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An Update on the Diagnostic, Predictive and Prognostic Biomarkers of Respiratory Diseases

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A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Pulmonology".

Deadline for manuscript submissions: 31 May 2024 | Viewed by 22201

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Prof. Andrei Malinovschi

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Guest Editor

Department of Medical Sciences, Clinical Physiology, Uppsala University, Uppsala, Sweden
Interests: asthma; chronic obstructive pulmonary disease; exacerbation; prognosis; biomarkers; exhaled breath; diagnosis; pulmonary function testing

Prof. Dr. Wojciech Piotrowski

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Guest Editor

Department of Pneumology, Medical University of Lodz, Lodz, Poland
Interests: idiopathic pulmonary fibrosis; hypersensitivity pneumonitis; interstitial lung disease; sarcoidosis

Special Issue Information

Dear Colleagues,

Respiratory diseases have become the leading cause of morbidity and mortality worldwide. Many chronic respiratory disorders have a progressive course, leading to irreversible changes in the respiratory system structure. Moreover, differentiation between specific clinical entities is frequently problematic, and in many patients, different disease states may overlap. The respiratory system may be only one of several body organs involved in systemic nature diseases. Phenotyping the disease, identifying suitable candidates for specific therapies and identiyfing indviduals at risk of exacerbation or poor outcome are often challenging, despite the real progress in imaging, laboratory, and other diagnostic techniques. Biomarkers have attracted researchers in the field of respiratory medicine for decades, but only a few of them have entered everyday practice and became standard procedures so far. Exhaled nitric oxide as an aid in diagnosing and monitoring asthma and the effect of treatment, blood eosinopils for treatment with anti-IL-5 in severe asthma or the recently proposed role on blood eosinophils in the ICS treatment decision-making in COPD patients are such examples. There are still many doubts about prognostic markers of lung fibrosis. Many unresolved issues considering sensitivity and specificity are unresolved. A tempting idea of using exhaled breath (condensate, volatile organic compounds, particles in exhaled air) for measurements of different substances with diagnostic or prognostic potential has been explored for many years, but results are frequently ambiguous. Researchers face many problems, and many questions are still unanswered, but the advantages of using biomarkers in diagnosis, differentiation, activity assessment, and prognostication in respiratory diseases could not be overestimated. The work in this field should go on. This special issue of JCM, devoted to an update of biomarkers’ role in phenotyping, treatment response and prognosis in respiratory diseases, may help organize and summarize this vast and heterogeneous knowledge with the hope of changing perspectives.

Prof. Andrei Malinovschi
Prof. Wojciech Piotrowski
Guest Editors

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Keywords

respiratory diseases
biomarkers
diagnosis
prognosis
activity monitoring
phenotypes
treatment response
exhaled breath

Published Papers (10 papers)

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Research

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20 pages, 1239 KiB

Open AccessArticle

Reliability of Total Serum IgE Levels to Define Type 2 High and Low Asthma Phenotypes

by Giuseppe Guida, Francesca Bertolini, Vitina Carriero, Stefano Levra, Andrea Elio Sprio, Martina Sciolla, Giulia Orpheu, Elisa Arrigo, Stefano Pizzimenti, Giorgio Ciprandi and Fabio Luigi Massimo Ricciardolo

J. Clin. Med. 2023, 12(17), 5447; https://doi.org/10.3390/jcm12175447 - 22 Aug 2023

Cited by 1 | Viewed by 2232

Abstract

Background: High total IgE levels are weak predictors of T2_High and have been reported in nonallergic asthma. Therefore, the role of total serum IgE (IgE) in the T2_High phenotype is still debated. Objective: This study investigated the reliability of stratifying asthmatics into IgE_High and IgE_Low within the T2_High and T2_Low phenotypes. Methods: This cross-sectional single-center study investigated the association of clinical, functional, and bio-humoral parameters in a large asthmatic population stratified by IgE ≥ 100 kU/L, allergen sensitization, B-EOS ≥ 300/µL, and F_ENO ≥ 30 ppb. Results: Combining T2 biomarkers and IgE identifies (1) T2_Low-IgE_Low (15.5%); (2) T2_Low-IgE_High (5.1%); (3) T2_High-IgE_Low (33.6%); and T2_High-IgE_High (45.7%). T2_Low-IgE_Low patients have more frequent cardiovascular and metabolic comorbidities, a higher prevalence of emphysema, and higher LAMA use than the two T2_High subgroups. Higher exacerbation rates, rhinitis, and anxiety/depression syndrome characterize the T2_Low-IgE_High phenotype vs. the T2_Low-IgE_Low phenotype. Within the T2_High, low IgE was associated with female sex, obesity, and anxiety/depression. Conclusions: High IgE in T2_Low patients is associated with a peculiar clinical phenotype, similar to T2_High in terms of disease severity and nasal comorbidities, while retaining the T2_Low features. IgE may represent an additional biomarker for clustering asthma in both T2_High and T2_Low phenotypes rather than a predictor of T2_High asthma “per se”. Full article

(This article belongs to the Special Issue An Update on the Diagnostic, Predictive and Prognostic Biomarkers of Respiratory Diseases)

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12 pages, 3008 KiB

Open AccessArticle

Oxidative Biomarkers Associated with the Pulmonary Manifestation of Post-COVID-19 Complications

by Kamil Siekacz, Anna Kumor-Kisielewska, Joanna Miłkowska-Dymanowska, Małgorzata Pietrusińska, Krystian Bartczak, Sebastian Majewski, Adam Stańczyk, Wojciech J. Piotrowski and Adam J. Białas

J. Clin. Med. 2023, 12(13), 4253; https://doi.org/10.3390/jcm12134253 - 25 Jun 2023

Cited by 3 | Viewed by 1228

Abstract

Introduction: The role of mitochondria in post coronavirus disease 2019 (post-COVID-19) complications is unclear, especially in the long-term pulmonary complications. This study aims to investigate the association between post-COVID-19 pulmonary complications and mitochondrial regulatory proteins in the context of oxidative stress. Methodology: Patients who had recovered from COVID-19 were enrolled. According to the evidence of persistent interstitial lung lesions on computed tomography (CT), patients were divided into a long-term pulmonary complications group (P(+)) and a control group without long-term pulmonary complications (P(−)). We randomly selected 80 patients for investigation (40 subjects for each group). Biomarkers levels were determined by enzyme-linked immunosorbent assay (ELISA). Results: The serum concentrations of mitochondrial regulatory proteins were significantly higher in the P(+) group, including PTEN-induced kinase 1 (PINK1): 1.62 [1.02–2.29] ng/mL vs. 1.34 [0.94–1.74] ng/mL (p = 0.046); Dynamin-1-like protein (DNM1L): 1.6 [0.9–2.4] ng/mL IQR vs. 0.9 [0.5–1.6] ng/mL (p = 0.004); and Mitofusin-2 (MFN2): 0.3 [0.2–0.5] ng/mL vs. 0.2 [0.1–0.3] ng/mL IQR (p = 0.001). Patients from the P(+) group also had higher serum levels of chemokine ligand 18 (PARC, CCL18), IL-6, and tumour necrosis factor-alpha (TNF-α) cytokines than the P(−) group. The concentration of interferon alpha (IFN-α) was decreased in the P(+) group. Furthermore, we observed statistically significant correlations between the advanced glycation end product (sRAGE) and TNF-α (Pearson’s factor R = 0.637; p < 0.001) and between serum levels of DNM1L and IFN-α (Pearson’s factor R = 0.501; p = 0.002) in P(+) patients. Conclusions: Elevated concentrations of mitochondrial biomarkers in post-COVID-19 patients with long-term pulmonary complications indicate their possible role in the pathobiology of COVID-19 pulmonary sequelae. Oxidative stress is associated with the immune response and inflammation after COVID-19. TNF-α could be a promising biomarker for predicting pulmonary complications and may be a potential target for therapeutic intervention in patients with post-COVID-19 complications. Full article

(This article belongs to the Special Issue An Update on the Diagnostic, Predictive and Prognostic Biomarkers of Respiratory Diseases)

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13 pages, 870 KiB

Open AccessArticle

IL18 Gene Polymorphism Is Associated with Total IgE in Adult Subjects with Asthma

by Valentina Lando, Lucia Calciano, Cosetta Minelli, Cristina Bombieri, Marcello Ferrari, Giovanni Malerba, Antonino Margagliotti, Nicola Murgia, Morena Nicolis, Mario Olivieri, James Potts, Stefano Tardivo and Simone Accordini

J. Clin. Med. 2023, 12(12), 3963; https://doi.org/10.3390/jcm12123963 - 10 Jun 2023

Cited by 1 | Viewed by 1378

Abstract

The allergic asthma phenotype is characterized by a T helper type 2 (Th2) immune response, based on Immunoglobulin E (IgE)-mediated type 1 hypersensitivity reactions. Total IgE is the sum of all IgE types produced by the human body and is used as a biomarker of inflammation in asthma. We analysed data collected in 143 asthma cases (median age 42.1 years) from the general Italian population (GEIRD survey; 2008–2010) to identify single nucleotide polymorphisms (SNPs) in candidate genes that are associated with total IgE in adult subjects with asthma. These patients reported respiratory symptoms in response to perennial allergens and provided data on 166 SNPs tagging 50 candidate genes or gene regions. Replication of the statistically significant results was performed in 842 asthma cases from other European countries (ECRHS II survey; 1998–2002). SNP rs549908 in interleukin 18 (IL18) gene was significantly associated with total IgE in GEIRD, and this result was replicated in ECRHS II. SNP rs1063320 in the human leukocyte antigen G (HLA-G) gene was identified in GEIRD, but this association was not replicated in ECRHS II. Further investigating IL18 and its biological pathways could be important for developing new therapeutic targets, due to its involvement in inflammatory response processes. Full article

(This article belongs to the Special Issue An Update on the Diagnostic, Predictive and Prognostic Biomarkers of Respiratory Diseases)

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17 pages, 2070 KiB

Open AccessArticle

Clustering Analysis Identified Three Long COVID Phenotypes and Their Association with General Health Status and Working Ability

by Marta A. Kisiel, Seika Lee, Sara Malmquist, Oliver Rykatkin, Sebastian Holgert, Helena Janols, Christer Janson and Xingwu Zhou

J. Clin. Med. 2023, 12(11), 3617; https://doi.org/10.3390/jcm12113617 - 23 May 2023

Cited by 4 | Viewed by 1780

Abstract

Background/aim: This study aimed to distinguish different phenotypes of long COVID through the post-COVID syndrome (PCS) score based on long-term persistent symptoms following COVID-19 and evaluate whether these symptoms affect general health and work ability. In addition, the study identified predictors for severe long COVID. Method: This cluster analysis included cross-sectional data from three cohorts of patients after COVID-19: non-hospitalized (n = 401), hospitalized (n = 98) and those enrolled at the post-COVID outpatient’s clinic (n = 85). All the subjects responded to the survey on persistent long-term symptoms and sociodemographic and clinical factors. K-Means cluster analysis and ordinal logistic regression were used to create PCS scores that were used to distinguish patients’ phenotypes. Results: 506 patients with complete data on persistent symptoms were divided into three distinct phenotypes: none/mild (59%), moderate (22%) and severe (19%). The patients with severe phenotype, with the predominating symptoms were fatigue, cognitive impairment and depression, had the most reduced general health status and work ability. Smoking, snuff, body mass index (BMI), diabetes, chronic pain and symptom severity at COVID-19 onset were factors predicting severe phenotype. Conclusion: This study suggested three phenotypes of long COVID, where the most severe was associated with the highest impact on general health status and working ability. This knowledge on long COVID phenotypes could be used by clinicians to support their medical decisions regarding prioritizing and more detailed follow-up of some patient groups. Full article

(This article belongs to the Special Issue An Update on the Diagnostic, Predictive and Prognostic Biomarkers of Respiratory Diseases)

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10 pages, 3164 KiB

Open AccessArticle

Soluble ITGaM and ITGb2 Integrin Subunits Are Involved in Long-Term Pulmonary Complications after COVID-19 Infection

J. Clin. Med. 2023, 12(1), 342; https://doi.org/10.3390/jcm12010342 - 01 Jan 2023

Cited by 4 | Viewed by 1991

Abstract

(1) Introduction: The role of soluble integrins in post-COVID-19 complications is unclear, especially in long-term pulmonary lesions. The purpose of this study was to investigate the association between soluble ITGa2, ITGaM and ITGb2 integrin subunits and long COVID-19 pulmonary complications. (2) Methodology: Post-COVID-19 patients were enrolled. According to the evidence of persistent interstitial lung lesions on CT, patients were divided into a long-term pulmonary complications group (P(+)) and a control group without long-term pulmonary complications (P(−)). We randomly selected 80 patients for further investigation (40 subjects for each group). Levels of ITGa2, ITGaM and ITGb2 integrin subunits were determined by ELISA assay. (3) Results: The serum concentration of sITGaM and sITGb2 were significantly higher in the P(+) group (sITGaM 18.63 ng/mL [IQR 14.17–28.83] vs. 14.75 ng/mL [IQR 10.91–20] p = 0.01 and sITGb2 10.55 ng/mL [IQR 6.53–15.83] vs. 6.34 ng/mL [IQR 4.98-9.68] p = 0.002). We observed a statistically significant correlation between sITGaM and sITGb2 elevation in the P(+) group (R = 0.42; p = 0.01). Patients from the P(+) group had a lower (1.82 +/−0.84 G/L) lymphocyte level than the P(−)group (2.28 +/−0.79 G/L), p = 0.03. Furthermore, we observed an inverse correlation in the P(−) group between blood lymphocyte count and sITGb2 integrin subunit levels (R = −0.49 p = 0.01). (4) Conclusions: Elevated concentrations of sITGaM and sITGb2 were associated with long-term pulmonary complications in post-COVID-19 patients. Both sITGaM and sITGb2 may be promising biomarkers for predicting pulmonary complications and could be a potential target for therapeutic intervention in post-COVID-19 patients. Full article

(This article belongs to the Special Issue An Update on the Diagnostic, Predictive and Prognostic Biomarkers of Respiratory Diseases)

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12 pages, 1599 KiB

Open AccessArticle

Dynamic Perfluorinated Gas MRI Shows Improved Lung Ventilation in People with Cystic Fibrosis after Elexacaftor/Tezacaftor/Ivacaftor: An Observational Study

by Jennifer L. Goralski, Sang Hun Chung, Agathe S. Ceppe, Margret Z. Powell, Muthu Sakthivel, Brian D. Handly, Yueh Z. Lee and Scott H. Donaldson

J. Clin. Med. 2022, 11(20), 6160; https://doi.org/10.3390/jcm11206160 - 19 Oct 2022

Cited by 7 | Viewed by 1634

Abstract

The availability of highly effective CFTR modulators is revolutionizing the treatment of cystic fibrosis (CF) and drastically improving outcomes. MRI-based imaging modalities are now emerging as highly sensitive endpoints, particularly in the setting of mild lung disease. Adult CF patients were recruited from a single center prior to starting treatment with E/T/I. The following studies were obtained before and after one month on treatment: spirometry, multiple breath nitrogen washout (MBW), ¹H UTE MRI (structural images) and ¹⁹F MRI (ventilation images). Changes between visits were calculated, as were correlations between FEV₁, lung clearance index (LCI), MRI structural scores, and MRI-based ventilation descriptors. Eight subjects had complete datasets for evaluation. Consistent with prior clinical trials, FEV₁ and LCI improved after 28 days of E/T/I use. ¹H UTE MRI detected improvements in bronchiectasis/airway wall thickening score and mucus plugging score after 28 days of therapy. ¹⁹F MRI demonstrated improvements in fractional lung volume with slow gas washout time (FLV↑tau2) and ventilation defect percentage (VDP). Improvements in FLV↑tau2 and VDP correlated with improvement in FEV₁ (r = 0.81 and 0.86, respectively, p < 0.05). This observational study establishes the ability of ¹⁹F MRI and ¹H UTE MRI to detect improvements in lung structure and function after E/T/I treatment. This study supports further development of ¹⁹F MRI and ¹H UTE MRI as outcome measures for cystic fibrosis research and drug development. Full article

(This article belongs to the Special Issue An Update on the Diagnostic, Predictive and Prognostic Biomarkers of Respiratory Diseases)

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23 pages, 1721 KiB

Open AccessArticle

Serial Measurements of Circulating KL-6, SP-D, MMP-7, CA19-9, CA-125, CCL18, and Periostin in Patients with Idiopathic Pulmonary Fibrosis Receiving Antifibrotic Therapy: An Exploratory Study

by Sebastian Majewski, Karolina Szewczyk, Aleksandra Żal, Adam J. Białas, Joanna Miłkowska-Dymanowska and Wojciech J. Piotrowski

J. Clin. Med. 2021, 10(17), 3864; https://doi.org/10.3390/jcm10173864 - 28 Aug 2021

Cited by 13 | Viewed by 2602

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive and inevitably fatal disease with a heterogeneous clinical course. This study aimed to evaluate the usefulness of circulating biomarkers in routine IPF clinical practice. We conducted an exploratory study in a cohort of 28 IPF subjects qualified for anti-fibrotic therapy with up to 24 months serial measurements of seven IPF biomarkers, including those that are well-established, Krebs von den Lungen-6 (KL-6), surfactant protein D (SP-D), matrix metalloproteinase 7 (MMP-7), and more recently introduced ones, cancer antigen 19-9 (CA19-9), cancer antigen 125 (CA-125), chemokine (C-C motif) ligand 18 (CCL18), and periostin. Among studied biomarkers, SP-D had the highest diagnostic accuracy to differentiate IPF subjects from controls, followed by MMP-7 and KL-6. At each study timepoint, KL-6 levels correlated inversely with forced vital capacity % predicted (FVC% pred.), and transfer factor of the lung for carbon monoxide % predicted (T_L,CO% pred.), while SP-D levels correlated inversely with FVC% pred. and T_L,CO% pred. at 24 months of anti-fibrotic therapy. Baseline KL-6 and CA19-9 concentrations were significantly elevated in patients with progressive disease in comparison to patients with stable disease. In addition, in the progressors subgroup CA19-9 concentrations significantly increased over the second year of study follow-up. In patients with progressive disease, we observed a significant inverse correlation between a change in SP-D levels and a change in FVC% pred. in the first year of treatment, whereas in the second year a significant inverse correlation between a change in KL-6 levels and a change in FVC% pred. was noted. Our study findings support the view that both well-established IPF biomarkers, including KL-6, SP-D, and MMP-7, and more recently introduced ones, like CA19-9, have the potential to support clinical practice in IPF. Full article

(This article belongs to the Special Issue An Update on the Diagnostic, Predictive and Prognostic Biomarkers of Respiratory Diseases)

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11 pages, 3099 KiB

Open AccessReview

Review: Serum Biomarkers of Lung Fibrosis in Interstitial Pneumonia with Autoimmune Features—What Do We Already Know?

by Ewa Miądlikowska, Patrycja Rzepka-Wrona, Joanna Miłkowska-Dymanowska, Adam Jerzy Białas and Wojciech Jerzy Piotrowski

J. Clin. Med. 2022, 11(1), 79; https://doi.org/10.3390/jcm11010079 - 24 Dec 2021

Cited by 11 | Viewed by 3790

Abstract

Interstitial pneumonia with autoimmune features (IPAF) belongs to a group of diseases called interstitial lung diseases (ILDs), which are disorders of a varied prognosis and course. Finding sufficiently specific and sensitive biomarkers would enable the progression to be predicted, the natural history to be monitored and patients to be stratified according to their treatment. To assess the significance of pulmonary fibrosis biomarkers studied thus far, we searched the PubMed, Medline and Cochrane Library databases for papers published between January 2015 and June 2021. We focused on circulating biomarkers. A primary review of the databases identified 38 articles of potential interest. Overall, seven articles fulfilled the inclusion criteria. This review aims to assess the diagnostic and prognostic value of molecules such as KL-6, SP-A, SP-D, circulating fibrocytes, CCL2, CXCL13, CXCL9, CXCL10 and CXCL11. All of these biomarkers have previously been studied in idiopathic pulmonary fibrosis (IPF) and connective tissue disease-associated interstitial lung disease (CTD-ILD). IPAF is a disorder of a heterogeneous nature. It explains the lack of coherent observations in terms of correlations with functional parameters. There is still no meta-analysis of pulmonary fibrosis biomarkers in IPAF. This is mainly due to the heterogeneity of the methodology and groups analysed in the research. More research in this area is needed. Full article

(This article belongs to the Special Issue An Update on the Diagnostic, Predictive and Prognostic Biomarkers of Respiratory Diseases)

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Other

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17 pages, 705 KiB

Open AccessSystematic Review

A Systematic Review of the Prognostic Significance of the Body Mass Index in Idiopathic Pulmonary Fibrosis

by Angelo Zinellu, Ciriaco Carru, Pietro Pirina, Alessandro G. Fois and Arduino A. Mangoni

J. Clin. Med. 2023, 12(2), 498; https://doi.org/10.3390/jcm12020498 - 07 Jan 2023

Cited by 4 | Viewed by 2066

Abstract

The identification of novel prognostic biomarkers might enhance individualized management strategies in patients with idiopathic pulmonary fibrosis (IPF). Although several patient characteristics are currently used to predict outcomes, the prognostic significance of the body mass index (BMI), a surrogate measure of excess fat mass, has not been specifically investigated until recently. We systematically searched PubMed, Web of Science, and Scopus, from inception to July 2022, for studies investigating associations between the BMI and clinical endpoints in IPF. The Joanna Briggs Institute Critical Appraisal Checklist was used to assess the risk of bias. The PRISMA 2020 statement on the reporting of systematic reviews was followed. Thirty-six studies were identified (9958 IPF patients, low risk of bias in 20), of which 26 were published over the last five years. Significant associations between lower BMI values and adverse outcomes were reported in 10 out of 21 studies on mortality, four out of six studies on disease progression or hospitalization, and two out of three studies on nintedanib tolerability. In contrast, 10 out of 11 studies did not report any significant association between the BMI and disease exacerbation. Our systematic review suggests that the BMI might be useful to predict mortality, disease progression, hospitalization, and treatment-related toxicity in IPF (PROSPERO registration number: CRD42022353363). Full article

(This article belongs to the Special Issue An Update on the Diagnostic, Predictive and Prognostic Biomarkers of Respiratory Diseases)

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25 pages, 713 KiB

Open AccessSystematic Review

The Emerging Clinical Significance of the Red Cell Distribution Width as a Biomarker in Chronic Obstructive Pulmonary Disease: A Systematic Review

by Angelo Zinellu and Arduino A. Mangoni

J. Clin. Med. 2022, 11(19), 5642; https://doi.org/10.3390/jcm11195642 - 25 Sep 2022

Cited by 11 | Viewed by 2024

Abstract

There is an intense focus on the identification of novel biomarkers of chronic obstructive pulmonary disease (COPD) to enhance clinical decisions in patients with stable disease and acute exacerbations (AECOPD). Though several local (airway) and circulatory inflammatory biomarkers have been proposed, emerging evidence also suggests a potential role for routine haematological parameters, e.g., the red cell distribution width (RDW). We conducted a systematic literature search in PubMed, Web of Science, and Scopus, from inception to April 2022, for articles investigating the diagnostic and prognostic role of the RDW in stable COPD and AECOPD. The risk of bias was assessed using the Joanna Briggs Institute Critical Appraisal Checklist. Significant associations between the RDW and the presence and severity of disease, outcomes (mortality, hospital readmission), and other relevant clinical parameters (right heart failure, pulmonary arterial hypertension) were reported in 13 out of 16 studies in stable COPD (low risk of bias in 11 studies), and 17 out of 21 studies of AECOPD (low risk of bias in 11 studies). Pending further research, our systematic review suggests that the RDW might be useful, singly or in combination with other parameters, for the diagnosis and risk stratification of patients with stable COPD and AECOPD (PROSPERO registration number: CRD42022348304). Full article

(This article belongs to the Special Issue An Update on the Diagnostic, Predictive and Prognostic Biomarkers of Respiratory Diseases)

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