Alveolar regeneration failure due to alveolar stem cell senescence is a defining feature of idiopathic pulmonary fibrosis (IPF), yet the epithelial mechanisms underlying this dysfunction remain incompletely understood. Recent single-cell and lineage-tracing studies have identified distinct transitional epithelial states, such as pre-alveolar type-1 transitional cells, damage-associated transient progenitors, and alveolar-basal intermediates, which normally serve as intermediates during type 2 alveolar cell (AT2) to type 1 alveolar cell (AT1) differentiation. While these states are transient and successfully resolved during acute lung injury, these populations persist abnormally in IPF lungs, exhibiting features of senescence, cell-cycle arrest, and impaired differentiation.We review recent evidence showing how premature alveolar epithelial senescence, suppression of developmental regenerative programmes, and sustained transforming growth factor-β signalling within the fibrotic niche contribute to this disruption. These factors promote the accumulation of dysfunctional transitional cells, such as cytokeratin (KRT)8+/KRT17+ basaloid cells, which fail to regenerate alveolar epithelium and instead contribute to fibrosis and bronchiolisation through pathological crosstalk with macrophages and fibroblasts. Notably, similar transitional states appear in COVID-19-associated acute respiratory distress syndrome, but they typically exhibit minimal features of senescence and resolve during regeneration, underscoring the pathological importance of accelerated epithelial senescence in IPF.Understanding the molecular checkpoints that regulate transitional cell fate may offer novel strategies to restore regenerative capacity in fibrosing lung diseases.
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, irreversible interstitial lung disease characterised by excessive collagen deposition, aberrant tissue remodelling, and impaired gas exchange, ultimately leading to respiratory failure and death. IPF carries a poor prognosis, with limited therapeutic options; currently approved treatments slow disease progression but do not reverse established fibrosis, and lung transplantation remains the only definitive therapy. Moreover, the prevalence and incidence of IPF continue to rise worldwide. These challenges underscore the urgent need to better understand the pathological mechanisms driving IPF, enabling the development of more effective therapeutic strategies. Robust and appropriate animal models are essential for investigating disease pathogenesis and therapeutic response. Although multiple murine models of pulmonary fibrosis are widely used, no single model fully recapitulates the clinical, pathological and temporal features of human IPF. In this review, we systematically summarise commonly used and new murine models of pulmonary fibrosis, emphasising induction methods, technical requirements, the time course of fibrosis development and persistence of fibrosis. Additionally, we highlight the advantages and limitations of each model, discuss how they inform mechanistic and translational studies, and provide practical guidance for selecting appropriate experimental systems based on specific scientific questions, with the goal of improving rigor and relevance in preclinical pulmonary fibrosis research.
Interstitial lung diseases (ILDs) comprise a heterogeneous group of lung disorders marked by progressive fibrosis and increased vulnerability to respiratory infections, which can trigger sudden outbreaks and worsen outcomes. Vaccination is a key preventive strategy in ILD patients to reduce infection-related morbidity and mortality. This review examines the importance of immunisation in individuals with ILDs, with particular emphasis on influenza, pneumococcal and severe acute respiratory syndrome coronavirus 2 vaccines endorsed by major health organisations. Despite evidence of their effectiveness, vaccination rates among patients with ILD remain low. Tailored vaccine strategies may enhance protection in this group. Additionally, although data are limited, immunisations against respiratory syncytial virus, Haemophilus influenzae , varicella-zoster virus, and pertussis may provide additional protection, particularly in older adults and those receiving immunosuppressive therapy. Hepatitis B vaccination should also be considered for patients on immunosuppressive therapies to prevent infection. Healthcare providers should actively encourage vaccination and address obstacles to immunisation in ILD patients. More research is necessary to assess the safety, effectiveness and optimal vaccination approaches for this vulnerable group. Ultimately, implementing systematic vaccination programmes and clear clinical guidelines is essential to improve preventive care and health outcomes for those with ILDs.
Home oxygen therapy is a well-accepted treatment for advanced respiratory disease; however, there are substantial evidence gaps and implementation challenges. The patient experience varies widely; oxygen therapy devices are often poorly matched to patient needs; and adherence is suboptimal. Recent clinical trials have failed to demonstrate positive outcomes of home oxygen therapy across a range of indications and patient groups, raising new questions regarding which patients will benefit. We convened a home oxygen therapy summit, bringing together experts in the fields of hypoxia biology, biomarkers, home oxygen therapy, behavioural science, and clinical trials, to identify the critical steps necessary to advance the science and practice of home oxygen therapy. Prescription of oxygen therapy depends on identification of hypoxaemia, with or without evidence of end-organ dysfunction. However, this does not acknowledge that hypoxaemia does not always yield hypoxia, and ignores adaptation to hypoxia. There is a pressing need for a hypoxia biomarker that is sensitive and specific, reflects the mechanisms of adaptation and maladaptation to chronic hypoxia, and is responsive to change with supplemental oxygen. Advances in research and clinical care will require more “usable” devices that meet the needs of patients and provide value for payers. Optimising oxygen devices will require new technologies with greater portability and greater capacity for oxygen delivery. Registry-based clinical trials may allow measurement of long-term outcomes and identification of patients most likely to benefit from oxygen therapy. Collaborations between patients, clinicians, researchers, payers and industry will be critical to drive this field forward.
BACKGROUND:Asthma remission is a meaningful treatment goal that requires patient and healthcare provider agreement. However, there is currently no validated way to incorporate patient perspectives of remission in this process. Patient-reported outcome measures (PROMs) can allow comprehensive assessment of remission by capturing the impact on individual patient experiences. The aim of this study was to identify PROMs used to define remission in other chronic diseases, thereby informing development of a PROM for asthma remission. METHODS:A scoping review of primary research studies was conducted using five databases. Eligible studies reported on the development or validation of PROMs that assess remission in chronic diseases. Data were extracted and analysed thematically to identify types of PROMs, health domains assessed and methodological quality. RESULTS:Nine studies met inclusion criteria, covering 12 PROMs for diseases such as rheumatoid arthritis, inflammatory bowel disease and ankylosis spondyloarthritis. Domains most frequently assessed included disease-specific symptoms (n=11), generalised symptoms (n=5) and mental health (n=2). PROMs generally asked patients about their current health (n=8) although some PROMs had longer recall periods (n=4). Only one PROM was developed with direct patient involvement. CONCLUSIONS:PROMs currently employed in other chronic diseases signify significant complexity when attempting to capture multidimensional aspects of disease remission from a patient perspective. However, fundamental domains and other health elements can be distinguished that will aid development of robust, patient-informed PROMs that align with patient-centred experiences of remission, thereby improving shared decision-making in asthma.
Right heart failure drives morbidity and mortality in pulmonary arterial hypertension (PAH). At present, there are no chronic pharmaceutical interventions that directly augment right heart function in humans despite many promising results in rodent studies. The lack of translational success may be due to the relative scarcity of studies examining large animal models of right heart failure. However, in recent years, a rapid expansion of large animal investigations worldwide is generating new important physiological and mechanistic data. Large animal models provide more human-relevant biology, which can be paired with physiological assessments and multi-omic profiling to expand our knowledge of right heart failure. Here, we highlight findings obtained from pigs, sheep, cows and dogs, and define some potential limitations of each large animal model. In addition, we outline important questions that could be addressed in future research. Although imperfect, large animals will likely serve important roles in the development of right heart-directed therapies ranging from mechanical interventions to pharmaceutical approaches as they move up the translational pipeline. Hopefully, the field will continue these critical lines of research to promote the discovery of novel therapeutics for our patients who are in desperate need of new options.
Hypersensitivity pneumonitis (HP) is a complex immune-mediated interstitial lung disease triggered by repeated or persistent inhalation of a variety of inhaled antigens in genetically predisposed individuals. The disease encompasses a wide clinical spectrum and may present as predominantly inflammatory or fibrotic forms, the latter associated with irreversible architectural distortion and progressive loss of pulmonary function. Although mechanisms involving dysregulated T-cell activation, aberrant antigen processing and maladaptive tissue-repair pathways are recognised as central contributors to HP pathogenesis, the precise mechanisms and the sequence of immunologic events that occur during inflammation and mainly those that drive the transition from inflammation to fibrosis remains unclear. Animal models, particularly murine systems, have helped in dissecting these mechanisms, yet they continue to fall short in fully recapitulating the heterogeneity and chronicity observed in human HP. In this review, we provide an in-depth and critical examination of existing wild-type and genetically modified mouse models used to investigate HP, with emphasis on antigen sources, exposure paradigms and the strengths and limitations of each approach. We synthesise current insights into how specific genes, signalling pathways and immune cell subsets, including T-helper cell polarisation, regulatory T-cell function, dendritic cell activation and immune complexes contribute to disease initiation, amplification and progression.
Normal limits for exercise Doppler echocardiography (ex-TTE) measurements of the right ventricle (RV), pulmonary artery (PA) and left atrial (LA) unit remain inadequately defined. This meta-analysis aims to establish normal limits for measurements of the RV-PA-LA unit. A comprehensive literature search of Medline, Web of Science and Scopus (1 January 1999-December 2024) was performed. We included ex-TTE studies performed using a supine/semi-recumbent cycle ergometer in healthy subjects that reported the following parameters: tricuspid regurgitation velocity (TRV), systolic pulmonary artery pressure (sPAP), mean pulmonary artery pressure (mPAP), mPAP/cardiac output (CO) slope, mitral Doppler E to tissue Doppler e' ratio (E/e'), tricuspid annular plane excursion (TAPSE) and TAPSE/sPAP. Summary mean estimates were calculated using a restricted maximum-likelihood random-effects model. Lower and upper limits of normal (LLN and ULN) were defined as the 5th and 95th percentiles. Between-study heterogeneity was assessed using the Q-statistic and quantified with the inconsistency index. Data on 1122 healthy subjects (mean±sd age: 42.8±18.3 years) across 19 eligible studies were analysed. The pooled mean estimates and limits of normal for ex-TTE measurements were as follows: TRV 2.5 m·s-1 (ULN 3.4), sPAP 38.5 mmHg (ULN 57.8), mPAP 29.8 mmHg (ULN 43.0), mPAP/CO slope 1.4 mmHg·min·L-1 (ULN 3.0), E/e' 7.1 (ULN 11.5), TAPSE 31.8 mm (LLN 24.6), TAPSE/sPAP 0.8 mm·mmHg-1 (LLN 0.4). Despite notable heterogeneity for several measurements, the present meta-analysis provides a robust framework for defining normal reference limits for ex-TTE measurements of the RV-PA-LA unit.
Adult obstructive sleep apnoea (OSA) is an established cardiovascular risk factor, but paediatric OSA has been framed mainly around neurocognition and growth. We reviewed PubMed, Ovid-Embase and Web of Science (2000-2026), prioritising eligible paediatric studies with quantifiable outcomes (ambulatory/office blood pressure (BP), autonomic indices/heart-rate variability, endothelial function/arterial stiffness, carotid intima-media thickness (cIMT) and echocardiographic structure/function) and key interventional data. Across cohorts, 24-h ambulatory blood pressure monitoring (ABPM) most consistently demonstrates higher nocturnal BP and reduced dipping; emerging exposure metrics such as hypoxic burden (the integrated depth and duration of oxygen desaturation across sleep) may capture physiological stress better than the apnoea-hypopnoea index alone. Autonomic imbalance, including sympathetic predominance, altered sleep-stage autonomic modulation and reduced baroreflex gain, provides a plausible bridge between respiratory events and early vascular/cardiac remodelling, and often improves after adenotonsillectomy. Vascular data suggest early functional abnormalities (endothelial reactivity, wave reflection/central haemodynamics) with smaller and inconsistent differences in structural markers, such as cIMT, strongly modified by obesity and development. Cardiac studies most reproducibly show increased left-ventricular mass/geometry and impaired diastolic relaxation, while right-heart and pulmonary vascular signals appear most relevant in selected higher-risk groups. Treatment effects appear more readily detectable in autonomic/endothelial measures than in office BP over short follow-up, reinforcing ABPM as a preferred research and selected high-risk clinical end-point. Paediatric OSA should therefore be approached through an early-risk framework, including identifying higher-risk phenotypes, quantifying nocturnal haemodynamic burden when feasible and integrating OSA therapy with weight and guideline-directed BP management.
BACKGROUND:Preferential phosphodiesterase 4B (PDE4B) inhibition with nerandomilast has demonstrated attenuation of forced vital capacity decline in idiopathic pulmonary fibrosis and progressive pulmonary fibrosis. Because PDE4 enzymes regulate cAMP-dependent inflammatory and endothelial signalling, class-level PDE4 inhibition has been consistently linked to vascular-immune pathways. Whether preferential PDE4B inhibition reproduces these effects remains uncertain. OBJECTIVES:To map the available mechanistic and translational literature on extrapulmonary or systemic biological effects of PDE4/PDE4B inhibition and to place nerandomilast trial findings within that framework without inferring clinical efficacy outside pre-specified trial outcomes. METHODS:We performed a the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews informed scoping review of PubMed/MEDLINE from database inception to 1 March 2026. Eligible studies included pre-clinical, translational and clinical reports addressing endothelial, immune, microvascular or organ-level effects of PDE4/PDE4B modulation. Evidence was charted and narratively synthesised rather than quantitatively pooled. RESULTS:71 studies were included. Experimental data (primarily derived from class-level PDE4 inhibition) consistently link these pathways to modulation of endothelial permeability, leukocyte-endothelial adhesion, thromboinflammatory signalling, and macrophage resolution programmes across pulmonary and extrapulmonary models. However, most extrapulmonary evidence derives from class-level PDE4 biology rather than nerandomilast-specific investigations, and clinical evidence for extrapulmonary benefit in fibrotic lung disease remains indirect. CONCLUSIONS:Because PDE4 enzymes regulate cAMP-dependent inflammatory and endothelial signalling, class-level PDE4 inhibition has been consistently linked to modulation of vascular-immune pathways. Whether preferential PDE4B inhibition reproduces these effects in humans remains to be established. While at present, extrapulmonary clinical benefit in fibrotic lung disease remains unproven, future studies should prospectively evaluate systemic biomarkers and organ-level outcomes rather than relying on post hoc interpretation of numerical signals.
Background/research question We investigated the increase in pulmonary artery pressure (PAP) with altitude gain in healthy low-altitude residents travelling to high altitude, analysing reported measures including systolic (sPAP) and mean pulmonary artery pressure (mPAP) and tricuspid regurgitation pressure gradient (TRPG). Methods A systematic literature search was performed in PubMed and Embase from database inception to 12 December 2024. Studies including healthy adults residing at <1000 m and reporting sPAP, mPAP or TRPG measured by echocardiography or right heart catheterisation at both low altitude and >1000 m within 30 days were included. Random effects meta-analyses and meta-regression assessed the increase in sPAP, mPAP and TRPG per 1000 m altitude gain. Results 60 articles with 1220 participants (75% males, age 34±4 years) were eligible; 54 were included into the meta-analysis. sPAP was reported in 38 studies, mPAP in nine and TRPG in 11. At high altitude, absolute sPAP ranged from 24 to 50 mmHg and mPAP from 20 to 26 mmHg. Meta-regression showed a linear increase per 1000 m: sPAP 3.4±0.5 mmHg, mPAP 2.5±0.7 mmHg and TRPG 3.3±1.0 mmHg. The estimated upper limit of normal for the increase per 1000 m was 4.5 mmHg for all three measures. Interpretation This systematic review and meta-analysis of healthy low-altitude residents travelling to high altitudes demonstrates a linear increase in PAP with altitude gain, based predominantly on data from elevations >2500 m and younger male populations. It defines upper reference limits for the increase in sPAP, mPAP and TRPG per 1000 m. These population-derived reference ranges may assist in the interpretation of PAP measurements and in counselling individuals evaluated at high altitude, but should be applied with consideration of the underlying population and exposure characteristics.
Exposure to e-cigarette aerosols, particulate matter with aerodynamic diameter ≤2.5 µm (PM 2.5 ) and respiratory viruses rarely occurs in isolation, but rather in complex polyexposure contexts during daily life. On a cellular and molecular level, vaping induces a distinct lipid-laden macrophage phenotype, alters pulmonary neutrophilic infiltration and impairs epithelial differentiation and ciliary function. In contrast, PM 2.5 alters the macrophage polarisation equilibrium, temporally favouring an acute pro-inflammatory phenotype and a subsequent chronic tissue-remodelling phenotype, while also driving an oxidative inflammatory epithelial milieu. Both exposures thus impair antiviral defences and enhance susceptibility to respiratory viral infections such as influenza A, rhinovirus and severe acute respiratory syndrome coronavirus 2. The triple-hit hypothesis proposes that concurrent exposure to vaping aerosols, PM 2.5 and respiratory viruses may exert additive or synergistic effects on chronic airway inflammation. PM 2.5 may amplify vaping-induced macrophage lipid accumulation, thereby reducing the macrophage clearance capacity. Decreased efferocytosis and autophagy may further exacerbate inflammation by increasing secondary necrosis from apoptotic cells and debris. This persistent inflammatory state coupled with epithelial injury and impaired antiviral responses may increase the risk of infection and accelerate the development or progression of chronic respiratory diseases such as asthma and COPD. These insights highlight the crucial need for polyexposure models to accurately reflect real-world environmental and behavioural exposures and evaluate their impact on respiratory health and disease exacerbations. Understanding this exposure triad is also crucial for refining exposure guidelines, updating risk assessments and implementing preventive strategies.
BACKGROUND:Obese children with asthma experience higher morbidity than their counterparts; whether different treatments should be considered remains to be clarified. OBJECTIVE:To explore the potential group differences in the treatment response to any asthma medications between overweight/obese and normal/underweight children. METHODS:We systematically reviewed case-control, cohort studies and randomised controlled trials (RCTs) examining treatment effects by weight status, identified in four bibliographic databases from inception until January 2025. A narrative synthesis was presented because a meta-analysis could not be conducted due to methodological issues. RESULTS:Nine studies (one RCT, five post hoc analyses of RCTs, two cohorts, and one post hoc analysis of a case-control study), including 7089 children (33.9% overweight/obese), met the inclusion criteria. Pharmacological treatment pertained to step 1-2 (n=1), step 2 (n=3), step 3 (n=2), step 5 (n=2), and bronchodilator-response (n=1). Compared with normal weight, step 1-2 showed a trend toward reduced inhaled corticosteroid (ICS) efficiency in minimising symptom days in overweight/obese preschoolers. Regarding step 2 monotherapy, overweight/obese children may benefit as much (or more) from nedocromil or leukotriene receptor antagonist (LTRA) than from ICS. In step 3, adding LTRA (versus placebo) to ICS monotherapy was more effective, whereas higher-dose ICS monotherapy was less effective than LTRA or long-acting β2-agonist (LABA) combination therapy in obese than normal-weight children; adding LABA appears equally effective across weight groups. A similar or better response to omalizumab was observed in obese compared to nonobese children. CONCLUSION:While no firm recommendations could be made regarding potential differential treatment responses, the superiority of ICS monotherapy or step-up therapy compared to other controllers appears lost in overweight/obese children.
Respiratory infections during critical periods of lung development can shape immune responses and cause lasting alterations in pulmonary structure and function. Lung development begins in utero , with airway branching, alveolarisation and epithelial differentiation continuing postnatally, making the lungs particularly vulnerable to early-life insults. Early-life respiratory syncytial virus infections are a major cause of severe respiratory diseases. Furthermore, risks are amplified by preterm birth and specific maternal environmental exposures. In this review, we discuss how early-life respiratory syncytial virus infection can disrupt normal lung development, predisposing to recurrent wheeze, asthma and other chronic lung diseases. We also discuss mechanistic studies, demonstrating how pathogenesis involves a complex interplay between epigenetic regulation, immune activation and airway remodelling. Finally, we highlight preclinical models that have provided some mechanistic insights into the determinants of lung health outcomes and the urgent need for better translational models to gain a deeper understanding of these processes. The intent of this review is to create impetus for developing targeted preventative and therapeutic strategies to mitigate the long-term impact of early-life viral infections on respiratory health.
Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disorder caused by defective motile cilia, resulting in impaired mucociliary clearance, chronic respiratory disease, laterality defects and subfertility. Currently, no disease-modifying treatments exist. Targeting PCD at its root cause requires emerging genetic therapies, such as small molecules, oligonucleotides, mRNA therapy, gene replacement and genome editing. With over 52 implicated genes and numerous patient-specific variants, there is a need for robust preclinical models to evaluate and accelerate these approaches. This review examines human preclinical models that recapitulate patient-specific genotypes and phenotypes while providing sufficient scalability for screening and detailed efficacy assessment. The models should also resolve knowledge gaps, including which cells need targeting and at what stage of differentiation. Air-liquid interface cultures of primary human airway epithelial cells or induced pluripotent stem cells (iPSCs) represent the current practice, alongside three-dimensional organoids, spheroids and lung-on-a-chip platforms. To overcome the limited proliferative capacity of primary cells, strategies include BMI-1 or hTERT transduction, conditional reprogramming with Rho-associated kinase (ROCK) inhibitors and feeder layers, and differentiation of iPSCs. Patient-derived and CRISPR-edited models have been developed for multiple PCD genes. Outcome measures to confirm efficacy of the therapy include high-speed video microscopy for quantifying ciliary beat pattern, transmission electron microscopy for ultrastructural assessment, mucociliary clearance assays and deep molecular phenotyping. There is a need for field-wide standardisation through consensus protocols, core outcome sets, minimum reporting criteria, quality benchmarks and regulatory alignment to facilitate accelerated translation of preclinical findings to clinical therapeutics.
The management of respiratory failure often necessitates the use of supplemental oxygen and mechanical ventilation, both crucial interventions in critical care. However, this combination of hyperoxia (defined as exposure to supra-atmospheric levels of oxygen) and mechanical ventilation can lead to significant additional lung injury. The aim of this review is to synthesise current evidence defining how hyperoxia primes the adult lung for increased susceptibility to the development of lung injury during mechanical ventilation and to contextualise these mechanisms within contemporary clinical research and practice. We review experimental and translational studies elucidating the interplay between oxidative stress, cytoskeletal remodelling, inflammation, and alveolar-capillary barrier dysfunction, highlighting how these processes initiate or amplify pre-existing lung injury. We also examine current approaches to oxygen therapy, both as a standalone intervention and in the context of ventilator management. While the injurious role of hyperoxia in animal models is highly consistent and reproducible, clinical trials have been less consistent in directly linking hyperoxia exposure to increased patient mortality. Although clinical trials comparing liberal versus conservative oxygen strategies have yielded conflicting results over decades, emerging mechanistic insights from pre-clinical models may help identify patient subpopulations at greatest risk for hyperoxia-associated lung injury. By integrating evidence from basic science and clinical studies, this review underscores the importance of judicious oxygen titration to mitigate iatrogenic lung injury and optimise outcomes in critically ill patients.
Air pollution is particularly harmful to people with chronic obstructive pulmonary disease (COPD). Exposure to air pollution from sources such as biomass burning leads to a unique COPD phenotype. This phenotype mainly shows airway damage, with less emphysema than typical smoking-related phenotypes. Across various COPD phenotypes, airway epithelial barrier dysfunction is a basic pathological mechanism. This narrative review summarises the current available evidence on how different types of airborne pollutants, including particulate matter (PM), ozone (O3), diesel exhaust and microplastics, damage the airway epithelial barrier. The toxicity of fine PM with a diameter of ≤2.5 µm, one of its main constituents, largely depends on its chemical composition. Some metals or organic chemicals with redox properties can initiate oxidation reactions and induce pathologic responses. The main injury mechanisms are direct physical damage to apical junctional complexes, serious impairment of mucociliary clearance and induction of oxidative stress. Apart from these immediate harms, pollutants also create epigenetic modifications and disturbed epithelium-immune cell cross-talk, which breaks down the equilibrium of the airway epithelial barrier. These system-wide effects are exacerbated through the gut-lung axis, which aggravates local lung damage via microbiome dysregulation. We evaluate emerging therapeutic strategies that aim to restore barrier integrity, including antioxidants, natural compounds, inhibitors directing specific pathways (e.g. epidermal growth factor receptor (EGFR), NLR family pyrin domain containing 3 (NLRP3)) and microbiome modulation via probiotics. Protection and repair of the airway epithelial barrier offer a promising approach to reducing the onset and progression of pollution-related COPD in populations vulnerable to highly polluted environments.
BACKGROUND:Mycoplasma pneumoniae is a major cause of paediatric community-acquired pneumonia. The prevalence of macrolide-resistant M. pneumoniae (MRMP) has exceeded 80% in East Asia, posing significant challenges to clinical management. Increasing evidence suggests that disease progression is driven not only by direct microbial injury but also by host-mediated hyperinflammatory responses. METHODS:This structured narrative review was conducted using PubMed and Embase databases to identify relevant studies published between 2000 and 2025. Clinical studies, biomarker analyses and regional guidelines, particularly from East Asia, were reviewed to examine the indications, timing and risk-stratified use of systemic corticosteroids in refractory and severe M. pneumoniae pneumonia. RESULTS:Available evidence suggests that management of MRMP often involves both second-line antimicrobial therapy and consideration of adjunctive immunomodulation. Among available biomarkers, lactate dehydrogenase (LDH) has been most frequently reported in association with refractory disease. Elevated LDH levels (commonly around 400 IU·L-1), particularly when dynamically rising, have been associated with increased risk of disease progression, although thresholds vary across studies. Reported treatment strategies include conventional-dose methylprednisolone (1-2 mg·kg-1·day-1) in refractory cases and higher-dose regimens (10-30 mg·kg-1·day-1) in severe hyperinflammatory presentations, with careful clinical assessment. CONCLUSION:Corticosteroids may represent a potential adjunctive strategy rather than a last-resort intervention in selected patients. A risk-stratified approach integrating clinical severity, radiologic progression and biomarker profiles may help guide individualised treatment decisions, although the overall evidence remains heterogeneous and further studies are needed.
