids (including mucocutaneous junction) is necessary to evaluate the extent of ocular involvement. One must assess for the presence of epithelial sloughing as evidenced by fluorescein staining on the above surfaces. In addition, a combined effort with dermatology and urology is useful for evaluation of dermatologic manifestations and for evaluation/treatment of patients with extensive genital mucosal involvement.

Signs

Clinical photo of patient with prominent oral mucositis including superficial erosions and ulcerations.
Figure 1. Clinical photo of patient with prominent oral mucositis including superficial erosions and ulcerations.

MIRM features a prominent mucositis and almost always has oral involvement that can be in the form of vesiculobullous lesions and extensive erosions (Figure 1).[2][13] It typically involves 2.5 mucosal sites, most commonly ocular and oral, and a characteristic cutaneous sparse vesiculobullous and/or targetoid eruption.[2] Ocular involvement is varied but generally includes a bilateral conjunctivitis without chemosis or corneal involvement. Additional potential findings include: mucoid discharge, conjunctival epithelial defects, eyelid margin hyperemia and staining, and/or pseudomembranes (Figure 2).[4] These ocular findings may initially be subtle, and thus the need for close ophthalmology follow up both inpatient and outpatient are important to prevent permanent ocular surface damage from MIRM.

Symptoms

Ocular symptoms are not as well described in the current literature, but can include redness, tearing, photophobia, and blurry vision.[2][4]

Clinical photo of patient with MIRM with conjunctival injection and ulceration of lid margin.
Figure 2. Clinical photo of patient with MIRM with conjunctival injection and ulceration of lid margin.

Clinical diagnosis

The diagnosis of MIRM depends on the typical features as described above and evidence of recent infection with M. Pneumoniae. Diagnostic criteria for typical cases of MIRM proposed by Canavan et. al are summarized below. These criteria also apply to atypical cases but with different skin findings. MIRM sine rash has few fleeting morbilliform lesions or few vesicles, while severe MIRM has extensive widespread blisters or flat atypical targets.[2]


Typical MIRM Criteria:

  • <10% BSA with detachment:
  • > 2 mucosal sites involved
  • Few vesiculobullous lesions, or scattered atypical targets
  • Presence or absence of targetoid lesions (Figure 3)
  • Atypical pneumonia
    • Signs: fever, cough, auscultatory findings
    • Labs: increase in M. Pneumoniae IgM antibodies, M. Pneumoniae in oropharyngeal or bullae cultures or PCR, and/or serial cold agglutinins
Clinical photo of patient with targetoid shaped lesions that involved their extremities and trunk.
Figure 3. Clinical photo of patient with targetoid shaped lesions that involved their extremities and trunk.

Laboratory test

Laboratory testing for M. Pneumoniae includes: isolation, complement fixation, molecular-based detection assays such as PCR, and serologic testing.[16] Serologic testing demonstrating IgM antibodies for M. Pneumoniae suggests recent infection, but these levels can remain elevated for several months. Therefore, more accurate diagnosis is found with paired serologic testing that demonstrates either seroconversion from absence of IgM to presence of IgM or four-fold increase of IgG titers from acute to convalescent phase samples.[17]

Differential diagnosis

Since MIRM predominantly affects the pediatric population the differential diagnosis summarized in Table 2 lists possibilities more prevalent in this demographic.

Table 2. Differential Diagnosis
Kawasaki Disease
Erythema Multiforme
Stevens-Johnson Syndrome
Toxic Epidermal Necrolysis
Vericella Zoster
Viral Exanthem

Prognosis

MIRM has a better overall prognosis compared to SJS and TEN in regards to morbidity and mortality.[2][3][4][9] Ocular complications of EM and SJS/TEN are well described in the literature and can result in debilitating sequelae, such as symblepharon, keratinized mucosal surfaces, scarred lid margins, entropion, trichiasis, limbal stem cell failure, and corneal scarring.[18][19][20][21] Based on the systematic review by Canavan et al. ophthalmic consequences of MIRM can include corneal ulcers, conjunctival shrinkage, blindness, synechiae, dry eyes and madarosis; however, these were present in only 8.9% of cases.[2] A more recent case series with far fewer patients demonstrated that with proper topical treatment most patients have a complete ocular recovery with BCVA 20/25 or better and only one patient suffered from eyelid margin scarring.[4]

Management

General treatment

Currently there is no standardized treatment regimen for patients with MIRM; however, the treatment guidelines for SJS by Gregory can be applied to these patients given the similar presentation. His guidelines for treatment of SJS categorize patients into mild, moderate, severe, and extremely severe based on the location and extent of conjunctival and corneal epithelial sloughing. This epithelial involvement can be measured with the amount of fluorescein staining. Patients that fall in the mild and moderate categories were treated medically with a combination of drops and those that were severe or extremely severe required surgical amniotic membrane transplant (AMT) in addition to medical therapy.[19] The criteria that stratified patients as severe was involvement of more than 1/3 of the eyelid margin, and/or more than 10 cm in diameter of bulbar conjunctiva, with or without more than punctate staining of the cornea.[19]

Medical therapy

Topical therapy following the SJS treatment protocol consists of an antibiotic drop QID, cyclosporine 0.05% drops BID, steroid drops BID, and an antibiotic or combination antibiotic/steroid ointment to eyelid margins BID to QID.[19]

Surgery

Surgical therapy is primarily AMT once patients meet criteria as listed above. Importantly AMT should be performed within seven to 10 days from onset of epithelial sloughing as prior studies have shown decreased efficacy past this time frame.[18][19][22]

Additional Recommendations

Patients with MIRM may have less impressive initial findings; however, like SJS/TEN these patients have a dynamic disease course that can vary drastically on a daily basis. Therefore, close followup with daily ophthalmic exam while patients are hospitalized is crucial to promptly institute necessary medical and/or surgical therapy in order to prevent permanent sequelae.


References

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  1. # ICD10Data. Accessed April 10, 020. https://www.icd10data.com/
  2. 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 2.13 2.14 2.15 2.16 2.17 Canavan TN, Mathes EF, Frieden I, Shinkai K. Mycoplasma pneumoniae-induced rash and mucositis as a syndrome distinct from Stevens-Johnson syndrome and erythema multiforme: a systematic review. J Am Acad Dermatol. 2015;72(2):239-245. doi:10.1016/j.jaad.2014.06.026
  3. 3.0 3.1 3.2 3.3 Prindaville B, Newell BD, Nopper AJ, Horii KA. Mycoplasma pneumonia--associated mucocutaneous disease in children: dilemmas in classification. Pediatr Dermatol. 2014;31(6):670-675. doi:10.1111/pde.12482
  4. 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 4.8 Shah PR, Williams AM, Pihlblad MS, Nischal KK. Ophthalmic Manifestations of Mycoplasma-Induced Rash and Mucositis. Cornea. 2019;38(10):1305-1308. doi:10.1097/ICO.0000000000001985
  5. 5.0 5.1 5.2 Martínez-Pérez M, Imbernón-Moya A, Lobato-Berezo A, Churruca-Grijelmo M. Mycoplasma pneumoniae-Induced Mucocutaneous Rash: A New Syndrome Distinct from Erythema Multiforme? Report of a New Case and Review of the Literature. Actas Dermosifiliogr. 2016;107(7):e47-51. doi:10.1016/j.ad.2015.09.023
  6. Forman R, Koren G, Shear NH. Erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis in children: a review of 10 years’ experience. Drug Saf. 2002;25(13):965-972. doi:10.2165/00002018-200225130-00006
  7. Roujeau JC. Stevens-Johnson syndrome and toxic epidermal necrolysis are severity variants of the same disease which differs from erythema multiforme. J Dermatol. 1997;24(11):726-729. doi:10.1111/j.1346-8138.1997.tb02524.x
  8. Tay YK, Huff JC, Weston WL. Mycoplasma pneumoniae infection is associated with Stevens-Johnson syndrome, not erythema multiforme (von Hebra). J Am Acad Dermatol. 1996;35(5 Pt 1):757-760. doi:10.1016/s0190-9622(96)90732-x
  9. 9.0 9.1 Chang Y-S, Huang F-C, Tseng S-H, Hsu C-K, Ho C-L, Sheu H-M. Erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis: acute ocular manifestations, causes, and management. Cornea. 2007;26(2):123-129. doi:10.1097/ICO.0b013e31802eb264
  10. Grayston JT, Alexander ER, Kenny GE, Clarke ER,Fremont JC, Maccoll WA. MYCOPLASMA PNEUMONIAE INFECTIONS. CLINICAL AND EPIDEMIOLOGIC STUDIES. JAMA. 1965;191:369-374.doi:10.1001/jama.1965.03080050015004
  11. He X, Wang X, Zhang R, et al. Investigation of Mycoplasma pneumoniae infection in pediatric population from 12,025 cases with respiratory infection. Diagn Microbiol Infect Dis. 2013;75(1):22-27. doi:10.1016/j.diagmicrobio.2012.08.027
  12. Moreau JF, Watson RS, Hartman ME, Linde-Zwirble WT, Ferris LK. Epidemiology of ophthalmologic disease associated with erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis in hospitalized children in the United States. Pediatr Dermatol. 2014;31(2):163-168. doi:10.1111/pde.12158
  13. 13.0 13.1 Morand M, Hatami A. Multiple superficial oral mucoceles after Mycoplasma-induced mucositis. Pediatr Dermatol. 2018;35(4):e210-e211. doi:10.1111/pde.13515
  14. Poddighe D, Bruni P. Mycoplasma pneumoniae-induced rash and mucositis (MIRM): an unusual mild skin rash associated with severe mucosal involvement. BMJ Case Rep. 2017;2017. doi:10.1136/bcr-2017-220749
  15. Bowling M, Schmutzler T, Glick S. Mycoplasma pneumoniae-induced mucositis without rash in an 11-year-old boy. Clin Case Rep. 2018;6(3):551-552. doi:10.1002/ccr3.1400
  16. Thurman KA, Walter ND, Schwartz SB, et al. Comparison of laboratory diagnostic procedures for detection of Mycoplasma pneumoniae in community outbreaks. Clin Infect Dis Off Publ Infect Dis Soc Am. 2009;48(9):1244-1249. doi:10.1086/597775
  17. Lee W-J, Huang E-Y, Tsai C-M, et al. Role of Serum Mycoplasma pneumoniae IgA, IgM, and IgG in the Diagnosis of Mycoplasma pneumoniae-Related Pneumonia in School-Age Children and Adolescents. Clin Vaccine Immunol CVI. 2017;24(1). doi:10.1128/CVI.00471-16
  18. 18.0 18.1 Gregory DG. Treatment of acute Stevens-Johnson syndrome and toxic epidermal necrolysis using amniotic membrane: a review of 10 consecutive cases. Ophthalmology. 2011;118(5):908-914. doi:10.1016/j.ophtha.2011.01.046
  19. 19.0 19.1 19.2 19.3 19.4 Gregory DG. New Grading System and Treatment Guidelines for the Acute Ocular Manifestations of Stevens-Johnson Syndrome. Ophthalmology. 2016;123(8):1653-1658. doi:10.1016/j.ophtha.2016.04.041
  20. Kohanim S, Palioura S, Saeed HN, et al. Acute and Chronic Ophthalmic Involvement in Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis - A Comprehensive Review and Guide to Therapy. II. Ophthalmic Disease. Ocul Surf. 2016;14(2):168-188. doi:10.1016/j.jtos.2016.02.001
  21. Sotozono C, Ang LPK, Koizumi N, et al. New grading system for the evaluation of chronic ocular manifestations in patients with Stevens-Johnson syndrome. Ophthalmology. 2007;114(7):1294-1302. doi:10.1016/j.ophtha.2006.10.029
  22. Gregory DG. The ophthalmologic management of acute Stevens-Johnson syndrome. Ocul Surf. 2008;6(2):87-95. doi:10.1016/s1542-0124(12)70273-2