Mycoplasma Mucositis


Article Author:
Garrett Frantz


Article Editor:
Scott McAninch


Editors In Chief:
Amanda Oakley
Jules Lipoff
Shyam Verma


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Frank Smeeks
Kristina Soman-Faulkner
Trevor Nezwek
Radia Jamil
Patrick Le
Sobhan Daneshfar
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Pritesh Sheth
Hassam Zulfiqar
Navid Mahabadi
Steve Bhimji
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Nazia Sadiq
Hajira Basit
Phillip Hynes
Tehmina Warsi


Updated:
4/3/2019 10:43:09 AM

Introduction

Mucocutaneous eruptions are rashes that have both mucous membrane and cutaneous distribution. Differences between the history and physical exam patterns of these rashes and associated inciting etiologies have led to the development of separate names for these mucocutaneous eruptions, such as erythema multiforme (EM), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS).  Recently, a separate pattern of the mucocutaneous rash pattern[1][2][3] in association with Mycoplasma pneumoniae respiratory infections has prompted the proposal for an additional mucocutaneous eruption entity, mycoplasma-induced rash and mucositis (MIRM). Canavan et al. proposed three types of MIRM,[4] all of which demonstrate:

  1. Evidence of “atypical pneumonia” by clinical symptoms (fever, cough) and laboratory evidence of M. pneumoniae infection (elevated M. pneumoniae IgM antibodies, positive cultures or polymerase chain reaction for M. pneumoniae from oropharyngeal or bullae, and/or serial cold agglutinins) AND
  2. A rash to the mucosa (usually greater than or equal to two sites)

However, the three types of MIRM differ by the characteristics of their cutaneous, non-mucosal rash patterns:

  1. Classic MIRM has evidence of a. and b. above plus a non-mucosal rash (vesiculobullous lesions (77%), scattered target lesions (48%), papules (14%), macules (12%) and morbilliform eruptions (9%).
  2. MIRM sine rash has a. and b. above, but there is no significant cutaneous, non-mucosal rash (although there may be a “few fleeting morbilliform lesions, or a few vesicles”).
  3. Severe MIRM has 1 and 2 (above), although greater than 2 sites have been reported, but the cutaneous rash is extensive with widespread non-mucosal blisters or flat atypical target lesions.  

Recognition of MIRM as a clinical entity distinct from other mucocutaneous eruptions may be clinically beneficial as treatment options, disease prognosis, and patient education of MIRM will be different from that of the latter.

Etiology

MIRM is caused by infection with M. pneumoniae. M. pneumoniae infections may produce both pulmonary and extra-pulmonary disease.[5] With respect to its pulmonary manifestation, M. pneumonia is associated with so-called atypical pneumonia. Extra-pulmonary conditions include vasculitides, neurologic, immunologic, thrombotic, and cutaneous.

Epidemiology

In general, MIRM is seen in children and young adolescents with a reported mean age of incidence of 12 years.[4] However, there have been case reports of MIRM in young adults as well.[6][7] Sixty-six percent of the identified cases of MIRM occurred in males.[4]

Pathophysiology

MIRM is believed to be caused by the cloning of B cells with subsequent cutaneous immune complex deposition and formation of compliment. Importantly, this is a different process than EM and SJS/TEN, which are mediated by delayed hypersensitivity reaction and Fas ligand-mediated toxicity,[8] leading to the differentiation of MIRM from other cutaneous reactions.

Histopathology

Whether histopathologic features unique to MIRM exist remains unclear. EM, SJS, and MIRM have similar histopathologic features. These include apoptotic keratinocytes and sparse perivascular dermal infiltrates. The existence of distinct biopsy features enabling histopathologic distinction between these diseases remains controversial. Rzany et al. examined specimens from erythema multiforme, SJS, and TEN, and did not find significant, consistent histologic differences; whereas, Wetter and Camilleri identified histopathologic features in drug-induced SJS that were not present in MIRM or immunization-induced SJS in some specimens examined.[9] SJS may have more necrotic keratinocytes, denser dermal infiltrates, and present with microscopic red blood cell extravasation, pigment incontinence, and parakeratosis as compared to MIRM.

History and Physical

History of present illness may help to differentiate MIRM from other mucocutaneous eruptions, such as EM and SJS/TEN. Nearly all patients with MIRM will have prodromal symptoms, such as fever, cough, and malaise approximately one week before the onset of the rash[4]; whereas, EM may be suggested by a history of herpes simplex infection (oral ulcerations). SJS/TEN, currently considered different spectrums of the same underlying process, is often preceded by a prodrome of fever and upper respiratory infection symptoms but is often disguised by a preceding history of exposure to new medications,[10] such as antibiotics (sulfonamides, beta-lactams), NSAIDs (oxicam), allopurinol, antiepileptics (phenytoin, carbamazepine, oxcarbazepine), and nevirapine.

Physical exam findings in MIRM include a predominance of mucosal rashes: oral mucosa (94%), ocular (82%) and urogenital (63%). Other mucosal sites include the nares and anus. Mucosal lesions are typically described as ulcerative or hemorrhagic and may be painful. Nares may demonstrate “dense hemorrhagic crusts,” sometimes manifesting as blood on the tissue. The anus, as part of the GI mucosa, may have lesions that cause pain with defecation.[11]

Additionally, a non-mucosal, cutaneous rash is present in 47%, and it is absent in the remainder of cases and classified as MIRM sine rash.  When present, the cutaneous rash of MIRM demonstrates some pattern differences compared to other mucocutaneous eruptions in that MIRM is sparse in overall distribution and, specifically, located more in the acral (limbs) regions (46%) than the trunk (23%). The cutaneous rash morphology is predominantly described as vesiculobullous (77%), as well as both typical target lesions which have three circumferential zones of demarcation, and atypical target lesions which have two color zones (48%). Less commonly, rashes are described as papules (14%), macules (12%), or morbilliform (9%). The amount of skin that is detached is usually less than 10% of the body surface area.

In contrast, EM presents initially as a cutaneous acral rash with macules that evolve into papules, plaques, and subsequently, typical target lesions and/or atypical target lesions (those that are raised). These target lesions spread centripetally to the trunk and face. EM minor has little or no mucous membrane involvement, and EM major has a rash to one or more mucous membranes. SJS/TEN manifests as a rash of macules, purpura, diffuse erythema, atypical target lesions (those that are flat), flaccid blisters that are extensive (not sparse) in number and initially more centrally located and then coalesce and spread to the face and limbs, with extensive mucous membrane involvement to two or more mucosal sites. The amount of skin detachment differentiates the extent of SJS/TEN. SJS has less than 10% skin detachment. Ten to 30% skin detachment is overlap SJS/TEN.  Greater than 30% skin detachment is TEN.

Evaluation

Patients diagnosed with MIRM will have pulmonary symptoms that may prompt ordering of a chest radiograph, which may demonstrate evidence of pneumonia.

Results for other laboratory markers in the currently-proposed MIRM diagnosis criteria, such as M. pneumoniae IgM antibodies (elevated), M. pneumoniae in oropharyngeal or bullae cultures or PCR, and/or serial cold agglutinins may not be available in most acute care settings when the diagnosis of MIRM may not yet be established.

Treatment / Management

In the acute care setting, the practitioner may not be able to differentiate MIRM from other mucocutaneous eruptions. Therefore, consultation with an infectious disease specialist or dermatologist or transfer to a facility with the appropriate resources may be considered.  All patients with MIRM warrant supportive care, pain control for skin lesions and oral ulcerations (“magic mouthwash” solution or sucralfate), mucosal care, and correction of any fluid and nutritional deficiencies due to decreased oral intake. Severe MIRM with extensive skin detachment may require early transfer to a burn center.[12] Lesions in particular mucosal areas may warrant specialty consultation to ophthalmology, otolaryngology, gastroenterology, and urology to mitigate long-term complications. Currently, there is no evidenced-based pharmacologic treatment paradigm for MIRM. However, patients diagnosed with MIRM often have evidence of atypical pneumonia, and therefore, reasonably benefit from antibiotic treatment.[13] Oral antibiotic options include azithromycin (10 mg/kg on day 1, followed by 5 mg/kg/day once daily on days 2 through 5 to a maximum of 500 mg on day 1, followed by 250 mg on days 2 through 5); oral clarithromycin (15 mg/kg/day in 2 doses to a maximum of 1 g/day); erythromycin, doxycycline for children greater than 7 years old. However, the paucity of data does not indicate if antibiotics instituted early in the course of atypical pneumonia decreases the incidence of MIRM. Additionally, the benefit of immunosuppression therapy in active MIRM is unclear. IVIG may be helpful for MIRM patients with severe mucositis and perhaps for MIRM sine rash. In the Canavan study, 35% of patients received systemic corticosteroids and 8% received IVIG.

Differential Diagnosis

Common differential considerations for MIRM include other conditions that can cause similar skin findings and/or mucosal manifestations[14]:

  • Erythema multiforme major
  • Toxic epidermal necrolysis/Stevens-Johnsons syndrome
  • Drug reaction with eosinophilia and systemic symptoms (DRESS)
  • Staphylococcal scalded skin syndrome (SSSS)
  • Hand-foot-and-mouth disease
  • Kawasaki disease
  • Herpetic gingivostomatitis
  • Severe cutaneous adverse reactions (SCAR) (e.g., Drug hypersensitivity syndrome)
  • Bullous systemic lupus erythematosus
  • Plasma cell stomatitis

Prognosis

Overall, the prognosis of MIRM is good. Only 4% of patients required admission to intensive care. Eighty-one percent of MIRM patients recover completely. Overall mortality from MIRM is 3%. Importantly, these cases were reported in the 1940s, which was a pre-macrolide antibiotic era (erythromycin A was first used clinically in 1952).[15] On the other hand, SJS/TEN patients require intensive care more frequently and have higher mortality.[12],[16] The recurrence rate of MIRM is 8%.

Complications

Eighty-one percent of patients with MIRM experience a full recovery.  The most commonly reported complications (approximately 11%) involve mucosal sequelae. Ocular mucosal damage occurs in 8.9% and includes conjunctival shrinkage, corneal ulcerations, blindness, ocular synechiae, and loss of eyelashes. Oral (0.8%) and genital (0.8%) mucosal synechiae were also reported. The other commonly reported complication was post-inflammatory pigmentary changes (5.6%). Rare complications include persistent cutaneous lesions, B-cell lymphopenia, restrictive lung disease, and chronic obliterative bronchitis. However, while the mortality of MIRM is 3% (reported in the 1940s), experts suspect that the vast majority of mild cases are underreported in the literature, and the true rate of morbidity and mortality is actually far lower.

Consultations

When the diagnosis of MIRM is being entertained, consultation with infectious diseases specialists or dermatology may be helpful. Consultation with otolaryngology, ophthalmology, gastroenterology, and urology may be obtained for site-dependent mucosal lesions to help mitigate long-term sequelae. Burn specialists should be consulted for extensive cutaneous lesions with detachment.

Deterrence and Patient Education

Patients with MIRM should be advised that mucosal lesions may become painful, limiting oral intake, and resulting in dehydration and lack of nutrient intake. Cutaneous lesions should be kept as clean as possible to avoid secondary bacterial infection. Although patterns of transmission of MIRM are not well established, it is reasonable for patients and close contacts of a suspected M. pneumoniae pulmonary infection to institute basic infection control measures, including droplet transmission precautions.

Pearls and Other Issues

  1. MIRM is thought to be a clinically distinct entity from other mucocutaneous eruptions.
  2. Historical features suggesting MIRM include a pulmonary infection approximately one week before the onset of the rash.  Other mucocutaneous reactions, such as EM often develops after a history of herpes simplex infection (recent oral ulcers), or the rash of SJS/TEN may occur in the context of new medication use. 
  3. The rash pattern of MIRM may be different than other conditions. Mucous membrane involvement is almost always seen. The cutaneous rash of MIRM is more often sparse, rather than consolidated. It is more often located in acral areas (limbs). The type of rash in MIRM is usually vesiculobullous or target lesions.  
  4. Although MIRM may have some long-term sequelae, such as mucous membrane damage and cutaneous skin changes, MIRM usually has a more benign course compared to other conditions, such as SJS/TEN.
  5. Treatment of different types of MIRM is not well defined, but patients with active pneumonia reasonably should receive organism directed antibiotics. Consultation with an infectious disease specialist or dermatologist may help to direct care.

Enhancing Healthcare Team Outcomes

MIRM is best managed by a multidisciplinary team that includes an infectious disease expert, internist, dentist, primary care provider, and even a dermatologist. The key is to educate the patient. An interprofessional team involving the clinician and nurse coordinating care and provide good patient education will result in the best outcomes. [Level V]

Patients with MIRM should be advised that mucosal lesions may become painful, limiting oral intake, and resulting in dehydration and lack of nutrient intake. Cutaneous lesions should be kept as clean as possible to avoid secondary bacterial infection. Although patterns of transmission of MIRM are not well established, it is reasonable for patients and close contacts of a suspected M. pneumoniae pulmonary infection to institute basic infection control measures, including droplet transmission precautions.


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Mycoplasma Mucositis - Questions

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A 6-year-old male presents to the emergency department with a 5-day history of fever and cough with subsequent development of vesicles and small bullae on the arms that spread to the face, lips and oral gingiva. His parents deny any recent medications use, previous oral rashes. What is the next best step in management?

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A 12-year-old male presents to the emergency department with a fever and cough with a subsequent development of vesicles and small bullae on the arms that have spread to the face, lips and oral gingiva. A chest x-ray shows pneumonia prompting you to make the diagnosis of Mycoplasma pneumoniae-induced rash and mucositis (MIRM). The parents of the patient are concerned and ask you, “Does MIRM have a high likelihood of death?” Which is the best response?



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An 11-year-old male presents to the emergency department with fever, cough, and subsequent development of vesicles and small bullae on the arms that spread to the face, lips, and oral gingiva. A chest x-ray demonstrates atypical pneumonia prompting a diagnosis of Mycoplasma pneumoniae-induced rash and mucositis (MIRM). According to the current evidence, which is the best first-line agent for outpatient treatment of presumed atypical pneumonia caused by M. pneumoniae in the pediatric patient?



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A 7-year-old male presents with a 4-day history of rhinorrhea, fever, and cough. The patient subsequently developed of vesicles and small bullae on the arms that spread to the face, lips and oral gingiva. His parents deny any recent medications use or previous oral rashes. What is the most likely etiology of the patient's rash?



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An 8-year-old male presents for evaluation of small bullae on the nares, oral gingiva, and urogenital areas. Patient's mother reports a recent cough and fever that have resolved. The patient has not been taking any medications or have any contacts with similar rashes. What are the most likely diagnosis and best management for this patient?



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Mycoplasma Mucositis - References

References

Vujic I,Shroff A,Grzelka M,Posch C,Monshi B,Sanlorenzo M,Ortiz-Urda S,Rappersberger K, Mycoplasma pneumoniae-associated mucositis--case report and systematic review of literature. Journal of the European Academy of Dermatology and Venereology : JEADV. 2015 Mar     [PubMed]
Santos RP,Silva M,Vieira AP,Brito C, {i}Mycoplasma pneumoniae-{/i}induced rash and mucositis: a recently described entity. BMJ case reports. 2017 Aug 22     [PubMed]
Varghese C,Sharain K,Skalski J,Ramar K, Mycoplasma pneumonia-associated mucositis. BMJ case reports. 2014 Mar 13     [PubMed]
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. Journal of the American Academy of Dermatology. 2015 Feb     [PubMed]
Narita M, Classification of Extrapulmonary Manifestations Due to Mycoplasma pneumoniae Infection on the Basis of Possible Pathogenesis. Frontiers in microbiology. 2016     [PubMed]
Alcántara-Reifs CM,García-Nieto AV, Mycoplasma pneumoniae-associated mucositis. CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne. 2016 Jul 12     [PubMed]
Figueira-Coelho J,Lourenço S,Pires AC,Mendonça P,Malhado JA, Mycoplasma pneumoniae-associated mucositis with minimal skin manifestations. American journal of clinical dermatology. 2008     [PubMed]
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 dermo-sifiliograficas. 2016 Sep     [PubMed]
Rzany B,Hering O,Mockenhaupt M,Schröder W,Goerttler E,Ring J,Schöpf E, Histopathological and epidemiological characteristics of patients with erythema exudativum multiforme major, Stevens-Johnson syndrome and toxic epidermal necrolysis. The British journal of dermatology. 1996 Jul     [PubMed]
Chatproedprai S,Wutticharoenwong V,Tempark T,Wananukul S, Clinical Features and Treatment Outcomes among Children with Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: A 20-Year Study in a Tertiary Referral Hospital. Dermatology research and practice. 2018     [PubMed]
Norton SA, Diagnosing Mycoplasma pneumoniae-induced rash and mucositis (MIRM) in the emergency room. Journal of the American Academy of Dermatology. 2015 Aug     [PubMed]
Gerull R,Nelle M,Schaible T, Toxic epidermal necrolysis and Stevens-Johnson syndrome: a review. Critical care medicine. 2011 Jun     [PubMed]
Bradley JS,Byington CL,Shah SS,Alverson B,Carter ER,Harrison C,Kaplan SL,Mace SE,McCracken GH Jr,Moore MR,St Peter SD,Stockwell JA,Swanson JT, Executive summary: the management of community-acquired pneumonia in infants and children older than 3 months of age: clinical practice guidelines by the Pediatric Infectious Diseases Society and the Infectious Diseases Society of America. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2011 Oct     [PubMed]
Mortazavi H,Safi Y,Baharvand M,Rahmani S, Diagnostic Features of Common Oral Ulcerative Lesions: An Updated Decision Tree. International journal of dentistry. 2016     [PubMed]
Jelić D,Antolović R, From Erythromycin to Azithromycin and New Potential Ribosome-Binding Antimicrobials. Antibiotics (Basel, Switzerland). 2016 Sep 1     [PubMed]
Wetter DA,Camilleri MJ, Clinical, etiologic, and histopathologic features of Stevens-Johnson syndrome during an 8-year period at Mayo Clinic. Mayo Clinic proceedings. 2010 Feb     [PubMed]

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