eFigure 1. Cases of Mycoplasma pneumoniae–Induced Mucocutaneous Disease, May 2016–April 2017
eFigure 2. Mycoplasma pneumoniae–Induced Rash and Mucositis (MIRM) in Case 1
eFigure 3. Acute Urticaria With Conjunctivitis in Case 5
eFigure 4. Bilateral Anterior Uveitis With Maculopapular Rash in Case 8
eFigure 5. Outcome of Mucocutaneous Lesions in Mycoplasma pneumoniae–Induced Rash and Mucositis (MIRM) in Case 3
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Meyer Sauteur PM, Theiler M, Buettcher M, Seiler M, Weibel L, Berger C. Frequency and Clinical Presentation of Mucocutaneous Disease Due to Mycoplasma pneumoniae Infection in Children With Community-Acquired Pneumonia. JAMA Dermatol. 2020;156(2):144–150. doi:10.1001/jamadermatol.2019.3602
What are the frequency and clinical characteristics of Mycoplasma pneumoniae–induced mucocutaneous disease in children with community-acquired pneumonia (CAP)?
In this cohort study of 152 children with CAP, mucocutaneous eruptions developed in 10 of 44 patients (22.7%) with CAP due to M pneumoniae and 3 of 108 patients (2.8%) with CAP of other causes, a significant difference. Among patients with M pneumoniae infection, mucocutaneous disease was significantly associated with longer duration of fever, higher C-reactive protein level, and greater likelihood of hospitalization, oxygen use, and sequelae.
The findings suggest that mucocutaneous disease is a frequent manifestation of M pneumoniae infection in children and is associated with increased systemic inflammation, morbidity, and a higher risk of long-term sequelae.
The diagnosis of Mycoplasma pneumoniae infection as the cause of mucocutaneous disease is challenging because current diagnostic tests are not able to differentiate M pneumoniae infection from carriage.
To examine the frequency and clinical presentation of M pneumoniae–induced mucocutaneous disease in children with community-acquired pneumonia (CAP) using improved diagnostics.
Design, Setting, and Participants
This prospective, longitudinal cohort study included 152 children aged 3 to 18 years with CAP enrolled in a CAP study from May 1, 2016, to April 30, 2017, at the University Children’s Hospital Zurich. Children were inpatients or outpatients with clinically defined CAP according to the British Thoracic Society guidelines. Data analysis was performed from July 10, 2017, to June 29, 2018.
Main Outcomes and Measures
Frequency and clinical presentation of M pneumoniae–induced mucocutaneous disease in childhood CAP. Mycoplasma pneumoniae infection was diagnosed by polymerase chain reaction (PCR) of oropharyngeal samples and confirmed with the measurement of specific peripheral blood IgM antibody-secreting cells by enzyme-linked immunospot assay to differentiate M pneumoniae–infected patients from carriers with CAP caused by other pathogens. Mucocutaneous disease was defined as any eruptive lesion that involved skin and/or mucous membranes occurring during the CAP episode.
Among 152 enrolled children with CAP (median [interquartile range] age, 5.7 [4.3–8.9] years; 84 [55.3%] male), 44 (28.9%) tested positive for M pneumoniae by PCR; of these, 10 children (22.7%) developed mucocutaneous lesions. All 10 patients with mucocutaneous eruptions tested positive for specific IgM antibody–secreting cells. Skin manifestations were found in 3 cases (2.8%) of M pneumoniae PCR-negative CAP (P < .001). The spectrum of M pneumoniae–induced mucocutaneous disease included M pneumoniae–induced rash and mucositis (3 cases [6.8%]), urticaria (2 cases [4.5%]), and maculopapular skin eruptions (5 cases [11.4%]). Two patients had ocular involvement as the sole mucosal manifestation (bilateral anterior uveitis and nonpurulent conjunctivitis). Patients with M pneumoniae–induced mucocutaneous disease had longer duration of prodromal fever (median [interquartile range], 10.5 [8.3-11.8] vs 7.0 [5.5-9.5] days; P = .02) and higher C-reactive protein levels (median [interquartile range], 31 [22-59] vs 16 [7-23] mg/L; P = .04) than patients with CAP due to M pneumoniae without mucocutaneous manifestations. They were also more likely to require oxygen (5 [50%] vs 1 [5%]; P = .007), to require hospitalization (7 [70%] vs 4 [19%]; P = .01), and to develop long-term sequelae (3 [30%] vs 0; P = .03).
Conclusions and Relevance
Mucocutaneous disease occurred significantly more frequently in children with CAP due to M pneumoniae than in children with CAP of other origins. Mycoplasma pneumoniae–induced mucocutaneous disease was associated with increased systemic inflammation, morbidity, and a higher risk of long-term sequelae.
Mycoplasma pneumoniae is a frequent cause of childhood community-acquired pneumonia (CAP).1 In addition, M pneumoniae can cause extrapulmonary disease, including mucocutaneous manifestations.2 These manifestations include maculopapular skin eruptions, urticaria, and mucocutaneous eruptions along the spectrum of erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis.2 Mucocutaneous eruptions due to M pneumoniae frequently present with prominent mucositis and minimal or even absent cutaneous involvement, referred to as M pneumoniae–induced rash and mucositis (MIRM).3 Diagnosis of M pneumoniae infection in such cases has mainly been based on serologic testing and rarely on polymerase chain reaction (PCR) of upper respiratory tract specimens.2-4 However, PCR and serologic testing for M pneumoniae are not able to reliably differentiate infected patients from carriers with CAP caused by other pathogens.5,6M pneumoniae carriage in the upper respiratory tract has been reported in up to 56% of healthy children.5-7 Thus, the detection of M pneumoniae with these currently available diagnostic tests may cause an overestimation of the M pneumoniae–induced mucocutaneous disease burden.
A recent prospective, longitudinal CAP study6 among children found that the measurement of specific peripheral blood IgM antibody–secreting cells (ASCs) by an enzyme-linked immunospot (ELISpot) assay improved diagnosis of M pneumoniae infection.6 Using this data set, we aimed to assess the frequency and clinical presentation of M pneumoniae–induced mucocutaneous disease in childhood CAP.
This cohort study included patients enrolled between May 1, 2016, and April 30, 2017, at University Children’s Hospital Zurich. The primary inclusion criterion was CAP defined according to the British Thoracic Society guidelines8 in previously healthy children aged 3 to 18 years.6 Mucocutaneous disease was defined as any eruptive lesion that involved skin and/or mucous membranes occurring during the CAP episode; MIRM was defined as involvement of 2 or more mucosal sites with absent or limited skin lesions.3 Data analysis was performed from July 10, 2017, to June 29, 2018. The ethics committee of Zurich, Switzerland, approved the protocol for the study. Written informed consent was obtained from all parents and from children 14 years or older. All data were deidentified.
Eligible patients with CAP were tested for the presence of M pneumoniae DNA in oropharyngeal swab samples by M pneumoniae–specific PCR.9 Patients with mucocutaneous disease who had positive PCR results were tested with the M pneumoniae–specific IgM ASC ELISpot assay to confirm M pneumoniae infection, as described previously.6 All children had a thorough clinical examination of the skin and mucous membranes. Patients with confirmed M pneumoniae–induced mucocutaneous disease were followed up for 6 months.
Categorical and continuous variables were compared with the Fisher exact test and Mann-Whitney test, respectively. A case-control analysis was performed between patients with CAP and mucocutaneous disease who tested positive on the M pneumoniae–specific IgM ASC ELISpot assay and those without mucocutaneous manifestations. A 2-tailed P < .05 was considered to be statistically significant. Analyses were performed with R software, version 3.6.0 (R Foundation for Statistical Computing).
Among 152 enrolled children with CAP (median [interquartile range] age, 5.7 [4.3–8.9] years; 84 [55.3%] male), 44 (28.9%) tested positive for M pneumoniae by PCR; of these, 10 children (22.7%) (median age, 8.7 years; range, 3.8-14.6 years; 6 [60%] male) developed mucocutaneous lesions (eFigure 1 in the Supplement). Diagnosis of M pneumoniae infection was confirmed in all 10 patients with mucocutaneous involvement by detection of M pneumoniae–specific IgM ASCs. In the 108 patients with CAP who tested negative for M pneumoniae by PCR, mucocutaneous disease (maculopapular skin eruptions and conjunctivitis) was observed in 3 (2.8%) (P < .001 compared with patients with CAP who tested positive by PCR).
Of the 44 patients with CAP who had positive M pneumoniae PCR results, 34 had peripheral blood mononuclear cells available for M pneumoniae–specific IgM ASC ELISpot assay testing and 31 tested positive. A case-control analysis of these 31 patients with CAP with positive M pneumoniae–specific IgM ASC ELISpot assay results found that the 10 patients with mucocutaneous disease had longer duration of prodromal fever (median, 10.5 days; interquartile range, 8.3-11.8 days; P = .02) and higher C-reactive protein levels (median, 31 mg/L; interquartile range, 22-59 mg/L [to convert to nanomoles per liter, multiply by 9.524]; P = .04) and were more likely to require oxygen (odds ratio, 17.6; 95% CI, 1.5-984.1; P = .007) compared with 21 patients without mucocutaneous manifestations (Table 1). Patients with mucocutaneous disease were more likely to be hospitalized (odds ratio, 9.0; 95% CI, 1.4-81.4; P = .01) and to develop long-term sequelae (3 [30%] vs 0; P = .03), including bronchiolitis obliterans, exertional dyspnea, and postinflammatory pigmentary alterations.
Among the 10 patients with M pneumoniae–induced mucocutaneous disease, 3 (6.8%) were diagnosed with MIRM, 2 (4.5%) with urticaria, and 5 (11.4%) with maculopapular skin eruptions (Figure and eFigures 2-4 in the Supplement). Detailed clinical characteristics of patients with M pneumoniae–induced mucocutaneous disease are given in Table 2. All patients with MIRM were hospitalized (median, 7.0 days; range, 5.0-13.0 days) and received antibiotics against M pneumoniae and a short course of systemic corticosteroids (methylprednisolone, 1-3 mg/kg, daily for 3 days). Mucocutaneous lesions healed without scarring, and postinflammatory pigmentary alterations were observed in 1 patient (eFigure 5 in the Supplement). No recurrences were observed during 6-month follow-up.
To our knowledge, this is the first prospective longitudinal cohort study to examine M pneumoniae–induced mucocutaneous disease in children. We found that M pneumoniae–induced mucocutaneous disease occurred in 1 of 4 children with CAP who tested positive for M pneumoniae by PCR, including a considerable proportion (6.8%) with MIRM. Mycoplasma pneumoniae infection was confirmed in all patients with mucocutaneous involvement by the detection of specific IgM ASCs, which allows, in contrast to PCR and IgM serologic testing, the differentiation of M pneumoniae infection from carriage.6
Our study’s observed frequency of M pneumoniae–induced mucocutaneous disease (22.7%) is in agreement with the estimates in the literature (25.0%-33.0%),2-4 but MIRM occurred in our study more frequently (6.8% vs 1.0%-5.0%).2 Although M pneumoniae may infrequently cause extensive blistering skin disease that is clinically indistinguishable from Stevens-Johnson syndrome and toxic epidermal necrolysis,2 our data support the concept of MIRM as a specific entity.3 A new proposed revised classification for severe cutaneous reactions in children suggests the term reactive infectious mucocutaneous eruption10 to capture other pathogens that can also trigger a MIRM-like clinical presentation, such as Chlamydophila pneumoniae.11 These case definitions are critical for patient management because early recognition of mucocutaneous disease as infection triggered rather than drug triggered (Stevens-Johnson syndrome and toxic epidermal necrolysis) enables more specific treatment and prognosis information and, most importantly, avoids restriction of possibly causative drugs.
The observation that M pneumoniae–induced mucocutaneous disease was associated with more pronounced inflammation is in agreement with a recent study about M pneumoniae–associated Stevens-Johnson syndrome12 and suggests a distinct immune reaction. The rare detection of M pneumoniae from mucocutaneous lesions3,4,13 further suggests an immune-mediated pathogenesis. Proposed immune mechanisms include immune complex–mediated vascular injury, cytotoxic T cell–mediated epithelial injury, or antibody-mediated disease.2-4,14
No evidence-based treatment guidelines exist for M pneumoniae–induced mucocutaneous disease. It remains unclear whether antibiotics and anti-inflammatory treatment, such as systemic corticosteroids or intravenous immunoglobulins, have any indication given the overall favorable disease course.3,15 Nevertheless, patients require close monitoring to detect early signs suggestive of potential complications, such as bronchiolitis obliterans or mucosal sequelae.2,3,12
This study may have a bias toward more severe disease because mild cases may not have been referred to our tertiary care center. We did not analyze M pneumoniae strains for genetic differences or test patients for other pathogens. Children younger than 3 years were excluded; therefore, the frequency and clinical presentation of M pneumoniae–induced mucocutaneous disease in children of that age are unknown. A significant proportion of children with maculopapular skin eruptions had prior amoxicillin (-clavulanate) treatment, making it difficult to differentiate infection- from drug-induced eruptions. However, the precise microbiological diagnosis of M pneumoniae infection together with the short period of drug exposure and the nonpruritic, faint presentation of eruptions in most of these cases favors an infectious cause.
In this study, mucocutaneous disease occurred significantly more frequently in children with CAP due to M pneumoniae than in children with CAP of other origins. Mycoplasma pneumoniae–induced mucocutaneous disease was associated with increased systemic inflammation, morbidity, and a higher risk of long-term sequelae. The overall prognosis of M pneumoniae–induced mucocutaneous disease was good. Further investigations are required to elucidate microbial or host characteristics that lead to this relevant and potentially severe extrapulmonary manifestation of M pneumoniae infection.
Accepted for Publication: September 24, 2019.
Corresponding Author: Patrick M. Meyer Sauteur, MD, PhD, Division of Infectious Diseases and Hospital Epidemiology, University Children’s Hospital Zurich, Steinwiesstrasse 75, Zurich CH-8032, Switzerland (firstname.lastname@example.org).
Published Online: December 18, 2019. doi:10.1001/jamadermatol.2019.3602
Author Contributions: Dr Meyer Sauteur had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Meyer Sauteur, Theiler, Berger.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Meyer Sauteur, Theiler.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Meyer Sauteur.
Obtained funding: Meyer Sauteur, Berger.
Administrative, technical, or material support: Meyer Sauteur, Weibel, Berger.
Supervision: Meyer Sauteur, Weibel, Berger.
Conflict of Interest Disclosures: Dr Meyer Sauteur reported receiving grants from a Fellowship Award of the European Society for Paediatric Infectious Diseases, the Promedica Foundation, and the Starr International Foundation outside the submitted work. No other disclosures were reported.
Additional Contributions: We thank the patients and their parents for granting permission to publish this information. We thank the emergency department staff and the outpatient clinic staff of University Children’s Hospital Zurich for recruiting participants and the microbiology laboratory staff of University Children’s Hospital Zurich for processing samples.
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