Sarcoidosis is an enigmatic, multi-system inflammatory disorder characterized by the formation of non-necrotizing granulomas in affected organs. Sarcoidosis may be self-limited or spontaneously resolve in up to two-thirds of individuals, but 10-30% develop a more chronic syndrome requiring long-term treatment. Most individuals will require treatment at some point during the course of disease. Currently guidelines recommend treatment in those at risk of future morbidity or organ dysfunction and to preserve quality of life. Careful identification of those likely to benefit from treatment is critical, as current agents are cumbersome to monitor and all have adverse effects. There is a lack of validated prognostic markers to identify those at risk for poor outcomes, but identifying characteristic manifestations of severe disease early can assist with treatment planning. While corticosteroids have been central to treatment of sarcoidosis, newer data have challenged the current treatment paradigm of steroids as first line agents. Recent and ongoing clinical trials may provide evidence for individualized approaches centered on shared decision-making with patients, as balancing the benefits of treatment must always be weighed with the potential for toxicity. This paper will provide an update on current treatment paradigms, new therapeutic strategies, and potential novel agents on the horizon while highlighting the existing challenges and barriers to progress.

Severe asthma affects approximately 3% to 10% of the asthmatic population and is characterized by persistent symptoms and frequent exacerbations despite high-intensity therapy. Historically, glucocorticoids (GCs) have been the mainstay of treatment due to their broad anti-inflammatory effects. However, long-term systemic GC use is associated with substantial toxicity and heterogeneous clinical response, largely influenced by underlying inflammatory endotypes. Type 2 (T2) asthma, marked by eosinophilia and cytokines such as IL-4, IL-5, and IL-13, generally responds well to GCs. In contrast, non-T2 phenotypes, often associated with neutrophilic inflammation, obesity, or smoking, exhibit GC resistance. Molecular mechanisms underlying GC resistance include GRβ overexpression, impaired GRα nuclear translocation via mitogen-activated protein kinase (MAPK) activation, and histone deacetylase-2 (HDAC2) inactivation by oxidative stress. Therapeutic strategies for severe asthma involve maximizing inhaled corticosteroids (ICSs) and adding long-acting bronchodilators or biologics before considering maintenance oral corticosteroids (OCSs). Despite these guidelines, OCS overuse remains common, with many patients exposed to cumulative doses associated with severe adverse effects. These include osteoporosis, diabetes, infections, neuropsychiatric symptoms, and adrenal suppression. Therefore, reducing systemic GC exposure is a key objective in modern asthma management. Biologic therapies targeting IgE (omalizumab), IL-5 (mepolizumab, reslizumab), IL-5Rα (benralizumab), IL-4Rα (dupilumab), and thymic stromal lymphopoietin (tezepelumab) have shown substantial OCS-sparing effects in clinical trials, enabling dose reduction or discontinuation in many patients with steroid-dependent asthma. These agents, aligned with precision medicine principles, allow for phenotype-specific treatment and improved safety profiles. Future efforts should focus on improving biomarker-driven treatment selection, expanding non-T2 therapeutic options, and implementing steroid stewardship protocols. In conclusion, while GCs remain essential for acute exacerbations and as bridging therapy, their chronic use should be minimized. Biologic therapies offer a transformative opportunity to reduce GC burden, improving long-term outcomes and quality of life in patients with severe asthma.

This paper reviews the development of the current edition (Ninth) of the Tumor, Node, and Metastasis (TNM) classification of lung cancer. This classification was proposed from the analyses of a global database of 124,581 patients diagnosed between 2011 and 2019 established by The International Association of the Study of Lung Cancer. Overall survival was calculated using the Kaplan-Meier method, and prognosis assessed using multivariable-adjusted Cox proportional hazards regression to guide proposed changes to the Eighth Edition TNM classification. The innovations in the Ninth Edition TNM are: the T categories remain the same as in the Eighth Edition but descriptors previously considered separately were transferred to the official list of descriptors; the N2 category was subdivided into N2a (involvement of a single N2 station) and N2b (involvement of multiple N2 stations); the M1c category was subdivided into M1c1 (multiple extrathoracic metastases in a single organ system) and M1c2 (multiple extrathoracic metastases in multiple organ systems); and tumor cells spread through air spaces was introduced as an additional pathological descriptor. The Ninth Edition TNM classification of lung cancer aids in the understanding of the prognostic relevance of the anatomical extent of lung cancer but requires thorough clinical and pathological evaluations to benefit from the changes in clinical practice and in research.

Pulmonary alveolar proteinosis (PAP) is a rare syndrome characterized by progressive accumulation of surfactant in pulmonary alveoli, resulting in hypoxemic respiratory insufficiency and an increased risk of secondary infections and pulmonary fibrosis. Secondary PAP (sPAP) occurs because of an underlying disease that reduces the number and/or functions of alveolar macrophages, with hematological disorders being the commonest underlying cause. sPAP accounts for 4% of PAP cases, often occurs in the fourth decade of life, and has a slight male predominance. Patients with sPAP often present in the context of their underlying clinical condition. The prognosis of sPAP is considerably worse than aPAP, with an estimated median survival of less than 20 months. Given the nonspecific clinical presentation of PAP, its diagnosis requires appropriate serological, radiological, and bronchoscopic evaluation. The characteristic "crazy-paving" appearance described in aPAP might not always be present in sPAP. Ground glass opacifications in sPAP typically show a more diffuse pattern compared with a patchy geographic pattern seen in aPAP. The only proven therapy for sPAP is the treatment of the underlying disease, with whole lung lavage demonstrating efficacy in a small number of cases. In this review, we discuss the presentation, prognosis, and treatment of sPAP.

Cardiac sarcoidosis (CS) is a potentially fatal but often underrecognized manifestation of systemic sarcoidosis. Its diagnosis remains a major clinical challenge due to nonspecific symptoms, overlapping features with other cardiac and genetic diseases, and the lack of a universal diagnostic gold standard. This review outlines seven key diagnostic dilemmas frequently encountered in clinical practice: (1) failure to consider CS, (2) premature attribution of findings to CS, (3) limitations and misinterpretation of echocardiogram and cardiac magnetic resonance imaging, (4) limitations of F-FDG positron emission tomography, (5) mistaking mutation for granuloma, (6) biopsy paradox, and (7) navigating diagnostic definitions. Each dilemma highlights the need for careful clinical reasoning, multimodal imaging interpretation, integration of data, and expert multidisciplinary collaboration. Ultimately, a nuanced, patient-centered, and evidence-informed approach is essential to improve diagnosis and outcomes in patients with suspected CS.

Pulmonary infection is an important cause of hospitalization, morbidity, and mortality in people living with human immunodeficiency virus (HIV; PWH) infection, especially in those with significant immunosuppression. Pneumonia, including Pneumocystis jirovecii and Mycobacterium tuberculosis etiologies, continues to be the most frequent pulmonary infection in PWH. However, identifying the etiology of pulmonary infection in PWH is challenging because of the overlap in clinical features and the frequency of co-infection. This review focuses on the current scientific evidence regarding pulmonary infection in PWH, including its epidemiology, clinical presentation, diagnosis, and management.

Sarcoidosis is a disease with high morbidity that has variable epidemiology based on genetics and sociodemographic factors. The etiology of this variability remains incompletely understood. This narrative review describes how genetics, social determinants of health, and the interactions between them may contribute to the differences in epidemiology and health outcomes observed in different patient groups with sarcoidosis.

Diffuse alveolar hemorrhage (DAH) is a life-threatening clinical syndrome characterized by bleeding from the pulmonary microcirculation into alveolar spaces. It typically presents with acute respiratory failure, anemia, and diffuse radiological infiltrates. Importantly hemoptysis may be absent in up to half of cases. Etiologies are diverse, encompassing systemic vasculitides, connective tissue diseases, coagulopathies, drugs, infections, hemodynamic disturbances, and idiopathic processes. Histopathologically, DAH manifests as one of three overlapping patterns: pulmonary capillaritis, bland alveolar hemorrhage, or diffuse alveolar damage, which help guide diagnostic and therapeutic strategies. Capillaritis, commonly associated with immune-mediated vasculitis such as antineutrophil cytoplasmic antibody-associated vasculitis and anti-glomerular basement membrane disease, typically necessitating prompt and aggressive immunosuppression. In contrast, bland hemorrhage often reflects coagulopathy or hemodynamic factors, whereas diffuse alveolar damage is linked to toxins, infections, or acute respiratory distress syndrome. Prompt recognition and systematic evaluation are critical to optimizing outcomes, given DAH's high in-hospital mortality exceeding 20%. Diagnosis relies on a combination of imaging, bronchoalveolar lavage (demonstrating progressively bloodier returns and hemosiderin-laden macrophages), and targeted laboratory evaluation for vasculitis, infection, and coagulopathy. Management includes patient stabilization with supplementary oxygen or indeed ventilatory support, careful avoidance of ventilator-induced lung injury, and etiology-directed therapy. High-dose corticosteroids, cytotoxic agents, and rituximab remain central in immune-mediated cases, whereas plasma exchange is indicated in anti-glomerular basement membrane disease and severe refractory hemoptysis. Antimicrobial therapy, drug withdrawal, hemostatic interventions, and, in select cases, extracorporeal support may also be required. This review outlines the histopathological spectrum, etiologic categories, diagnostic algorithms, and evidence-based therapeutic approaches to DAH, emphasizing the importance of early multidisciplinary management to improve survival and functional recovery.

Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare disease characterized by abnormal accumulation of surfactant in alveoli. Pathogenetically, in aPAP, the presence of granulocyte macrophage-colony stimulating factor (GM-CSF) autoantibodies hinders physiological binding of GM-CSF to its receptor, disrupting terminal differentiation of alveolar macrophages and the activation GM-CSF-PU.1-PPARG1-ABCG1 axis, resulting in a primary reduction in cholesterol efflux from alveolar macrophages and a secondary reduction in surfactant clearance through macrophages from the alveolar surface. APAP is the most common, accounting for more than 90 to 95% of all patients included under the PAP term, which encompasses and classifies all forms of PAP according to etiopathogenetic mechanisms, as primary, secondary, congenital, and unclassified. APAP is worldwide distributed with an estimated prevalence fluctuating between 7.0 and 9.7 cases/million and an annual incidence of 1.65, affecting middle-aged men and women. Clinical manifestation may be gradual and insidious, mainly manifesting with progressive dyspnea, but the natural history is variable, since some patients stabilize for a long period, while others progress to respiratory failure and death; in a minority, spontaneous resolution may be observed, while some develop lung and/or systemic infections, and rarely pulmonary fibrosis. Until recently, whole lung lavage (WLL) was universally accepted as the gold-standard therapeutic modality in aPAP. However, after considerable progress in the past 25 years and the publication of several positive studies, replacing the use of inhaled-GM-CSF as the standard of care for aPAP and conceding WLL a rescue option is becoming more and more concrete. In conclusion, aPAP is the classic paradigm of a scientific disease progressing from the "bench-to-bedside," since several discoveries made in the laboratory setting have become necessary to clarify its pathogenetic mechanisms, define diagnostic tools, and implement new therapeutic modalities, which established the disease as treatable and fully reversible, literally, moving patients from "hell to heaven."

Sarcoidosis is a granulomatous disease of unknown cause, triggered by an unidentified antigen. Although classically considered a T cell-mediated disorder with an IFN-γ signature driven by Th1, Th17, and Th17.1 cells, its pathogenesis reflects dysregulated crosstalk between innate and adaptive immunity. Granulomas form through macrophage differentiation at the core, fueled by aberrantly programmed monocytes and sustained by persistent antigen presentation to T cells. Hyperactive macrophages drive excessive peripheral cell recruitment, while dysregulated T cell responses promote T cell expansion, impaired effector regulation, and eventual exhaustion. Deficient regulatory pathways fail to counterbalance this activation, creating a perpetuating inflammatory loop that underlies disease persistence and fibrotic progression. This review integrates up-to-date transcriptomic and biological data to define the cellular and molecular mechanisms that initiate, sustain, and dysregulate immune responses in sarcoidosis.

Sarcoidosis is a complex, immune-mediated disease characterized by a broad spectrum of clinical and molecular phenotypes-often referred to as endophenotypes-some of which progress to chronic outcomes such as pulmonary fibrosis. Despite decades of research, the pathogenesis of sarcoidosis remains incompletely understood, primarily due to its clinical heterogeneity and the absence of robust preclinical models. Established risk factors include age, sex, ethnicity, geographic origin, and environmental exposures, all of which contribute to granuloma formation and the activation of profibrotic pathways. These inflammatory cascades promote fibroblast proliferation and aberrant tissue remodeling, ultimately leading to interstitial lung pathology and fibrosis. A central feature of sarcoidosis is the dysregulation of immune regulatory mechanisms, likely driven by genetic susceptibility and immune dysfunction. Understanding the genetic architecture of sarcoidosis is crucial for identifying the molecular drivers of the disease, discovering biomarkers for early diagnosis and prognosis, and developing targeted therapies. This review synthesizes current knowledge on the genetic and genomic landscape of sarcoidosis, highlighting key loci and biological pathways implicated in disease susceptibility and progression.

. Sarcoidosis remains a diagnostic and therapeutic challenge due to its heterogeneous clinical presentation and lack of pathognomonic features. Despite five decades of biomarker research, no single marker has achieved sufficient accuracy for standalone diagnosis. Traditional biomarkers retain clinical utility when used strategically: high-sensitivity markers (sIL-2R, SAA, chitotriosidase) excel at confirming disease, while high-specificity markers (lysozyme) better exclude sarcoidosis. Chitotriosidase has emerged as superior to ACE for disease monitoring, and sIL-2R remains invaluable for detecting extrapulmonary involvement. However, their limitations necessitate multi-biomarker approaches tailored to specific clinical phenotypes. Recent advances address critical unmet needs. High-sensitivity troponin T provides crucial prognostic information in cardiac sarcoidosis, with levels >14 ng/L predicting adverse outcomes. Novel fibrosis markers including alveolar nitric oxide, HSP90α, and advanced KL-6 measurement enable better assessment of disease progression. Pre-diagnostic inflammatory proteins elevated years before clinical manifestation suggest opportunities for early intervention. Revolutionary omics technologies are transforming biomarker discovery. Extracellular vesicle proteomics identifies treatment-responsive signatures, retrotrans-genomics reveals viral element activation in pathogenesis, and Mendelian randomization distinguishes causal from associative proteins. Integration of multi-omics data through machine learning algorithms promises personalized diagnostic and therapeutic strategies. The future of sarcoidosis management lies in intelligent biomarker integration rather than reliance on single tests. Success will be measured by improved patient outcomes through earlier diagnosis, accurate risk stratification, and personalized treatment selection. This paradigm shift from empirical to precision medicine requires continued collaboration between researchers, clinicians, and patients to translate biomarker discoveries into clinical practice.

Acute respiratory distress syndrome (ARDS) remains a heterogeneous and a major challenge disease process despite five decades of study. Emerging translational data delineate three overlapping phases: exudative, proliferative, and fibroproliferative, each driven by distinct immune-mechanical pathways and potentially modifiable by glucocorticosteroids (GC) modulation. Contemporary clinical randomized trials and meta-analyses indicate that early (≤72 hours) administration of systemic GCs at receptor-saturating doses (e.g., dexamethasone from 20 to 10 mg/day, or methylprednisolone 1-2 mg/kg/day) accelerates resolution of pulmonary edema, shortens mechanical ventilation duration, and improves intensive care survival, while prolonged tapering regimens are required once fibroproliferation is established. Conversely, delayed initiation (>14 days), viral pneumonitis with high viral load, recent surgical anastomosis, or uncontrolled fungal coinfection constitute "red flags" in which GCs might increase mortality. Latent-class analyses-a statistical modeling approach in which multivariable data are reduced to indirectly observed (latent) variables-identified two (hyper- and hypoinflammatory) ARDS phenotypes that likely might respond differentially to GC exposure, although we lack validation studies. Therefore, it seems that biomarker-guided precision therapy is poised to replace the historical one-size-fits-all approach. This narrative review integrates epidemiology, pathobiology, pharmacology, and clinical evidence to provide a phase-specific, phenotype-directed framework for GC use in ARDS and outlines future research priorities aimed at harmonizing molecular endotyping with dose, timing, and tapering strategies.

Sarcoidosis is a systemic inflammatory disorder of unknown cause, mainly affecting the lungs and lymph nodes. Symptoms are diverse and range from dyspnea and cough to fatigue, cognitive impairment, and pain. An important cause of pain in patients with sarcoidosis is small fiber neuropathy (SFN), with an estimated prevalence of 33 to 86%. The underlying pathogenesis of SFN in sarcoidosis is not known. In sarcoidosis, symptoms related to SFN can be grouped into general symptoms (e.g., fatigue), sensory symptoms (e.g., pain and numbness), and autonomic symptoms (e.g., gastrointestinal dysmotility, palpitations, or sexual dysfunction). Presentation of SFN in patients with sarcoidosis is heterogeneous and can either be length-dependent or nonlength-dependent. The small fiber neuropathy screening list assesses the frequency and severity of symptoms suggestive of SFN. As a diagnostic gold standard is lacking for SFN, the diagnosis is made on different levels of certainty based on the presence of clinical signs, normal nerve conduction studies, and either abnormal quantitative sensory testing or decreased intraepidermal nerve fiber density on skin biopsy. Autonomic dysfunction in sarcoidosis is even more difficult to diagnose, often under-recognized, and may also have a negative impact on quality of life. At present, only symptomatic relief can sometimes be achieved. While treatment of sarcoidosis usually includes corticosteroids and other immunosuppressants, these drugs are not proven effective in alleviating SFN symptoms related to sarcoidosis. This review provides an overview of symptoms, available diagnostic tools, and treatment options specific to sarcoidosis-associated SFN and autonomic dysfunction.

Amyloidosis is a heterogeneous group of rare diseases characterized by the deposition of misfolded and insoluble proteins in tissues. Lung involvement, airways or parenchyma, is relatively common, but usually mild. Some patients may develop chronic progressive forms or experience life-threatening complications. In this review, we summarize the most recent advances in the comprehension of molecular mechanisms and classification of amyloidosis. We then illustrate the different forms of lung amyloidosis and the current treatment options. Increased awareness in the medical community and the creation of referral centers' networks are of paramount importance to ensure adequate management and access to treatment.

Noninfectious pulmonary complications are a significant cause of morbidity and mortality in immunocompromised patients, particularly in those undergoing hematopoietic stem cell transplantation, solid organ transplantation, chemotherapy, or immunotherapy. These syndromes often mimic infections, leading to delayed diagnosis and inappropriate treatment. Acute complications include peri-engraftment respiratory distress syndrome, diffuse alveolar hemorrhage, drug-induced lung injury, immune checkpoint inhibitor-related pneumonitis, and radiation pneumonitis, while late or chronic complications, such as organizing pneumonia, interstitial lung disease, bronchiolitis obliterans syndrome, and chronic graft-versus-host disease-related lung involvement, typically develop months to years after therapy. Accurate and timely diagnosis is essential, relying on high-resolution CT, bronchoalveolar lavage, and, in selected cases, lung biopsy to differentiate these conditions from infections. Current treatments remain largely empirical, focusing on corticosteroids, supportive intensive care, and immunosuppressive adjustment, although novel strategies, including inhaled hemostatic agents and JAK inhibitors, are emerging. Despite advances in supportive management, late-onset complications remain associated with poor long-term functional outcomes. Future directions include the development of biomarkers, artificial intelligence-assisted radiological tools, and multicenter registries to improve classification, risk stratification, and treatment. In this narrative review, we highlight current evidence around noninfectious pulmonary complications in the critical care setting, diagnosis, and treatment.

Non-invasive ventilation (NIV) is commonly recommended as respiratory support for selected immunocompromised patients with acute respiratory failure (ARF), offering an alternative to tracheal intubation, which historically carried high mortality rates in this population. Initial enthusiasm for NIV stemmed from its potential to avoid invasive ventilation. However, evolving evidence has demonstrated a gradual reduction in mortality among intubated immunocompromised patients, attributed to advances in oncologic therapies, improvements in intensive care unit (ICU) management, and refined triage criteria. These findings have led to a reassessment of NIV's role in this context, suggesting that immunocompromised patients with ARF may benefit from treatment strategies similar to those used in the general population, including timely intubation when clinically indicated. Notably, survival outcomes remain influenced by inconsistent intubation criteria across studies, underlying causes of immunosuppression, and patient severity. Recent studies also highlight poor ICU outcomes in patients with specific oncohematologic profiles and fragile physical states, tempering enthusiasm for invasive support in these subgroups. Identifying predictors of NIV failure is critical to guide ventilation strategies in immunocompromised patients with ARF and determine when ongoing non-invasive support may become counterproductive. However, since there are no validated tools to predict the success or failure of NIV in these patients, careful bedside assessment of their response to non-invasive strategies is essential to ensure timely intubation and prevent dangerous delays in those who do not show signs of improvement. After the widespread adoption of NIV, the introduction of high-flow nasal cannula oxygenation has emerged as a new tool in managing specific scenarios of respiratory failure, playing a central role in influencing the prognosis of critically ill patients. Its effectiveness has also been investigated in immunocompromised patients.

Pulmonary alveolar microlithiasis (PAM) has been well characterized in terms of its description, genetic background, and diagnostic process for decades; however, no effective prevention or treatment has yet been established. PAM is classified as an ultrarare lung disease linked to mutations in the autosomal recessive sodium-phosphate co-transporter gene , which may serve as a potential target for future therapies. As new variants of mutations continue to be identified, a broader genetic understanding could help predict the variable clinical course among patients and guide the development of therapies beyond palliative care. The creation of a disease severity score would be valuable for assessing disease burden, stratifying patients, and designing research studies. Given the clinico-radiological dissociation and heterogeneity of PAM, such a score should be developed as a composite index. Coupled with objective severity measures and identification of factors underlying individual variability, this approach could enhance insight into preventive and therapeutic strategies. Clinical advances in PAM remain limited, underscoring the need for international registries and cohorts as an urgent priority. Systematic re-evaluation of diagnosed cases and structured follow-up, rather than arbitrary visits, would generate standardized data critical for future research. A standardized patient evaluation form may facilitate the collection of data in a shared database.