Mycoplasma pneumoniae: Extrapulmonary Manifestations in Children With Focus on Mucocutaneous Disease

Mycoplasma pneumoniae is a common cause of respiratory tract infections in children. The clinical significance has been impressively demonstrated by its delayed reemergence after coronavirus disease 2019 (COVID-19) pandemic restrictions, resulting in community-acquired pneumonia (CAP) outbreaks worldwide.1M. pneumoniae is transmitted via aerosol particles and respiratory droplets through close contact and has a relatively long incubation period of up to 3 weeks.2 Its lack of a cell wall naturally renders it resistant to beta-lactam antibiotics, which are the first-line treatment for childhood CAP.3 Although the infection is usually mild and self-limiting, patients of all ages can develop severe disease and extrapulmonary manifestations.2,4 Extrapulmonary manifestations of M. pneumoniae infection have been reported in up to 25% of cases of manifest M. pneumoniae infection, and can affect almost every organ.2 However, most of the reported cases are based on a serological diagnosis of M. pneumoniae infection, which may lead to an overestimation of the M. pneumoniae-related disease burden. This review aims to provide an up-to-date synthesis of recent findings on M. pneumoniae-associated extrapulmonary manifestations, with a particular focus on mucocutaneous disease. EPIDEMIOLOGY In the prospective myCAP study, dermatological manifestations were observed in 23% and neurological manifestations in 2% of children with M. pneumoniae CAP before the COVID-19 pandemic.5,6M. pneumoniae infection was diagnosed by polymerase chain reaction (PCR) of upper respiratory tract (URT) samples and confirmed with the detection of pathogen-specific IgM antibody-secreting cells (ASCs) by enzyme-linked immunospot (ELISpot) assay.7 In a retrospective follow-up cohort study, extrapulmonary manifestations in children with M. pneumoniae detection by PCR of URT samples were found in 30% before and 19% after the COVID-19 pandemic.8 These manifestations affected most frequently the dermatological system (18%), but also the neurological (2%) and gastrointestinal (2%) systems. A Danish population-based cohort study reported extrapulmonary manifestations in children with M. pneumoniae infection, as detected by PCR in URT or lower respiratory tract specimens, at a rate of 16% (13 per 1,000,000 population) before and 23% (47 per 1,000,000 population) after the COVID-19 pandemic.9 These manifestations involved the dermatological (9%), gastrointestinal (6%), and neurological (3%) system, as well as the hematological, nephrological, and cardiovascular system (<1%).9 Although no statistically significant increase in severe or worse outcomes could be observed globally compared with pre-COVID-19 pandemic M. pneumoniae epidemics,1 this Danish nationwide multicenter study observed a significant increase in dermatological manifestations (mucocutaneous disease) during the reemergence.9 PATHOGENESIS The pathogenesis of extrapulmonary manifestations associated with M. pneumoniae is not well understood. These manifestations may be pathogen-mediated through local effects (direct), after the bacteria have disseminated throughout the body, host-mediated through immune responses (indirect), or a combination of the two.2 Narita has proposed vascular occlusion as a third possible pathomechanism, induced either directly or indirectly by the bacterium.10 The rare direct detection of M. pneumoniae in the cerebrospinal fluid (CSF) of patients with central nervous system (CNS) disease, and even more rarely at other extrapulmonary sites, supports an immune-mediated pathogenesis in most cases of extrapulmonary manifestation.2 The cell membrane of M. pneumoniae consists of adhesion proteins and glycolipids that exhibit sequence homology with mammalian tissues (molecular mimicry).11 This can trigger the production of cross-reactive antibodies, which may cause autoimmune disease.2 M. pneumoniae genotypes were not found to be associated with specific clinical outcomes such as mucocutaneous disease, CAP, URT infection, or carriage.12 Other studies have also investigated an association of M. pneumoniae genotypes with outbreaks of extrapulmonary manifestations.4,13 These studies also concluded that the increase in extrapulmonary manifestations was most likely due to an overall increase in M. pneumoniae prevalence and related extrapulmonary manifestations, rather than being truly associated with genotypes.9,12,13 These key findings corroborate the hypothesis that host factors determine the development of specific outcomes following exposure to M. pneumoniae. EXTRAPULMONARY MANIFESTATIONS Extrapulmonary manifestations of M. pneumoniae infection are summarized in Supplemental Digital Content 1, https://links.lww.com/INF/G328, according to the organ system affected, ranked by frequency and strength of association. The incidence of extrapulmonary manifestations is highest among children, particularly those of school age.2 Dermatologic Manifestations Mucocutaneous disease occurs in up to one-third of M. pneumoniae infections and is the most frequent reason for hospital admission after pulmonary complications.6,9 The reported skin manifestations are protean, including maculopapular eruptions, acute urticaria, and erythema nodosum among many others (Supplemental Digital Content 1, https://links.lww.com/INF/G328). Clinically most important, however, are severe eruptions affecting the mucous membranes with or without skin involvement. Canavan et al14 were the first to better characterize these eruptions and distinguish them from Stevens-Johnson syndrome and erythema multiforme. They suggested the term “M. pneumoniae-induced rash and mucositis – MIRM.” In the last decade, this work has been further developed, and a pathogenesis-based classification and diagnostic criteria for pediatric severe mucocutaneous adverse reactions were established (Fig. 1).15 Given the observation that about 25% of “MIRM” cases are associated with other respiratory pathogens, the more inclusive term “reactive infectious mucocutaneous eruption – RIME” was coined.15FIGURE 1.: Revised classification of severe mucocutaneous adverse reactions in children. BSA indicates body surface area; DEN, drug-induced epidermal necrolysis; EM, erythema multiforme; MIRM, Mycoplasma pneumoniae-induced rash and mucositis; RIME, reactive infectious mucocutaneous eruption; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis.RIME is characterized by severe mucositis of 2 or more mucosal surfaces along with typically limited skin involvement consisting of vesiculobullous or atypical target lesions (Supplemental Digital Content 2, https://links.lww.com/INF/G328). However, skin involvement can occasionally be severe, and this does not exclude a diagnosis of RIME in the absence of a plausible triggering medication for drug-induced epidermal necrolysis. While a diagnosis of RIME is likely in a child with a respiratory infection and mucocutaneous disease, other diagnoses such as herpetic gingivostomatitis, extensive hand-foot-mouth-disease, autoimmune bullous diseases (eg, paraneoplastic pemphigus) among others need to be considered. Differentiating RIME from early drug-induced epidermal necrolysis may be especially challenging given that many children with respiratory infections are treated with anti-inflammatory agents and antibiotics. While there are no randomized controlled studies regarding the management of RIME, expert consensus guidelines are being developed (manuscript in preparation). Current management recommendations are detailed in the Supplemental Digital Content 3, https://links.lww.com/INF/G328. Although the role of systemic immunomodulators remains controversial, the recent Danish study9 found that the use of systemic corticosteroids led to a significant reduction in disease duration. This finding is consistent with observations of more pronounced systemic inflammation in M. pneumoniae-infected patients with mucocutaneous disease.6 Potential mechanisms include T-cell-mediated epithelial injury, immune complex-mediated vascular injury, or antibody-mediated responses.6,14 Recent studies of patients described as M. pneumoniae-induced erythema multiforme (who would meet criteria for RIME) have reported histology resembling toxic epidermal necrolysis, suggesting T-cell-induced keratinocyte apoptosis via Fas ligand,16 as well as serum antibodies against desmosomal plaque proteins (plakins).17 We similarly observed the most pronounced specific T-cell response in patients infected with M. pneumoniae and presenting with mucocutaneous disease, which is suggestive of a T-cell-mediated immunopathogenesis.6,18 Prognosis of RIME is typically excellent; however, mucocutaneous sequelae may occur. Special attention should be given to ocular sequelae reported in 9% of affected individuals (ie, dry eyes, synechiae, corneal ulcerations, and legal blindness).19 Up to 38% of patients may experience recurrent RIME with the same or other infectious triggers, which is often milder than the initial episode.20 However, recurrent episodes over many years may be encountered, leading to a high morbidity and psychiatric complications. Neurologic Manifestations Neurologic manifestations are the most severe and occur in around 0.1% of all M. pneumoniae infections.2 The most frequent manifestations include (meningo-)encephalitis, meningitis, Guillain-Barré syndrome (GBS), transverse myelitis, acute disseminated encephalomyelitis, cerebellar involvement, and cranial and peripheral neuropathies (Supplemental Digital Content 1, https://links.lww.com/INF/G328). In children with CNS involvement, CSF analysis typically reveals lymphocytic pleocytosis, elevated protein levels, and normal glucose concentrations. However, the detection rate of M. pneumoniae in CSF by PCR is relatively low (0%–14%), which suggests an immune-mediated pathogenesis in most cases.11 Interestingly, the detection rate of M. pneumoniae in CSF by PCR was observed at a higher rate in CSF of patients presenting with encephalitis within 1 week of prodromal fever and respiratory symptoms (“early-onset”) than in patients with prodromal symptoms for more than 1 week (“late-onset”).21 Patients in whom M. pneumoniae was detected in the respiratory tract, but not in CSF, were more likely to show pulmonary infiltrates on chest radiograph than patients with a positive CSF PCR result.22 These findings support the hypothesis of 2 distinct disease patterns (direct vs. indirect). Encephalitis patients with negative CSF PCR results were found to have intrathecal antibodies directed against galactocerebroside (GalC),23,24 one of the major glycolipids of both the peripheral nervous system and CNS. In fact, antibodies against M. pneumoniae have been demonstrated to cross-react with GalC in patients with GBS.25 These results suggest that the development of anti-GalC, particularly the IgG isotype, is a critical step in the pathogenesis of M. pneumoniae-associated nervous system disease.24,25 Neurologic sequelae in patients with encephalitis were described in up to 50%, including epilepsy, focal neurologic deficits, and persistent headaches, but no deaths were reported.22 Among patients with GBS, those with preceding M. pneumoniae infection had a better outcome.25 Hematologic Manifestations Hemolytic anemia is a relatively rare manifestation of M. pneumoniae infection, occurring more frequently in children than in adults.2 It can be severe, particularly in patients with underlying sickle cell disease, and result from cross-reactive cold agglutinins (IgM antibodies) that target the I antigen of erythrocytes.11 Cold agglutinins are present in around half of patients with M. pneumoniae infections and were historically used as “bedside test” (cold agglutinin test). Other Manifestations Gastrointestinal (<10%), as well as musculoskeletal, cardiovascular, nephrological, urogenital, and sensory organ system manifestations (<1%) are also listed in Supplemental Digital Content 1, https://links.lww.com/INF/G328. ETIOLOGIC DIAGNOSIS The presence of a respiratory tract infection with M. pneumoniae provides evidence for a potential causal relationship between the pathogen and extrapulmonary manifestations.3,5 In fact, respiratory disease and a specific immune response in blood are present in almost all children presenting with extrapulmonary manifestations (except for “early-onset” encephalitis), suggesting an underlying M. pneumoniae infection. Therefore, it is essential to actively confirm the presence of respiratory disease and detect M. pneumoniae in the respiratory tract of patients presenting with extrapulmonary manifestations. Diagnostic Testing The current diagnostic standard for diagnosing acute respiratory tract infection with M. pneumoniae is PCR.26 A shortcoming of PCR is that it cannot reliably discriminate between M. pneumoniae infection and carriage.7 Carriage of M. pneumoniae in the URT of healthy children has been reported at rates ranging from 0% to 56% in different studies.4 However, the near-total absence of M. pneumoniae detections by PCR worldwide during the 3 years of the COVID-19 pandemic suggests that carriage did not occur during this period.1,9 Serology is also limited because M. pneumoniae-specific IgM and IgG antibodies cannot differentiate between infection and carriage, and both isotypes can be detected in serum months or even years after infection.1,27 Thus, PCR seems to be an accurate diagnostic method for the diagnosis of M. pneumoniae respiratory tract infection in patients with a high pretest probability based on clinical criteria (ie, age >5 years, prolonged prodromal symptoms >6 days, family with respiratory symptoms, or C-reactive protein and procalcitonin levels that are normal or only slightly elevated3,5). The confirmation of M. pneumoniae infection in cases of extrapulmonary manifestations can be achieved through the direct and/or indirect detection of M. pneumoniae at the affected site. However, based on previous findings regarding the pathogenesis of extrapulmonary manifestations, direct detection by PCR appears to be useful only in the CSF of patients with (“early-onset”) CNS involvement. The indirect detection of M. pneumoniae can be established by intrathecal antibody synthesis as a highly specific marker for CNS infection, either by calculation of an antibody index or through parallel immunoblotting of simultaneously collected CSF and serum samples.11 A causal relationship with M. pneumoniae infection may also be established by the detection of pathogen-specific ASCs in blood by ELISpot assay, which can reliably differentiate between M. pneumoniae infection and carriage.7 The M. pneumoniae-specific ASC ELISpot assay itself is not commercially available, but can be readily implemented in a clinical setting using the established published protocol.27 Although long considered the gold standard for diagnosis of M. pneumoniae infection, the detection of seroconversion or a 4-fold increase in antibody titers can have limited specificity,7,22,27 and is not relevant to acute clinical management, as paired serum samples must be taken at least 2 weeks apart. Furthermore, this method can no longer be used after the administration of intravenous immunoglobulin. Etiologic Case Definitions Based on these considerations, the following etiological case definitions can be proposed to establish a relationship between M. pneumoniae and extrapulmonary manifestations in children (Supplemental Digital Content 1, https://links.lww.com/INF/G328), adapted from the studies by Meyer Sauteur et al,11 Al-Zaidy et al,22 Granerod et al,28 and Meyer Sauteur et al29: (i) definite: positive PCR in extrapulmonary samples (mainly CSF); (ii) confirmed: positive ASC ELISpot assay (blood) or intrathecal antibody synthesis (CSF); (iii) probable: positive PCR in respiratory tract samples, or seroconversion and/or 4-fold antibody titer increase (blood); and (iv) possible: positive single-sample IgM (blood). MANAGEMENT Children with extrapulmonary manifestations should generally be referred to secondary care for further assessment.3 Since host immune responses play a critical role in the development of extrapulmonary manifestations, immunomodulators, such as corticosteroids or intravenous immunoglobulin, should be considered for severe cases once other potential causes have been ruled out. Corticosteroids may be effective in M. pneumoniae-associated encephalitis2 and RIME (Supplemental Digital Content 3, https://links.lww.com/INF/G328). There are also case reports of etanercept and cyclosporine reducing severity and time to healing in M. pneumoniae-triggered RIME (Supplemental Digital Content 3, https://links.lww.com/INF/G328). The aim is to halt the progression of the disease in patients whose condition is deteriorating rapidly. Although the clinical benefits30 and antimicrobial effects27 of antibiotic treatment for M. pneumoniae (ie, macrolides, tetracyclines, and fluoroquinolones) remain unclear, treatment is recommended due to the generally severe nature of extrapulmonary manifestations, to reduce or eliminate the trigger of the inflammatory process. New evidence suggests that doxycycline can be administered regardless of the patient’s age or the duration of treatment (American Academy of Pediatrics). Clarithromycin is the preferred macrolide, as azithromycin has a very long half-life, which significantly increases the likelihood of antimicrobial resistance.3,31 The choice of the antimicrobial agent should also be based on its ability to penetrate the CNS: macrolides generally do not traverse the blood-brain barrier, whereas doxycycline achieves therapeutic levels in the CNS.2 Doxycycline is also preferred to macrolides due to the growing number of reports of macrolide-resistant M. pneumoniae infections, which are associated with more severe disease and an increased risk of extrapulmonary manifestations.1 CONCLUSION Extrapulmonary manifestations, particularly of the skin, represent a relevant disease burden of M. pneumoniae infection. They are thought to be primarily immune-mediated, which supports the use of immunomodulators in severe cases. Macrolides remain first-line antibiotics, though doxycycline is increasingly considered due to macrolide resistance and CNS penetration. Prompt recognition of extrapulmonary manifestations, especially mucocutaneous and neurological, is essential for appropriate management, as M. pneumoniae-triggered RIME and encephalitis may lead to significant morbidity and long-term sequelae. ACKNOWLEDGMENTS The authors thank the patients and their parents for granting written permission to publish photographs presented in Figure 1 and Supplemental Digital Content 2, https://links.lww.com/INF/G328.

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