As-needed low-dose inhaled corticosteroid/formoterol therapy in patients with severe asthma included in the German Asthma Net cohort.

After the GINA update in 2019, the proportion of SMART therapy increased with evidence for better disease control in SMART patients compared to SABA alone https://bit.ly/3SSPX1C.

Deep immune profiling of chronic rhinosinusitis in allergic and non-allergic cohorts using mass cytometry.

Chronic rhinosinusitis (CRS) is a persistent nasal and paranasal sinus mucosa inflammation comprising two phenotypes, namely CRS with nasal polyps (CRSwNP) and without (CRSsNP). CRSwNP can be associated with asthma and hypersensitivity to non-steroidal anti-inflammatory drug (NSAID) in a syndrome known as NSAID-exacerbated respiratory disease (N-ERD). Furthermore, CRS frequently intertwines with respiratory allergies. This study investigated levels of 33 different nasal and serum cytokines and phenotypic characteristics of peripheral blood mononuclear cells (PBMCs) within cohorts of CRS patients (n = 24), additionally examining the influence of comorbid respiratory allergies by mass cytometry. N-ERD patients showed heightened type 2 nasal cytokine levels. Mass cytometry revealed increased activated naive B cell levels in CRSwNP and N-ERD, while resting naive B cells were higher in CRSsNP. Th2a cell levels were significantly elevated in allergic subjects, but not in CRS groups. In conclusion, there are distinct immunological features in PBMCs of CRS phenotypes and allergy.

Pharmacokinetics of isavuconazole at different target sites in healthy volunteers after single and multiple intravenous infusions.

BACKGROUND: Invasive aspergillosis is a severe fungal infection that affects multiple organ systems including the CNS and the lungs. Isavuconazole, a novel triazole antifungal agent, has demonstrated promising activity against Aspergillus spp. However, data on the penetration of isavuconazole into the CNS and ELF and intracellular accumulation remain limited. MATERIALS AND METHODS: We conducted a prospective single-centre pharmacokinetic (PK) study in 12 healthy volunteers. Subjects received seven doses of 200 mg isavuconazole to achieve an assumed steady-state. After the first and final infusion, plasma sampling was conducted over 8 and 12 h, respectively. All subjects underwent one lumbar puncture and bronchoalveolar lavage, at either 2, 6 or 12 h post-infusion of the final dose. PBMCs were collected in six subjects from blood to determine intracellular isavuconazole concentrations at 6, 8 or 12 h. The AUC/MIC was calculated for an MIC value of 1 mg/L, which marks the EUCAST susceptibility breakpoint for Aspergillus fumigatus and Aspergillus flavus. RESULTS: C max and AUC0-24h of isavuconazole in plasma under assumed steady-state conditions were 6.57 ±â€Š1.68 mg/L (mean ±â€ŠSD) and 106 ±â€Š32.1 h·mg/L, respectively. The average concentrations measured in CSF, ELF and in PBMCs were 0.07 ±â€Š0.03, 0.94 ±â€Š0.46 and 27.1 ±â€Š17.8 mg/L, respectively. The AUC/MIC in plasma, CSF, ELF and in PBMCs under steady-state conditions were 106 ±â€Š32.1, 1.68 ±â€Š0.72, 22.6 ±â€Š11.0 and 650 ±â€Š426 mg·h/L, respectively. CONCLUSION: Isavuconazole demonstrated moderate penetration into ELF, low penetrability into CSF and high accumulation in PBMCs. Current dosing regimens resulted in sufficient plasma exposure in all subjects to treat isolates with MICs ≤ 1 mg/L.

Phase I dose-escalation study to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of an inhaled recombinant human ACE2.

Background: APN01 is a soluble recombinant human angiotensin-converting enzyme 2 (rhACE2), a key player in the renin-aldosterone-angiotensin system (RAAS). In clinical studies, APN01 was administered intravenously only, so far. The aim of this study (ClinicalTrials.gov: NCT05065645) was to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of inhaled APN01. Methods: This was a phase I, double-blind, placebo-controlled, dose-escalation study. Inhalation was conducted via a nebuliser over 15 min in three single ascending dose (SAD) cohorts (n=24) and two multiple ascending dose (MAD) cohorts (n=16: every 12 h for 7 days). Doses in the SAD cohort were 1.25, 2.5 and 5 mg·mL-1; doses in the MAD cohort were 2.5 and 5 mg·mL-1. Safety (including adverse events (AEs), laboratory findings and lung function results), PK and PD data were assessed. Results: In the SAD and MAD cohorts, treatment-related AEs were slightly more frequent in the active treatment group than in the placebo group. AEs were mild to moderate, with no dose-limiting toxicities. No clinically relevant changes in lung function and laboratory results were observed. The mean maximum observed plasma concentration (Cmax) values after single and multiple doses of 5 mg·mL-1 APN01 were 1.88 and 6.61 ng·mL-1, respectively. Among the PD variables, significance was found for ACE2 and angiotensin 1-5. Conclusions: The application of aerosolised APN01 is safe and well tolerated after single and multiple doses. By achieving a high local concentration in the lungs and low systemic bioavailability, inhaled rhACE2 may present a therapeutic option in ACE2-related diseases.

PD-L1 assessment in lung cancer biopsies-pitfalls and limitations.

The programmed cell death-ligand 1 (PD-L1) protein expression on tumor cells predicts the efficacy of immunotherapy in patients with non-small cell lung cancer. However, the assessment of PD-L1 expression on tumor cells has limited power for selecting patients for immunotherapy due to intra-tumoral heterogeneity and inter-tumoral heterogeneity of PD-L1 expression, the inter-observer variability in scoring PD-L1 staining, and reproducibility. These difficulties and pitfalls in interpreting the PD-L1 assessment are discussed in detail in this review.

Initiation, response assessment, and switch of antibody therapies in patients with severe asthma - A survey among German specialists.

Background: For therapy of severe asthma 5 monoclonal antibodies have been available in Germany up to November 2022, but no clear rules exist on choice of initial therapy, assessment of response, and switch. Objective: To assess current practice on all aspects of biologic therapy by specialists in Germany. Methods: A questionnaire was created by specialists for severe asthma, which was tested and modified by further experts. We invited 119 pulmonologists of the German Asthma Net (GAN) to complete the survey and used SoSci Survey and SPSS for data collection and analysis. Results: Forty-seven pulmonologists took part in the survey with a median annual number of patients treated with biologics of 35, 55% worked in an outpatient practice, and 40% in a hospital. Exacerbations and oral steroid use were the most important factors for the decision to start a biologic therapy. Accordingly, these parameters were also the most relevant for assessment of response. Most participants considered type-2 inflammation biomarkers and comorbidities (foremost CRSwNP and AD) for choosing initial biologic. Asthma Control Test (ACT) was the most common instrument for assessing status of disease control. There was no consensus on thresholds for response of pulmonary function tests including FEV1, FVC, and RV. Eighty-five percent of participants distinguished between "responders", "partial responders" and "non-responders". Comorbidities played an important role for the decision to switch to another biologic, eg, when initial therapy had insufficient effectiveness on CRSwNP. Conclusion: This study provides a detailed insight into current opinions and practice of biologic use in severe asthma in Germany.

Consensus goals and standards for specialist cough clinics: the NEUROCOUGH international Delphi study.

Background: Current guidelines on the management of chronic cough do not provide recommendations for the operation of specialist cough clinics. The objective of the present study was to develop expert consensus on goals and standard procedures for specialist cough clinics. Methods: We undertook a modified Delphi process, whereby initial statements proposed by experts were categorised and presented back to panellists over two ranking rounds using an 11-point Likert scale to identify consensus. Results: An international panel of 57 experts from 19 countries participated, with consensus reached on 15 out of 16 statements, covering the aims, roles and standard procedures of specialist cough clinics. Panellists agreed that specialist cough clinics offer optimal care for patients with chronic cough. They also agreed that history taking should enquire as to cough triggers, cough severity rating scales should be routinely used, and a minimum of chest radiography, spirometry and measurements of type 2 inflammatory markers should be undertaken in newly referred patients. The importance of specialist cough clinics in promoting clinical research and cough specialty training was acknowledged. Variability in healthcare resources and clinical needs between geographical regions was noted. Conclusions: The Delphi exercise provides a platform and guidance for both established cough clinics and those in planning stages.

Ventilatory support and inflammatory peptides in hospitalised patients with COVID-19: A prospective cohort trial.

PURPOSE: Several studies have shown that SARS-CoV-2 can induce a massive release of cytokines which contributes to disease severity and mortality. Therefore, cytokine levels in the serum may help to predict disease severity and survival in COVID-19 patients. METHODS: In this prospective trial, 88 patients who were hospitalised for COVID-19 were enrolled. Blood samples for serum peptide measurements were taken at the time closest to hospitalisation, at day 5, 9 and 13 (±1). The concentrations of cytokines (IL-1α, IL-1ß, IL-1RA, IL-6, L-7, L-10, IFN-γ and TNF-α), chemokines (CCL-3, CCL-4 and CCL-7) and growth factors (G-CSF, GM-CSF and VEGF) were assessed and correlated with the type of ventilation, occurrence of consolidations on imaging and the level of care. RESULTS: COVID-19 patients (median age 68 years, IQR 55-77) stayed in hospital between 5-171 days. Compared to patients in the general care unit, patients in the intermediate care unit (IMCU) and intensive care unit (ICU) presented significantly elevated serum IL-6 (p = 0.004) and lower IFN-γ levels (p = 0.005), respectively. The peak inspiratory pressure in ventilated patients correlated positively with IL-1RA, G-CSF and inversely with IFN-γ serum levels (all p<0.05). VEGF serum levels inversely correlated with the fraction of inspired oxygen in patients receiving high-flow nasal canula oxygen therapy (p = 0.047). No significant correlation between serum concentrations of the measured peptides and the type of ventilation, occurrence of radiological consolidations or in-hospital mortality has been observed. CONCLUSION: IL1-RA, IL-6, IFN-γ, G-CSF, CCL-7 and VEGF serum levels could prove helpful as biomarkers to assess disease severity and the need for intensive care in COVID-19 patients.

Cell-type-specific role of P2Y2 receptor in HDM-driven model of allergic airway inflammation.

Allergic airway inflammation (AAI) is a chronic respiratory disease that is considered a severe restriction in daily life and is accompanied by a constant risk of acute aggravation. It is characterized by IgE-dependent activation of mast cells, infiltration of eosinophils, and activated T-helper cell type 2 (Th2) lymphocytes into airway mucosa. Purinergic receptor signaling is known to play a crucial role in inducing and maintaining allergic airway inflammation. Previous studies in an ovalbumin (OVA)-alum mouse model demonstrated a contribution of the P2Y2 purinergic receptor subtype (P2RY2) in allergic airway inflammation. However, conflicting data concerning the mechanism by which P2RY2 triggers AAI has been reported. Thus, we aimed at elucidating the cell-type-specific role of P2RY2 signaling in house dust mite (HDM)-driven model of allergic airway inflammation. Thereupon, HDM-driven AAI was induced in conditional knockout mice, deficient or intact for P2ry2 in either alveolar epithelial cells, hematopoietic cells, myeloid cells, helper T cells, or dendritic cells. To analyze the functional role of P2RY2 in these mice models, flow cytometry of bronchoalveolar lavage fluid (BALF), cytokine measurement of BALF, invasive lung function measurement, HDM re-stimulation of mediastinal lymph node (MLN) cells, and lung histology were performed. Mice that were subjected to an HDM-based model of allergic airway inflammation resulted in reduced signs of acute airway inflammation including eosinophilia in BALF, peribronchial inflammation, Th2 cytokine production, and bronchial hyperresponsiveness in mice deficient for P2ry2 in alveolar epithelial cells, hematopoietic cells, myeloid cells, or dendritic cells. Furthermore, the migration of bone-marrow-derived dendritic cells and bone-marrow-derived monocytes, both deficient in P2ry2, towards ATP was impaired. Additionally, we found reduced levels of MCP-1/CCL2 and IL-8 homologues in the BALF of mice deficient in P2ry2 in myeloid cells and lower concentrations of IL-33 in the lung tissue of mice deficient in P2ry2 in alveolar epithelial cells. In summary, our results show that P2RY2 contributes to HDM-induced airway inflammation by mediating proinflammatory cytokine production in airway epithelial cells, monocytes, and dendritic cells and drives the recruitment of lung dendritic cells and monocytes.

Characterization of Austrian severe asthma patients.

INTRODUCTION: The Severe Asthma Registry, founded by German Asthma Net (GAN) in 2011, is a prospective registry recording clinical parameters from participating centers in Germany, Austria and Switzerland. This article presents the baseline characteristics of severe asthma patients from Austrian centers. METHODS: We analyzed the baseline visit data of all patients recruited to the GAN Severe Asthma Registry from participating Austrian centers. RESULTS: Baseline visit data were available for 214 Austrian severe asthma patients from 6 Austrian centers from 2013 to 2022. Mean age was 53.7 years. Mean BMI was 26.4 kg/m2. More than a third (37.4%) of all patients had daily daytime asthma symptoms at baseline and had to use their reliever medication at least once per day. Forty-one percent of patients were classified as uncontrolled according to GINA and 24.8% as partially controlled at baseline visit. The median annual exacerbation frequency was 3 in the previous 12 months. At the time of baseline visit, 23.4% of all patients had regular treatment with oral corticosteroids. Furthermore, 23.9% had received any severe asthma monoclonal antibody prior to the baseline visit. There were no notable differences in baseline characteristics between patients categorized by smoking history or measurable type 2 inflammation. CONCLUSIONS: This study provides the first multi-center characterization of Austrian severe asthma patients. Patients in this cohort had better asthma control and less frequent exacerbations compared to most international registries.

Sustained Treatment Response after Intravenous Cyclophosphamide in a Patient with Therapy-Resistant COVID-19 Acute Respiratory Distress Syndrome: A Case Report.

Treatment of acute respiratory distress syndrome (ARDS) represents a severe complication of coronavirus disease 2019 (COVID-19) infection and is often challenging in intensive care treatment. Potential positive effects of intravenous cyclophosphamide have been reported in interstitial lung diseases (ILDs). However, there are no data on the use of high-dose cyclophosphamide in therapy-resistant COVID-19 ARDS. We report the case of a 32-year-old male patient admitted to the intensive care unit (ICU) of the Medical University of Vienna due to severe COVID-19 ARDS who required venovenous extracorporeal membrane oxygenation (ECMO) with a total runtime of 85 days. Despite all these therapeutic efforts, he remained in a condition of therapy-resistant ARDS. Unfortunately, the patient was denied for lung transplantation. However, a significant improvement in his respiratory condition was achieved after the administration of an intravenous regimen of cyclophosphamide and prednisolone. After a period of consecutive stabilization, the patient was transferred to the normal ward after 125 days of intensive care treatment. There is a substantial lack of therapeutic options in therapy-resistant ARDS. Our case report suggests that cyclophosphamide may represent a new treatment strategy in therapy-resistant ARDS. Due to its severe adverse effect profile, cyclophosphamide should be used after careful evaluation of a patient's general condition.

[Diagnosis and treatment of asthma: a guideline for respiratory specialists 2023 - published by the German Respiratory Society (DGP) e. V.] / S2k-Leitlinie zur fachärztlichen Diagnostik und Therapie von Asthma 2023.

The management of asthma has fundamentally changed during the past decades. The present guideline for the diagnosis and treatment of asthma was developed for respiratory specialists who need detailed and evidence-based information on the new diagnostic and therapeutic options in asthma. The guideline shows the new role of biomarkers, especially blood eosinophils and fractional exhaled NO (FeNO), in diagnostic algorithms of asthma. Of note, this guideline is the first worldwide to announce symptom prevention and asthma remission as the ultimate goals of asthma treatment, which can be achieved by using individually tailored, disease-modifying anti-asthmatic drugs such as inhaled steroids, allergen immunotherapy or biologics. In addition, the central role of the treatment of comorbidities is emphasized. Finally, the document addresses several challenges in asthma management, including asthma treatment during pregnancy, treatment of severe asthma or the diagnosis and treatment of work-related asthma.

Characterization of Obesity in Severe Asthma in the German Asthma Net.

BACKGROUND: Asthma is increasingly recognized as heterogeneous, characterized by different endotypes, with obesity not only a distinct phenotype but a risk factor for severe asthma. OBJECTIVE: We sought to understand the associations of obesity with relevant parameters of severe asthma, including asthma control, disease burden, and lung function. METHODS: The German Asthma Net registry is a multicenter international real-life registry capturing long-term follow-up data. This analysis included 2213 patients (52 ± 16 years, 58% female, 29% with obesity [body mass index ≥30 kg/m2], 4.2 ± 4.3 exacerbations/year). The primary analysis assessed relationships between BMI and variables through univariate tests, followed by a multiple regression model. Secondary outcomes regarded clinically relevant variables in relation to weight groups. RESULTS: Patients with obesity were more frequently female, more likely to have depression and gastroesophageal reflux, and suffered from worse asthma control, lower quality of life, reduced static lung volumes, more pronounced hypoxemia, and higher blood neutrophil counts, all statistically significant. Blood eosinophils, exhaled nitric oxide, and total IgE were independent of obesity. In the multiple regression analysis, obesity was significantly associated with more frequent reflux and depression, reduced static lung function values, older age, poor asthma control, and long-acting muscarinic antagonist therapy, and inversely associated with bronchiectasis and nonsmoking status. CONCLUSION: In this large, well-characterized cohort, we identified the association of obesity with a significantly higher disease burden and a similar portfolio of inflammation type 2 markers in patients with and without obesity; therefore, patients with obesity seem similarly eligible for the treatment with biologics targeting these disease endotypes.

Response to Biologics and Clinical Remission in the Adult German Asthma Net Severe Asthma Registry Cohort.

BACKGROUND: Recently, criteria for evaluation of response to biologics have been proposed and the concept of clinical remission has gained attention as a possible goal even in severe asthma. OBJECTIVE: To analyze the response and remission in the German Asthma Net severe asthma registry cohort. METHODS: We included adults not using a biologic at baseline (V0) and compared patients treated between V0 and 1-year visit (V1) without using a biologic (group A) to patients starting with a biologic after V0 and continuing it up to V1 (group B). We applied the Biologics Asthma Response Score to quantify composite response in good, intermediate, or insufficient. We defined clinical remission (R) as absence of significant symptoms (Asthma Control Test score ≥ 20 at V1) in the absence of exacerbations and oral corticosteroid therapy. RESULTS: Group A included 233 and group B 210 patients, the latter receiving omalizumab (n = 33), mepolizumab (n = 40), benralizumab (n = 81), reslizumab (n = 1), or dupilumab (n = 56). At baseline, group B had less often an allergic phenotype (35.2% vs 41.6%), lower Asthma Control Test score (median, 12 vs 14), more exacerbations in the past year (median, 3 vs 2), and more often high-dose inhaled corticosteroid treatment (71.4% vs 51.5%) than group A. After 1 year of treatment, rates of response (good: 61.4% vs 34.8%; intermediate: 26.7% vs 42.9%; insufficient: 11.9% vs. 22.3%) and/or clinical remission (37.6% vs 17.2%) were higher in group B than in group A. CONCLUSIONS: Despite more severe asthma at baseline, patients treated with biologics had a markedly higher probability of achieving good clinical response and/or remission than patients treated without biologics.

Cardiovascular Diseases in COPD: From Diagnosis and Prevalence to Therapy.

Chronic obstructive pulmonary disease (COPD) is considered one of the leading causes of mortality. Cardiovascular comorbidities are diagnosed often in COPD patients, not only because of the common risk factors these two diseases share, but also because of the systemic inflammation which characterizes COPD and has deleterious effects in the cardiovascular system. The comorbid cardiovascular diseases in COPD result in several difficulties in the holistic treatment of these patients and affect outcomes such as morbidity and mortality. Several studies have reported that mortality from cardiovascular causes is common among COPD patients, while the risk for acute cardiovascular events increases during COPD exacerbations and remains high for a long time even after recovery. In this review, we focus on the prevalence of cardiovascular comorbidities in COPD patients, presenting the evidence regarding the interaction of the pathophysiological pathways which characterize each disease. Furthermore, we summarize information regarding the effects of cardiovascular treatment on COPD outcomes and vice versa. Finally, we present the current evidence regarding the impact of cardiovascular comorbidities on exacerbations, quality of life and survival of COPD patients.

Prevention of M2 polarization and temporal limitation of differentiation in monocytes by extracellular ATP.

BACKGROUND: Elevated levels of extracellular adenosine triphosphate (ATP) modulate immunologic pathways and are considered to be a danger signal in inflammation, lung fibrosis and cancer. Macrophages can be classified into two main types: M1 macrophages are classically activated, pro-inflammatory macrophages, whereas M2 macrophages are alternatively activated, pro-fibrotic macrophages. In this study, we examined the effect of ATP on differentiation of native human monocytes into these macrophage subtypes. We characterized M1 and M2 like macrophages by their release of Interleukin-1beta (IL-1ß) and Chemokine (C-C motif) ligand 18 (CCL18), respectively. RESULTS: Monocytes were stimulated with ATP or the P2X7 receptor agonist Benzoylbenzoyl-ATP (Bz-ATP), and the production of various cytokines was analyzed, with a particular focus on CCL18 and IL-1ß, along with the expression of different purinergic receptors. Over a 72 h period of cell culture, monocytes spontaneously differentiated to M2 like macrophages, as indicated by an increased release of CCL18. Immediate stimulation of monocytes with ATP resulted in a dose-dependent reduction in CCL18 release, but had no effect on the concentration of IL-1ß. In contrast, delayed stimulation with ATP had no effect on either CCL18 or IL-1ß release. Similar results were observed in a model of inflammation using lipopolysaccharide-stimulated human monocytes. Stimulation with the P2X7 receptor agonist Bz-ATP mimicked the effect of ATP on M2-macrophage differentiation, indicating that P2X7 is involved in ATP-induced inhibition of CCL18 release. Indeed, P2X7 was downregulated during spontaneous M2 differentiation, which may partially explain the ineffectiveness of late ATP stimulation of monocytes. However, pre-incubation of monocytes with PPADS, Suramin (unselective P2X- and P2Y-receptor blockers) and KN62 (P2X7-antagonist) failed to reverse the reduction of CCL18 by ATP. CONCLUSIONS: ATP prevents spontaneous differentiation of monocytes into M2-like macrophages in a dose- and time-dependent manner. These effects were not mediated by P2X and P2Y receptors.

Personality traits and mental distress after COVID-19 testing. Prospective long-term analysis in a Viennese cohort.

Background: Symptoms of mental stress are a hallmark of the COVID-19 pandemic. We hypothesized that just testing for COVID-19 could act as an effective stressor for persisting symptoms of mental distress including posttraumatic stress disorder. Our study aimed to determine whether personal beliefs on individual control and competence (locus of control, LoC) correlate with symptoms of mental distress and positive screening for post-traumatic stress disorder during a 9-month observational period. Methods: Between March and December 2021, we applied online versions of the Questionnaire on Competence and Control Expectations (FKK), the Depression, Anxiety, and Stress Score (DASS), the Short Screening Scale for DSM-IV Posttraumatic Stress Disorder (PTSD), and a medical history questionnaire for COVID-19 symptoms (visit 1). 48 hours after negative COVID-19 testing, DASS was repeated to address relief effects on mental distress (visit 2). Following 90 days (visit 3), development of mental distress was addressed by a combination of DASS and PTSD, while the possible long-term manifestation of PTSD was evaluated 9 months later (visit 4). Results: At visit 1, 7.4 percent of the total sample (n = 867) demonstrated a positive screening for PTSD, while after nine months (at visit 4), 8.9 percent of the remaining sample (n = 204) had positive screening results. The mean age was 36.2 years; 60.8% were women, 39.2% men. In contrast to individuals with negative PTSD screening, these participants demonstrated a significantly different LoC personality profile. This was confirmed by the results of both DASS and the COVID-19 medical history questionnaire. Conclusion: Following testing for COVID-19, individuals with positive long-term PTSD screening present with significantly different personality traits than those w/o suggesting that self-confidence and effective control over one's own actions serve as a protective function against mental distress.

Immune cell profiles and patient clustering in complex cases of interstitial lung disease.

Interstitial lung disease comprises numerous clinical entities posing significant challenges towards a prompt and accurate diagnosis. Amongst the contributing factors are intricate pathophysiological mechanisms, an overlap between conditions, and interobserver disagreement. We developed a model for patient clustering offering an additional approach to such complex clinical cases. The model is based on surface phenotyping of over 40 markers on immune cells isolated from bronchoalveolar lavage in combination with clinical data. Based on the marker expression pattern we constructed an individual immune cell profile, then merged these to create a global profile encompassing various pathologies. The contribution of each participant to the global profile was assessed through dimensionality reduction tools and the ensuing similarity between samples was calculated. Our model enables two approaches. First, assessing the immune cell population landscape similarity between patients within a diagnostic group allows rapid identification of divergent profiles, which is particularly helpful for cases with uncertain diagnoses. Second, sample clustering is based exclusively on the calculated similarity of the immune cell profiles, thereby removing physician bias and relying on cellular nearest neighbors.