Recurrent reactive infectious mucocutaneous eruption (RIME): Insights from a child with three episodes
First published:15 March 2020
Abstract
Reactive infectious mucocutaneous eruption (RIME) was recently proposed to replace the term Mycoplasma pneumoniae (MP)‐induced rash and mucositis to account for the fact that non‐MP pathogens may also cause rash and mucositis. In this report, we describe a unique case of recurrent RIME featuring a total of three episodes. As two of the episodes demonstrated contemporaneous infection with MP and group A streptococcus or influenza B, this case lends further support to use of the term RIME. In addition, although RIME typically involves at least two mucous membranes, this case shows that recurrent episodes may fall into the rare exception in which mucositis is limited to one site.
1 CASE
A previously healthy 8‐year‐old girl presented for 3 days of severe oral, ocular, and vulvar mucositis and mild rash. The mucositis was associated with significant dysphagia and dysuria. One week earlier, she had developed a cough and dyspnea; a throat culture was positive for group A streptococcus (GAS), for which she received amoxicillin/clavulanate potassium and oral azithromycin. There was no family history of mucocutaneous eruptions.
On physical examination, the patient was ill‐appearing with a temperature of 100.6°F, pulse of 120 beats per minute, respiratory rate of 20 breaths per minute, and oxygen saturation of 93% on room air. There was purulent bilateral conjunctivitis, periorbital edema and erythema, bullae and denudation of the entire oral cavity (Figure 1), and edema, erythema, and hemorrhagic bullae of the vulva (Figure 2). In addition, there were few two‐zone target papules scattered on the left cheek, right upper chest, back, right arm, and thighs, altogether accounting for less than 1% body surface area. The Nikolsky sign was negative. Initial laboratory studies revealed leukocytosis of 17.3 K/µL with 73% neutrophils and 12% bands, and an erythrocyte sedimentation rate (ESR) of >145 mm/h. The patient was admitted to the pediatric intensive care unit with a differential diagnosis of Mycoplasma pneumoniae (MP)‐induced rash and mucositis (MIRM), which Ramien et al1 have since proposed be renamed reactive infectious mucocutaneous eruption (RIME), and Stevens‐Johnson syndrome secondary to amoxicillin or azithromycin. Further workup included identification of cold agglutinins, MP IgM by enzyme immunoassay that was positive at >2500 units/mL, a chest radiograph that demonstrated a focal opacity, and a polymerase chain reaction (PCR)‐based nasopharyngeal swab that was negative for MP. These results, combined with the absence of significant skin involvement, led to the final diagnosis of RIME due to MP and GAS. The patient was treated with supportive care, intravenous levofloxacin, and intravenous immunoglobulin, with gradual resolution of her mucocutaneous and pulmonary disease over the next 3 weeks.
Figure 1
Bullae and denudation of the vermillion lips and tongue during the patient's initial presentation (Previoulsy published in Atlas of Pediatric Emergency Medicine (McGraw‐Hill Education, 2019))
Figure 2
Edema and erythema of the vulva, as well as a hemorrhagic bulla on the clitoris, during the patient's initial presentation (Previoulsy published in Atlas of Pediatric Emergency Medicine (McGraw‐Hill Education, 2019))
Nine months later, the patient presented with one week of mild cough and oral mucositis without dysphagia or fever. Physical examination demonstrated an ulcer on the right upper mucosal lip, as well as erosions with hemorrhagic crust on the upper and lower mucosal lips, tongue, and palate. The conjunctivae, vulva, anus, and skin were clear. The lungs were clear to auscultation. Vital signs were normal. The white blood cell count was normal. MP IgM was positive at 1611 units/mL, consistent with a diagnosis of recurrent RIME due to MP. A PCR‐based nasopharyngeal swab was not performed. The patient received supportive care and oral azithromycin with resolution of most of her oral lesions over the next 5 days.
Two years later, the patient presented for 5 days of oral mucositis and dysphagia that persisted despite oral azithromycin. The other mucosal surfaces and skin were spared. Her symptoms had been preceded by 3 weeks of cough and a diagnosis of influenza B confirmed by a PCR‐based nasopharyngeal swab, for which she did not receive antiviral therapy. Physical examination demonstrated denudation of the mucosal lips, tongue, buccal mucosa, and palate. The white blood cell count was normal, ESR was elevated at 39 mm/h, and a chest radiograph was normal. The patient was hospitalized due to dysphagia and treated with supportive care with near resolution of her oral mucositis over the following 2 weeks. Vital signs were normal throughout admission. A PCR‐based nasopharyngeal swab was negative for MP. MP IgM was negative at 349 units/mL (negative <770 units/mL) upon admission and low‐positive at 798 units/mL when repeated 1 week later, consistent with a second recurrence of RIME due to MP and influenza B. The MP IgG titer was positive at 2.08.
An immunologic workup revealed normal CD4 and CD8 counts of 953/µL and 668/µL, respectively. Quantitative serum IgA, IgG (total and all four subclasses), IgM, and IgE were all normal. CH50 was normal at 47 U/mL. Tetanus antitoxoid IgG was 0.69 IU/mL and diphtheria antitoxoid IgG was 0.48 IU/mL, indicating adequate immune responses to vaccination.
2 DISCUSSION
Mucocutaneous eruptions associated with respiratory pathogens, specifically Mycoplasma pneumoniae (MP), have gone by various names ranging from Fuchs syndrome to MP‐induced rash and mucositis (MIRM).1, 2 Recently, Ramien et al proposed the umbrella term reactive infectious mucocutaneous eruption (RIME) to account for the fact that non‐MP pathogens, including Chlamydophila pneumoniae, enterovirus, human metapneumovirus, human parainfluenzavirus 2, rhinovirus, and influenza B virus, may also cause similar rash and mucositis.1 Although the recurrence rate of RIME is unknown, MIRM has been reported to recur at a frequency of 8%.2 Proposed mechanisms of pathogenesis include immune complex deposition, complement activation, and molecular mimicry.2 Supportive care is generally accepted to be the mainstay of treatment, as the role of antimicrobial agents and immunomodulatory agents is unclear.2
In this article, we present a unique case of a child who had three episodes of RIME, the first due to MP and group A streptococcus (GAS), the second due to MP, and the third due to MP and influenza B. In each episode, infection with MP was confirmed by a positive MP IgM titer. This test has been criticized for remaining positive for years after infection and thus not necessarily reflecting active or recent infection. In our case, it is unlikely that the MP IgM titers were falsely positive, given the evidence of pneumonia during the initial presentation and the rise in titer from negative to low‐positive during the second recurrence. Although PCR‐based assays for MP are highly sensitive and specific, they may become negative as soon as 2 days after antibiotic treatment.3 As a result, we suspect the PCR‐based swabs were negative in our case because the patient had already taken azithromycin prior to swab collection.
There are no established risk factors for recurrent RIME. Although IgA deficiency was reported in one case of recurrent rash and mucositis,4 immunologic abnormalities have not been detected in most cases, including ours.4-6 This raises the possibility of an abnormality not identified by routine bloodwork, such as a genetic mutation that could explain why some cases have involved first‐degree relatives.2, 7 Although not previously reported to be a risk factor for RIME, coinfection with MP and non‐MP pathogens has been previously documented. For example, studies of children with MP pneumonia have shown that 7% are coinfected with GAS8 and 1.2%‐5%8, 9 are coinfected with influenza. Furthermore, like MP, both GAS10, 11 and influenza B4, 12, 13 have been individually implicated in mucocutaneous eruptions. In our case, we speculate that MP synergized with GAS during the initial presentation and with influenza B during the second recurrence to give rise to RIME. To test this conjecture, in vitro and in vivo models could be used to assess whether incubating MP with GAS or influenza potentiates any of the proposed mechanisms in RIME.
Another important feature of this case is the decreased severity of the two recurrent episodes relative to the initial presentation. This reduction in severity is consistent with the few descriptive reports of recurrent MIRM in the literature.5, 14, 15 In these reports, the recurrent episodes were associated with shorter recovery times and either less or the same degree of mucosal involvement as compared to the initial episodes.5, 14, 15 Similarly, in our case, the initial presentation was characterized by sepsis requiring admission to an intensive care unit, severe involvement of three mucous membranes, sparse skin involvement, maximally elevated MP IgM and ESR, and a prolonged recovery. On the other hand, during both recurrences, the patient was not septic and could be treated in the outpatient or general inpatient setting. In addition, she had milder mucositis limited to one site (the oral mucosa), no skin involvement, lower MP IgM and ESR, and shorter recovery times. Particularly notable is the evolution of mucosal involvement from three sites in the initial presentation to only one site during both recurrences. RIME has been described as typically involving at least two mucosal surfaces.1 Although several reports consistent with recurrent RIME have involved at least two mucous membranes,4-6, 15 this case and one other14 show that recurrent RIME may fall into the rare exception in which fewer than two mucosal sites are affected. This clinical observation could be confirmed on a larger scale using a multi‐center cohort.
In conclusion, we report a unique case of recurrent RIME featuring a total of three episodes. As two of the episodes demonstrated contemporaneous infection with MP and GAS or influenza B, this case suggests that respiratory pathogens may synergize to give rise to a mucocutaneous eruption. In so doing, this case lends further support to use of the term RIME to expand the notion of MIRM beyond MP. Based on this observation, clinicians may consider testing patients with suspected RIME for multiple respiratory pathogens, not only MP. Finally, although RIME has been proposed to involve at least two mucosal sites, both recurrent episodes in our case were milder than the initial presentation such that mucositis was limited to one site. As a result, this case shows that recurrent RIME may fall into the rare exception where fewer than two mucosal sites are affected. Further study is required to confirm these observations.
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