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Background: Mycoplasma pneumoniae is a major cause of community-acquired pneumonia (CAP) in school-aged children. Macrolides are the first-line treatment for this infection. However, it is unclear whether macrolides are effective in treating M. pneumoniae CAP, mainly due to limitations in microbiological diagnosis of previous studies. The extensive global use of macrolides has led to increasing antimicrobial resistance. The overall objective of this trial is to produce efficacy data for macrolide treatment in children with M. pneumoniae CAP., Methods: The MYTHIC Study is a randomized, double-blind, placebo-controlled, multicenter, non-inferiority trial in 13 Swiss pediatric centers. Previously healthy ambulatory and hospitalized children aged 3-17 years with clinically diagnosed CAP will be screened with a sensitive and commercially available M. pneumoniae-specific IgM lateral flow assay from capillary blood. Mycoplasma pneumoniae infection in screened patients will be verified retrospectively by respiratory PCR (reference test) and IgM antibody-secreting cell enzyme-linked immunospot (ELISpot) assay (confirmatory test for distinguishing between carriage and infection). Patients will be randomized 1:1 to receive a 5-day treatment of macrolides (azithromycin) or placebo. The co-primary endpoints are (1) time to normalization of all vital signs, including body temperature, respiratory rate, heart rate, and saturation of peripheral oxygen (efficacy), and (2) CAP-related change in patient care status (i.e., admission, re-admission, or intensive care unit transfer) within 28 days (safety). Secondary outcomes include adverse events (AEs), as well as antimicrobial and anti-inflammatory effects. For both co-primary endpoints, we aim to show non-inferiority of placebo compared to macrolide treatment. We expect no macrolide effect (hazard ratio of 1, absolute risk difference of 0) and set the corresponding non-inferiority margins to 0.7 and -7.5%. The "at least one" success criterion is used to handle multiplicity with the two co-primary endpoints. With a power of 80% to reject at least one null hypothesis at a one-sided significance level of 1.25%, 376 patients will be required., Discussion: This trial will produce efficacy data for macrolide treatment in children with M. pneumoniae CAP that might help to reduce the prescription of antibiotics and therefore contribute to the global efforts toward reducing antimicrobial resistance., Trial Registration: ClinicalTrials.gov, NCT06325293. Registered on 24 April 2024., (© 2024. The Author(s).)

Background: Host-response biomarkers to differentiate bacterial from viral etiology in children with respiratory infections have shown high accuracies, but are understudied in Mycoplasma pneumoniae (Mp) infections., Methods: We compared BV scores (0-34 indicating viral etiology, and 66-100 indicating bacterial etiology), tumor necrosis factor-related apoptosis-inducing ligand (TRAIL; pg/mL), interferon-γ inducible protein 10 (IP-10; pg/mL), and C-reactive protein (CRP; mg/L) serum levels between Mp-positive (Mp+) and Mp-negative (Mp-) community-acquired pneumonia (CAP) patients. We performed receiver operating characteristic (ROC) curve analyses for clinical features and biomarkers., Results: Of 80 CAP patients (median age, 6.3 years; 57.5% male), 26 had Mp+CAP. In Mp+CAP patients, compared to Mp-CAP patients, BV scores were lower (14.0 [3.0-27.8] vs 54.0 [12.0-84.8]; P = .0008), TRAIL levels were higher (86.5 [67.4-123.0] vs 65.5 [42.5-103.9]; P = .025), CRP levels were lower (12.9 [4.0-22.3] vs 36.7 [13.0-132.8]; P = .0019), and IP-10 levels were comparable (366.0 [150.2-603.8] vs 331.0 [154.3-878.8]; P = .73) (all median [interquartile range]). ROC analyses yielded a comparable discriminatory accuracy for the combination of age, fever duration, and duration of respiratory symptoms, with either procalcitonin or BV score (area under the ROC curve, 0.87 vs 0.86; P = .94)., Conclusions: Children with Mp+CAP have atypically low, viral levels of the BV score, underscoring the complementary role of microbiological testing., Competing Interests: Potential conflicts of interest . All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Community-acquired pneumonia (CAP) is a common disease in children, and its aetiological and clinical diagnosis are challenging for physicians in both private practice and hospitals. Over the past three decades, conjugate vaccines have successfully reduced the burden of the former main causes of CAP, Streptococcus pneumoniae and Haemophilus influenzae type b. Today, viruses are by far the most commonly detected pathogens in children with CAP.  Conclusion: New insights into the aetiology and treatment of CAP in children in recent years have influenced management and are the focus of this review. In addition to reducing diagnostic uncertainty, there is an urgent need to reduce antibiotic overuse and antimicrobial resistance in children with CAP. What is Known: • Conjugate vaccines against Streptococcus pneumoniae and Haemophilus influenzae type b have shifted the epidemiology of childhood CAP to predominantly viral pathogens and Mycoplasma pneumoniae. • Clinical, laboratory, and radiological criteria cannot reliably distinguish between bacterial and viral aetiology in children with CAP. What is New: • Test results and epidemiological data must be carefully interpreted, as no single diagnostic method applied to non-pulmonary specimens has both high sensitivity and high specificity for determining pneumonia aetiology in childhood CAP. • This review provides a simple and pragmatic management algorithm for children with CAP to aid physicians in providing optimal and safe care and reducing antibiotic prescribing., (© 2023. The Author(s).)

Aims of the Study: Globally, since the introduction of conjugate-vaccines against encapsulated bacteria, respiratory viruses have caused most hospitalisations for community-acquired pneumonia. The aim of this study was to describe pathogens detected and their association with clinical findings in Switzerland., Methods: Baseline data were analysed for all trial participants enrolled between September 2018 and September 2020 into the KIDS-STEP Trial, a randomised controlled superiority trial on the effect of betamethasone on clinical stabilisation of children admitted with community-acquired pneumonia. Data included clinical presentation, antibiotic use and results of pathogen detection. In addition to routine sampling, nasopharyngeal specimens were analysed for respiratory pathogens using a panel polymerase chain reaction test covering 18 viral and 4 bacterial pathogens., Results: 138 children with a median age of 3 years were enrolled at the eight trial sites. Fever (obligatory for enrolment) had been present for median 5 days before admission. Most common symptoms were reduced activity (129, 93.5%) and reduced oral intake (108, 78.3%). Oxygen saturation <92% was found in 43 (31.2%). Forty-three participants (29.0%) were already on antibiotic treatment prior to admission and 104 participants (75.4%) received antibiotic treatment on admission. Pathogen testing results were available from 132 children: 31 (23.5%) had respiratory syncytial virus detected, 21 (15.9%) human metapneumovirus. The pathogens detected showed expected seasonal and age preponderance and were not associated with chest X-ray findings., Conclusions: In the context of the predominantly viral pathogens detected, the majority of antibiotic treatment is probably unnecessary. The ongoing trial, as well as other studies, will be able to provide comparative pathogen detection data to compare pre- and post-COVID-19-pandemic settings.

Background: Mycoplasma pneumoniae is the most common bacterial cause of pneumonia in children hospitalised for community-acquired pneumonia (CAP). Prevention of infection by vaccines may be an important strategy in the presence of emerging macrolide-resistant M. pneumoniae. However, knowledge of immune responses to M. pneumoniae is limited, complicating vaccine design., Methods: We studied the antibody response during M. pneumoniae respiratory tract infection and asymptomatic carriage in two different cohorts., Results: In a nested case-control study (n=80) of M. pneumoniae carriers and matched controls we observed that carriage by M. pneumoniae does not lead to a rise in either mucosal or systemic M. pneumoniae- specific antibodies, even after months of persistent carriage. We replicated this finding in a second cohort (n=69) and also found that during M. pneumoniae CAP, mucosal levels of M. pneumoniae- specific IgA and IgG did increase significantly. In vitro adhesion assays revealed that high levels of M. pneumoniae- specific antibodies in nasal secretions of paediatric patients prevented the adhesion of M. pneumoniae to respiratory epithelial cells., Conclusions: Our study demonstrates that M. pneumoniae- specific mucosal antibodies protect against bacterial adhesion to respiratory epithelial cells, and are induced only during M. pneumoniae infection and not during asymptomatic carriage. This is strikingly different from carriage with bacteria such as Streptococcus pneumoniae where mucosal antibodies are induced by bacterial carriage., Competing Interests: Conflict of interest: None declared., (Copyright ©The authors 2022.)

Background: There are no reliable signs or symptoms that differentiate Mycoplasma pneumoniae (Mp) infection in community-acquired pneumonia (CAP) from other etiologies. Additionally, current diagnostic tests do not reliably distinguish between Mp infection and carriage. We previously determined that the measurement of Mp-specific immunoglobulin M antibody-secreting cells (ASCs) by enzyme-linked immunospot assay allowed for differentiation between infection and carriage. Using this new diagnostic test, we aimed to identify clinical and laboratory features associated with Mp infection., Methods: This is a prospective cohort study of children, 3-18 years of age, with CAP from 2016 to 2017. Clinical features and biomarkers were compared between Mp-positive and -negative groups by Mann-Whitney U test or Fisher exact test, as appropriate. Area under the receiver operating characteristic curve (AUC) differences and optimal thresholds were determined by using the DeLong test and Youden J statistic, respectively., Results: Of 63 CAP patients, 29 were Mp-positive (46%). Mp positivity was statistically associated with older age (median, 8.6 vs 4.7 years), no underlying disease, family with respiratory symptoms, prior antibiotic treatment, prolonged prodromal respiratory symptoms and fever, and extrapulmonary (skin) manifestations. Lower levels of C-reactive protein, white blood cell count, absolute neutrophil count, and procalcitonin (PCT), specifically PCT <0.25 μg/L, were statistically associated with Mp infection. A combination of age >5 years (AUC = 0.77), prodromal fever and respiratory symptoms >6 days (AUC = 0.79), and PCT <0.25 μg/L (AUC = 0.81) improved diagnostic performance (AUC = 0.90) (P = .05)., Conclusions: A combination of clinical features and biomarkers may aid physicians in identifying patients at high risk for Mp CAP., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: We recently demonstrated that the measurement of Mycoplasma pneumoniae (Mp)-specific immunoglobulin (Ig)M antibody-secreting cells (ASCs) improved diagnosis of Mp infection. Here, we aimed to describe Mp ASC kinetics and duration in comparison to conventional measures such as pharyngeal Mp deoxyribonucleic acid (DNA) and serum antibodies., Methods: This is a prospective longitudinal study of 63 community-acquired pneumonia (CAP) patients and 21 healthy controls (HCs), 3-18 years of age, from 2016 to 2017. Mycoplasma pneumoniae ASCs measured by enzyme-linked immunospot assay were assessed alongside Mp DNA and antibodies during 6-month follow-up., Results: Mycoplasma pneumoniae ASCs of the isotype IgM were found in 29 (46%), IgG were found in 27 (43%), and IgA were found in 27 (43%) CAP patients. Mycoplasma pneumoniae ASCs were detected from 2 days to a maximum of 6 weeks after symptom onset, whereas Mp DNA and antibodies persisted until 4 months (P = .03) and 6 months (P < .01). Mycoplasma pneumoniae ASCs were undetectable in HCs, in contrast to detection of Mp DNA in 10 (48%) or antibodies in 6 (29%) controls for a prolonged time. The Mp ASC response correlated with clinical disease, but it did not differ between patients treated with or without antibiotics against Mp., Conclusions: Mycoplasma pneumoniae-specific ASCs are short-lived and associated with clinical disease, making it an optimal resource for determining Mp pneumonia etiology., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Importance: 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., Objective: 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., Results: 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.