Don’t Be Rash: Exploring Mucositis in a Teenager

A 15-year-old previously healthy girl presented to the emergency department (ED) with chest pain, intermittent fevers, and oral ulcers. She reported developing a fever and dry cough 10 days prior to presentation. On day 3 of illness, she was seen in the ED where a chest radiograph was concerning for developing pneumonia. For empirical community-acquired bacterial pneumonia treatment, she was prescribed 5 days of clindamycin rather than amoxicillin due to her documented penicillin allergy and was discharged home. The patient was then seen by her outpatient primary care physician on day 5 of illness for ongoing cough and worsening shortness of breath with continued intermittent low-grade fevers, all of which were above 38 °C. At that time, she was prescribed an albuterol inhaler to use every 4 hours and a 3-day course of prednisone. She reported no improvement from the albuterol inhaler but began to feel better after taking the steroids. She finished her clindamycin course on day 8 of illness but woke up 2 days later with a worsening cough, a heavy sensation in her chest, oral ulcers, and itchy red eyes, prompting another visit to the ED. There was no eye drainage, blurry vision, joint swelling, diarrhea, nausea, abdominal pain, lymphadenopathy, or weakness upon ED presentation. She was admitted to the general pediatrics service for continued diagnostic evaluation and management.On examination, her temperature was 36.7 °C, heart rate was 84 beats/min, respiratory rate was 20 breaths/min, blood pressure was 115/73 mm Hg, and oxygen saturation was 98% in room air. She had bilateral conjunctival injection (Figure 1); weepy, erythematous, erosive lesions on her buccal and labial mucosa; mild tenderness with palpation of her sternocleidomastoid muscles; and reproducible pain and tenderness with palpation of her chest. She had clear breath sounds, was not in respiratory distress, and did not have any cervical lymphadenopathy.Initial laboratory evaluation showed a white blood count (WBC) of 14 900/uL with neutrophilia of 67%, an elevated erythrocyte sedimentation rate (ESR) of 53 mm/h, a normal C-reactive protein (CRP) of 0.5 mg/dL, a slightly elevated D-dimer of 519 ng/mL, and a negative nasopharyngeal expanded respiratory viral panel with 22 of the most common viral and bacterial infections, including pertussis, adenovirus, mycoplasma, rhino/enterovirus, parainfluenza, and metapneumovirus, among other viruses. Herpes simplex virus 1 (HSV-1), HSV-2, and varicella zoster virus polymerase chain reaction (PCR) swabs of oral ulcers were negative. Three days later, the patient reported pain, but no bleeding, when urinating. This clinical change prompted repeat laboratory evaluation and showed a stable WBC of 14 200 K/uL, rising ESR of 112 mm/h and CRP of 1.5 mg/dL, and a urinalysis with a large amount of leukocyte esterase but negative nitrites. Nonsterile urine culture grew mixed gram-positive bacteria, which was likely a contaminant. Physical examination now showed ongoing dyspnea, progression of oral ulcers, and new genitourinary lesions similar in appearance to the oral lesions (Figure 2). Additional laboratory work confirmed the diagnosis.The initial differential diagnosis was multifaceted. The chest pain and dyspnea differential included costochondritis, ongoing pneumonia, and pulmonary embolism. The differential for the oral ulcers included HSV infection, coxsackie infection, erythema multiforme, pemphigus vulgaris, and Stevens-Johnson syndrome (SJS) or clindamycin-induced mucositis due to her recent antibiotic course and suspected infection. The initial differential for dysuria included urinary tract infection and sexually transmitted infection. Once the patient’s Mycoplasma pneumoniae IgM titer resulted positive at 4268 U/mL (positive is >950 U/mL) and IgG titer resulted negative at less than 0.90 U/mL (negative is ≤0.90 U/mL), indicating an acute M. pneumoniae infection, she was diagnosed with mycoplasma-associated reactive infectious mucocutaneous eruption (RIME).RIME, formerly known as mycoplasma-induced rash and mucositis, encompasses the pulmonary and extrapulmonary manifestations of M. pneumoniae.1,2 Although M. pneumoniae is a well-known cause of community-acquired pneumonia, about one-fourth of patients also have extrapulmonary involvement, including vasculitis, neurological events, and mucocutaneous conditions.3Three mycoplasma-associated RIME classifications have been identified3: Classical mycoplasma-associated RIME meets the following criteria: less than or equal to 10% of total body surface area involvement, greater than or equal to 2 mucosal sites involved, few vesiculobullous lesions or scattered atypical target lesions present, and evidence of atypical pneumonia through clinical evaluation or laboratory confirmation.“Mycoplasma-associated RIME sine rash,” meaning without significant cutaneous involvement, meets the same criteria as classical mycoplasma-associated RIME but only has a few or fleeting morbilliform lesions or vesicles.Severe mycoplasma-associated RIME includes more extensive widespread blisters or flat atypical targets, yet still with involvement of less than or equal to 10% of total body surface area.The prodrome to mycoplasma-associated RIME is nonspecific. It typically includes fever, malaise, cough, and shortness of breath and most commonly begins with a pneumonia picture prior to becoming extrapulmonary. The rash and mucositis tend to begin about 1 week after the onset of the prodromal symptoms.3M. pneumoniae is a known trigger of urticaria, erythema multiforme, and SJS; however, the mucocutaneous involvement in RIME has distinguishing features when compared with better-known cutaneous diagnoses. RIME has significantly more mucosal than cutaneous involvement. The mucosal lesions are characterized as ulcerative or hemorrhagic in nature and most commonly involve the oral mucosa, followed by the ocular and then urogenital mucosa. If there is a cutaneous rash present, it can be distinguished from erythema multiforme as the rash in RIME is more likely to be vesiculobullous rather than targetoid. It can be distinguished from SJS because the RIME rash is overall very sparse and predominantly in the acral regions rather than the central body regions seen in SJS. Importantly, a rash does not have to be present in RIME and would then be coined RIME sine rash.3Ocular involvement most commonly presents as bilateral conjunctivitis without chemosis or corneal involvement. More severe ocular manifestations can include mucoid discharge, eyelid margin hyperemia and staining, and pseudomembranous formation. If the patient is endorsing tearing, photophobia, or blurry vision, a more extensive ophthalmologic examination may be warranted.4An official mycoplasma-associated RIME diagnosis can be made with a combination of clinical symptoms, imaging, and laboratory work. Chest imaging can be used to confirm suspicion for pneumonia. The key to diagnosis, however, is detection of M. pneumoniae. M. pneumoniae detection can be completed via oropharyngeal PCR. In the setting of suspected respiratory illness, respiratory viral panel is typically collected via the nares, but this modality is not as sensitive for M. pneumoniae when compared with an oropharyngeal sample.3 Another modality for mycoplasma detection is through culture of the vesiculobullous skin lesions, if present, and by trending cold agglutinins.3 The presence of elevated M. pnuemoniae IgM titers is especially helpful for diagnosis because it indicates an acute mycoplasma infection, but these antibodies do not start to rise until 7 to 9 days after infection and do not peak until 3 to 6 weeks into the course of illness. IgG titers, which indicate chronic or past infection, follow the rise and peak of IgM titers by about 2 weeks. Therefore, IgM and IgG may be within normal range in the early stages of mycoplasma-associated RIME. Once elevated, IgM titers persist for months, and IgG titers persist for years.2Fortunately, mycoplasma-associated RIME has an excellent prognosis. Management is mostly supportive care. Most notably, the mucositis can be very painful and impact oral intake. Magic mouthwash or sucralfate can be helpful in making oral intake more tolerable. Intravenous fluids may be necessary in the setting of minimal oral intake to avoid dehydration or electrolyte abnormalities. If there is severe mucositis secondary to mycoplasma-associated RIME, systemic corticosteroids or, more rarely, intravenous immunoglobulin may be administered.3 There may be utility in antibiotics to treat any active or severe symptoms of atypical pneumonia upon presentation. Macrolides are most commonly used for atypical pneumonia treatment, but tetracyclines and fluoroquinolones also can be used.1,3The pathophysiology of mycoplasma-associated RIME is not well known. One theory suggests there is cloning between B cells and cutaneous immune complexes, which then activates the complement system and manifests as extrapulmonary symptoms.3 Another less popular theory suggests there is molecular mimicry between the mycoplasma adhesion molecules and keratinocyte antigens, causing skin cells to be targeted.3The patient received a 5-day course of azithromycin. Other treatments focused on pain control and supportive care, and she was discharged after 10 days once she was able to tolerate oral intake. Symptoms ultimately resolved, and the patient returned to her baseline. She has had no further recurrences of mucositis.SummaryMycoplasma-associated RIME should be considered in a patient with a recent history of an atypical pneumonia who develops a new rash, mucositis, or ocular findings.The rash in RIME is more mucosal than rashes typically seen in SJS.The diagnosis of mycoplasma-associated RIME can be made by clinical examination with concurrent laboratory evidence of M. pneumoniae infection. The presence of positive M. pneumoniae IgM titers and negative IgG titers specifically indicates an acute M. pneumoniae infection.Mycoplasma-associated RIME is usually self-limited and self-resolving but often needs supportive care for pain and hydration. Antibiotics may be used for atypical pneumonia but are not required.