T2-low severe asthma clinical spectrum and impact: The Greek PHOLLOW cross-sectional study

Konstantinos Porpodis¹, Nikolaos Zias², Konstantinos Kostikas³, Argyris Tzouvelekis⁴, Michael Makris⁵, George N Konstantinou⁶, Eleftherios Zervas⁷, Stelios Loukides⁸, Paschalis Steiropoulos⁹, Konstantinos Katsoulis¹⁰, Anastasios Palamidas¹¹, Aikaterini Syrigou¹², Maria Gangadi¹³, Antonios Christopoulos¹⁴, Dimosthenis Papapetrou¹⁵, Fotios Psarros¹⁶, Konstantinos Gourgoulianis¹⁷, Eleni Tzortzaki¹⁸, Stylianos K Vittorakis¹⁹, Ioannis Paraskevopoulos²⁰, Ilias Papanikolaou²¹, Georgios Krommidas²², Dimitrios Latsios²³, Nikolaos Tzanakis²⁴, Miltiadis Markatos²⁵, Angeliki Damianaki²⁶, Argyrios Manikas²⁷, Alexia Chatzipetrou²⁸, Dimitrios Vourdas²⁹, Ioanna Tsiouprou¹, Christina Papista³⁰, Marina Bartsakoulia³⁰, Nikolas Mathioudakis³⁰, Petros Galanakis³⁰, Petros Bakakos³¹

Affiliations

¹ Pulmonary Department, Aristotle University of Thessaloniki, G. Papanikolaou Hospital, Thessaloniki, Greece.
² Respiratory Department, Navy Hospital of Athens, Athens, Greece.
³ Respiratory Medicine Department, School of Medicine, University of Ioannina, Ioannina, Greece.
⁴ Department of Respiratory Medicine, Medical School, University of Patras, Patras, Greece.
⁵ 2nd Department of Dermatology and Venereology, Allergy Unit, Medical School, Attikon University General Hospital, National and Kapodistrian University of Athens, Athens, Greece.
⁶ Department of Allergy and Clinical Immunology, 424 General Military Training Hospital, Thessaloniki, Greece.
⁷ 7th Respiratory Department, Athens Chest Hospital Sotiria, Athens, Greece.
⁸ 2nd Respiratory Department, Medical School, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece.
⁹ Department of Respiratory Medicine, Medical School, University General Hospital, Democritus University of Thrace, Alexandroupolis, Greece.
¹⁰ Pulmonary Department, 424 Army General Hospital, Thessaloniki, Greece.
¹¹ Athens Medical Center-Marousi Clinic, Athens, Greece.
¹² Allergy Department, Sotiria General Hospital, Athens, Greece.
¹³ 10th Department of Pulmonary Medicine, Athens Chest Hospital Sotiria, Athens, Greece.
¹⁴ Department of Respiratory Medicine, University Hospital Patras, Patra, Greece.
¹⁵ Athens Medical Group, Paleo Faliro Clinic, Athens, Greece.
¹⁶ Allergy Department, Athens Naval Hospital, Athens, Greece.
¹⁷ Faculty of Medicine, Department of Respiratory Medicine, University Hospital of Larissa, University of Thessaly, Larissa, Greece.
¹⁸ Outpatient Respiratory Clinic, Heraklion, Greece.
¹⁹ Private Practice, Chania, Greece.
²⁰ 401 General Military Hospital Athens, Athens, Greece.
²¹ Pulmonary Department, Corfu General Hospital, Corfu, Greece.
²² Private Practice, Athens, Greece.
²³ Private Practice, Drama, Greece.
²⁴ Department of Respiratory Medicine, Medical School, University General Hospital of Heraklion, Laboratory of Molecular and Cellular Pneumonology, University of Crete, Heraklion, Greece.
²⁵ Outpatient Clinic for Pulmonary Diseases, Chania, Greece.
²⁶ Pulmonary and Sleep Medical Department, Chania General Hospital Agios Georgios, Chania, Greece.
²⁷ European Interbalkan Medical Center, Thessaloniki, Greece.
²⁸ 2nd Department of Dermatology and Venereology, Allergy Unit, University General Hospital Attikon, National and Kapodistrian University of Athens, Athens, Greece.
²⁹ Department of Allergy and Clinical Immunology, 251 General Airforce Hospital, Athens, Greece.
³⁰ Medical Affairs Department, Respiratory and Immunology, AstraZeneca, Athens, Greece.
³¹ 1st University Department of Respiratory Medicine, National and Kapodistrian University of Athens, Athens, Greece.

PMID: 39887925
PMCID: PMC11779522
DOI: 10.1002/clt2.70035

T2-low severe asthma clinical spectrum and impact: The Greek PHOLLOW cross-sectional study

Konstantinos Porpodis et al. Clin Transl Allergy. 2025 Feb.

. 2025 Feb;15(2):e70035.

doi: 10.1002/clt2.70035.

Authors

Affiliations

¹ Pulmonary Department, Aristotle University of Thessaloniki, G. Papanikolaou Hospital, Thessaloniki, Greece.
² Respiratory Department, Navy Hospital of Athens, Athens, Greece.
³ Respiratory Medicine Department, School of Medicine, University of Ioannina, Ioannina, Greece.
⁴ Department of Respiratory Medicine, Medical School, University of Patras, Patras, Greece.
⁵ 2nd Department of Dermatology and Venereology, Allergy Unit, Medical School, Attikon University General Hospital, National and Kapodistrian University of Athens, Athens, Greece.
⁶ Department of Allergy and Clinical Immunology, 424 General Military Training Hospital, Thessaloniki, Greece.
⁷ 7th Respiratory Department, Athens Chest Hospital Sotiria, Athens, Greece.
⁸ 2nd Respiratory Department, Medical School, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece.
⁹ Department of Respiratory Medicine, Medical School, University General Hospital, Democritus University of Thrace, Alexandroupolis, Greece.
¹⁰ Pulmonary Department, 424 Army General Hospital, Thessaloniki, Greece.
¹¹ Athens Medical Center-Marousi Clinic, Athens, Greece.
¹² Allergy Department, Sotiria General Hospital, Athens, Greece.
¹³ 10th Department of Pulmonary Medicine, Athens Chest Hospital Sotiria, Athens, Greece.
¹⁴ Department of Respiratory Medicine, University Hospital Patras, Patra, Greece.
¹⁵ Athens Medical Group, Paleo Faliro Clinic, Athens, Greece.
¹⁶ Allergy Department, Athens Naval Hospital, Athens, Greece.
¹⁷ Faculty of Medicine, Department of Respiratory Medicine, University Hospital of Larissa, University of Thessaly, Larissa, Greece.
¹⁸ Outpatient Respiratory Clinic, Heraklion, Greece.
¹⁹ Private Practice, Chania, Greece.
²⁰ 401 General Military Hospital Athens, Athens, Greece.
²¹ Pulmonary Department, Corfu General Hospital, Corfu, Greece.
²² Private Practice, Athens, Greece.
²³ Private Practice, Drama, Greece.
²⁴ Department of Respiratory Medicine, Medical School, University General Hospital of Heraklion, Laboratory of Molecular and Cellular Pneumonology, University of Crete, Heraklion, Greece.
²⁵ Outpatient Clinic for Pulmonary Diseases, Chania, Greece.
²⁶ Pulmonary and Sleep Medical Department, Chania General Hospital Agios Georgios, Chania, Greece.
²⁷ European Interbalkan Medical Center, Thessaloniki, Greece.
²⁸ 2nd Department of Dermatology and Venereology, Allergy Unit, University General Hospital Attikon, National and Kapodistrian University of Athens, Athens, Greece.
²⁹ Department of Allergy and Clinical Immunology, 251 General Airforce Hospital, Athens, Greece.
³⁰ Medical Affairs Department, Respiratory and Immunology, AstraZeneca, Athens, Greece.
³¹ 1st University Department of Respiratory Medicine, National and Kapodistrian University of Athens, Athens, Greece.

PMID: 39887925
PMCID: PMC11779522
DOI: 10.1002/clt2.70035

Abstract

Background: Data on type 2 (T2)-low severe asthma (SA) frequency is scarce, resulting in an undefined unmet therapeutic need in this patient population. Our objective was to assess the frequency and characterize the profile and burden of T2-low SA in Greece.

Methods: PHOLLOW was a cross-sectional study of adult SA patients. Based on a novel proposed classification system, patients were classified as T2-low if blood eosinophil count (BEC; cells/μL) was <150, fractional exhaled nitric oxide (FeNO) < 25 ppb and any allergy status or BEC < 150/FeNO < 50 ppb/no allergy or BEC < 300/FeNO < 25 ppb/no allergy. For patients receiving biologics and/or oral corticosteroids, only those with BEC < 150/FeNO < 25 ppb/no allergy/no response to therapy were classified as T2-low. Secondary outcome measures were: Asthma Control Test (ACT^TM), Mini-Asthma Quality of Life Questionnaire (Mini-AQLQ), hospital anxiety and depression scale (HADS), and Work Productivity and Activity Impairment:Respiratory Symptoms (WPAI:RS) questionnaire.

Results: From 22-Mar-2022 to 15-Mar-2023, 602 eligible SA patients were enrolled. The frequency of T2-low asthma was 20.1%. Of those, 71.1% had experienced ≥1 clinically significant exacerbations in the past year, 62.8% had ACT score <20 (uncontrolled asthma), and 22.3% were biologic-treated. Mini-AQLQ score was <6 (impairment) in 79.5% of patients, HADS-total score was ≥15 (clinically significant emotional distress) in 43.8%, while median percent activity impairment and work productivity loss were 30.0 for both domains. Clinical and patient-reported outcomes were worse among patients with ACT-defined uncontrolled asthma.

Conclusions: One-fifth of SA patients present with a T2-low endotype. These patients frequently have uncontrolled disease and experience impairments in their quality of life, emotions and work ability.

Keywords: clinically significant exacerbations; quality of life; real‐world; symptom control; treatment patterns.

PubMed Disclaimer

Conflict of interest statement

K. Porpodis has received grants or contracts from Boehringer Ingelheim, Menarini, AstraZeneca, GSK, Elpen and Pfizer; consulting fees from Boehringer Ingelheim, Menarini, AstraZeneca, GSK, Elpen and Pfizer; payment or honoraria from Boehringer Ingelheim, Menarini, AstraZeneca, GSK, Elpen and Pfizer; payment for expert testimony from Boehringer Ingelheim, Menarini, AstraZeneca, GSK, Elpen and Pfizer; and support for attending meetings and/or travel from Boehringer Ingelheim, Menarini, AstraZeneca, GSK, Elpen and Pfizer. K. Kostikas has received grants or contracts from AstraZeneca, Boehringer Ingelheim, Chiesi, Innovis, Elpen, GSK, Menarini, Novartis and NuvoAir; has received consulting fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Csl Behring, Elpen, GSK, Menarini, Novartis, Pfizer and Sanofi Genzyme; has received payment or honoraria from Alector Pharmaceuticals, AstraZeneca, Boehringer Ingelheim, Chiesi, Elpen, Gilead, GSK, Menarini, MSD, Novartis, Sanofi Genzyme, Pfizer and WebMD; has participated in Data Safety Monitoring Board or Advisory Board for Chiesi; and is a member of GOLD Assembly. A. Tzouvelekis has received grants or honoraria from Boehringer Ingelheim, Hoffman La Roche, Menarini, AstraZeneca, GSK, Elpen, Pfizer and Bayer (financial support for department); is holder of therapeutic patents “Inhaled or aerosolized delivery of thyroid hormone to the lung as a novel therapeutic agent in fibrotic lung diseases, OCR#6368“ and “Administering Thyroid receptor b‐agonist hormone for preventing or treating a fibrotic lung disease, OCR#20230372275“ both disclosed to Yale University (both outside the submitted work); has received consulting fees from Boehringer Ingelheim, Hoffman La Roche, Menarini, AstraZeneca, GSK, Elpen, Pfizer, Pliant, Puretech, Guidotti and Genentech (outside the submitted work); has received payment or honoraria from Boehringer Ingelheim, Hoffman La Roche, Menarini, AstraZeneca, GSK, Elpen, Pfizer, Bayer, Sobi and Gilead (outside the submitted work); has received payment for expert testimony for Boehringer Ingelheim, Hoffman La Roche, Elpen, Pliant and Puretech (outside the submitted work); and has received support for attending meetings and/or travel from Boehringer Ingelheim, Hoffman La Roche, Menarini, AstraZeneca, GSK, Elpen and Pfizer. M. Makris has received grants or contracts from GSK, Chiesi, Sanofi Aventis, AstraZeneca, Elpen, Pfizer and Abbvie; consulting fees from GSK, Chiesi, Sanofi Aventis, AstraZeneca, Elpen and Pfizer (personal); payment or honoraria from GSK, Chiesi, Sanofi Aventis, AstraZeneca, Elpen, Pfizer, Abbvie and Takeda (personal); and support to attend meetings and/or travel from Chiesi (personal and staff members), Menarini (staff members) and Takeda (personal). G. Konstantinou has received payment or honoraria from AstraZeneca, Chiesi, Menarini, Sanofi, Novartis and Vianex. E. Zervas has received advisory board fees from AstraZeneca, Chiesi, Elpen, GSK, Menarini, MSD and Novartis; has received honoraria and fees for lectures from AstraZeneca, Boehringer Ingelheim, Bristol Myers, Chiesi, Elpen, GSK, Menarini, MSD and Novartis; has received travel accommodations and meeting expenses from AstraZeneca, Chiesi, GSK and Roche; and is treasurer of the Hellenic Thoracic Society. S. Loukides has received a grant from AstraZeneca (support for department); has received payment or honoraria from AstraZeneca, GSK, Menarini, Chiesi and Elpen and has participated in an advisory board for AstraZeneca, GSK, Chiesi and Menarini. P. Steiropoulos has received consulting fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Elpen, GSK, Guidotti and Menarini; payment or honoraria from AstraZeneca, Boehringer Ingelheim, Chiesi, Elpen, GSK, Guidotti, Menarini and Pfizer; and support for attending meetings and/or travel from AstraZeneca, Boehringer Ingelheim, Chiesi, Elpen, GSK, Guidotti, Menarini and Pfizer. K. Katsoulis has received payment or honoraria from GSK and support for attending meetings and/or travel from Menarini Hellas. E. Syrigou has received payment or honoraria from AstraZeneca and Menarini. M. Gangadi has received support to attend meetings and/or travel from AstraZeneca and Chiesi. A. Christopoulos has received honoraria for lectures and educational events from GSK, AstraZeneca, Menarini and Chiesi, and support for attending scientific meetings from GSK and Menarini. D. Papapetrou has received consulting fees from AstraZeneca, Menarini, Roche and GSK; payment or honoraria from AstraZeneca and Menarini and support for attending meetings and/or travel from Menarini, Elpen, Chiesi, Guidotti, AstraZeneca, Novartis, Lilly, Boehringer Ingelheim, Faran and Bayer. E. Tzortzaki has received grants or contracts from AstraZeneca, Chiesi, GSk, Elpen and Menarini (private practice), payment or honoraria from AstraZeneca, Chiesi, GSK, Elpen and Menarini (private practice); and support for attending meetings and/or travel from AstraZeneca and GSK. I. Papanikolaou has received grants or contracts from Boehringer Ingelheim, Elpen, GSK, AstraZeneca and Menarini (for institution), payment or honoraria from Boehringer Ingelheim, GSK and AstraZeneca, and support for attending meetings and/or travel from Chiesi, Boehringer Ingelheim and AstraZeneca. G. Kromidas has received support from AstraZeneca (personal). D. Latsios has received consulting fees from Chiesi, GSK, Menarini, payment or honoraria from Chiesi, Elpen, GSK, Menarini and AstraZeneca, and support for attending meetings and/or travel from Menarini and Boehringer Ingelheim. N. Tzanakis has received consulting fees from AstraZeneca, Chiesi, GSK, Guidotti, Menarini, Boehringer Ingelheim, Special Therapeutics, Pfizer and Gilead; payment or honoraria from AstraZeneca, Chiesi, GSK, Guidotti, Menarini, Boehringer Ingelheim, Special Therapeutics and Pfizer; and support for attending meetings and/or travel from AstraZeneca, Chiesi, GSK, Guidotti, Menarini, Boehringer Ingelheim, Special Therapeutics and Pfizer. M. Markatos has received consulting fees from AstraZeneca, Chiesi, GSk, Guidotti and Menarini, payment or honoraria from AstraZeneca, Chiesi, Elpen, GSK Guidotti and Menarini and support for attending meetings and/or travel from AstraZeneca, Chiesi, Elpen, GSK, Guidotti and Menarini. A. Damianaki has received a FeNO counter from AstraZeneca; grants or contracts from Chiesi; support to attend meetings and/or travel from Chiesi, Guidotti, AstraZeneca, Elpen, Menarini and Viatris; and sleep recorders for sleep lab from Menarini. A. Chatzipetrou has received payment or honoraria from GSK, Pfizer, Sanofi Aventis and AstraZeneca and support for attending meetings and/or travel from Sanofi, Vianex and Pfizer. C. Papista, M. Bartsakoulia, N. Mathioudakis, and P. Galanakis are employees of AstraZeneca Greece. P. Bakakos has received consulting fees from GSK, Menarini, Elpen, AstraZeneca, Pfizer, Vianex and MSD and payment or honoraria from AstraZeneca, Chiesi, Elpen, Menarini, Gilead, GSK and Pfizer. The rest of the authors declare that they have no relevant conflicts of interest.

Figures

**FIGURE 1**
Frequency of T2‐low SA based on the composite scoring system for SA phenotype classification. Patient distribution per (A) score and (B) cumulative score, in the subpopulations per current receipt of biologic and/or OCS treatment. *Defined as fulfillment of at least 2 of the following: Total Immunoglobulin E ≥ 100 IU/mL; skin prick test positivity; Early‐onset asthma (<18 years old). BEC, blood eosinophil count; FeNO, fractional exhaled nitric oxide; mOCS, maintenance oral corticosteroids; n, number of patients with variable; N, number of patients with available data; SA, severe asthma; T2, type‐2.

**FIGURE 2**
Eligible patient disposition by SA phenotype, treatment with biologics and/or mOCS, type of healthcare institution and site location. mOCS, maintenance oral corticosteroids; n, number of patients with variable; N, number of patients with available data; SA, severe asthma; T2, type‐2.

**FIGURE 3**
CSEs in the overall T2‐low SA population, its subpopulations by ACT‐based asthma control level, and the T2‐high SA population (A, B). Association through multivariable logistic regression models of factors of interest with (C) T2‐low SA phenotype, and (D) ACT score in the T2‐low SA population. *CSEs are defined as a worsening of asthma symptoms that required any of the following: (a) treatment with systemic corticosteroids for at least 3 days; (b) an increase of the maintenance dose of oral corticosteroids for at least 3 days or a single depo‐injectable dose of corticosteroids; (c) an emergency department visit that required use of systemic corticosteroids; (d) hospitalization. †The modeled probability was T2‐low SA phenotype: “Yes” versus “No”. The following variables were entered in the initial step of the stepwise procedure: Patient's age at study visit (≤65 vs. > 65), Patient's age at asthma symptom onset (≤18 vs. > 18), Patient's age at SA diagnosis (continuous), BMI (kg/m²) (<30 vs. ≥ 30), Number of CSEs in the previous 12 months (0 vs. ≥ 1), Place of residence, Sex, Smoking status (Former smokers with ≥10 pack‐years vs. Other). The type of institution and administrative region were *not* identified as confounders based on multivariable analyses (data not shown). Hosmer‐Lemeshow p‐value = 0.2373 (at α = 0.05 we fail to reject the hypothesis that the data fit the model, therefore we conclude that the model provides adequate fit). ^‡The modeled probability was ‘ACT ≥ 20 Controlled’ versus ‘ACT < 20 Uncontrolled’. The following variables were entered in the initial step of the stepwise procedure: Patient's age at study visit (continuous), Patient's age at asthma symptoms (continuous), BMI (kg/m2) (continuous), Number of CSEs in the previous 12 months (continuous), Place of residence, Sex, Nasal polyposis, Allergic rhinitis, Adherence to asthma treatment and correct inhaler technique, Current receipt of biologic treatment, HADS total score (≥15 vs. < 15), FEV1, BEC (cells/μL) (continuous), IgE (IU/mL) (<150 vs. other). The following covariates were not included in the analysis due to quasi/complete separation issues and/or extremely unbalanced groups: Number of CSEs in the previous 12 months (≤2 vs. > 2 or ≤3 vs. > 3) and Current receipt of mOCS treatment (Yes vs. No). Type of institution and administrative region were identified as *confounders* based on multivariable analyses (data not shown), thus were excluded from the stepwise process, and forced in the final model. Hosmer‐Lemeshow p‐value = 0.99 (at α = 0.05 we fail to reject the hypothesis that the data fit the model, therefore we conclude that the model provides adequate fit). ACT, asthma control test; BMI, body mass index; CI, confidence interval; CSE, clinically significant exacerbation; FEV₁, forced‐expiratory volume in 1 s; HADS, hospital anxiety and depression scale; n _CSEs, number of clinically significant exacerbations; n _pts, number of patients; N, number of patients with available data; OR, odds ratio; SA, severe asthma; SD, standard deviation; T2, type‐2.

**FIGURE 4**
Current management strategies in the overall T2‐low SA population, its subpopulations by ACT‐based asthma control level, and the T2‐high SA population. *Macrolide antibiotic was used in 1 (0.2%) T2‐high patient. †Excluding LTRA, NCS, SABA, and SAMA. ACT, asthma control test; ICS, inhaled corticosteroids; IgE, immunoglobulin E; IL, interleukin; IL‐5R, interleukin‐5 receptor; LABA, long‐acting beta agonist; LAMA, long‐acting muscarinic antagonist; LTRA, leukotriene receptor antagonist; N, number of patients with available data; NCS, nasal corticosteroids; OCS, oral corticosteroids; SA, severe asthma; SABA, short‐acting β‐agonist; SAMA, short‐acting muscarinic antagonist; T2, type‐2.

**FIGURE 5**
Asthma‐specific QoL at the study visit, in the overall T2‐low SA and its subpopulations by ACT‐based asthma control level. Box‐plots depict median with IQR, including whiskers that extend from minimum to maximum values. ACT, asthma control test; AQLQ, asthma quality of life questionnaire; IQR, interquartile range; N, number of patients with available data; QoL, quality of life; SA, severe asthma; SD, standard deviation; T2, type‐2.

See this image and copyright information in PMC

References

1. Momtazmanesh S, Moghaddam SS, Ghamari SH, et al. Global burden of chronic respiratory diseases and risk factors, 1990‐2019: an update from the Global Burden of Disease Study 2019. EClinicalMedicine. 2023;59:101936. 10.1016/j.eclinm.2023.101936 - DOI - PMC - PubMed
1. Kourlaba G, Bakakos P, Loukides S, Vellopoulou K, Solakidi A, Maniadakis N. The self‐reported prevalence and disease burden of asthma in Greece. J Asthma. 2019;56(5):478‐497. 10.1080/02770903.2018.1471704 - DOI - PubMed
1. Chung KF, Wenzel SE, Brozek JL, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J. 2014;43(2):343‐373. 10.1183/09031936.00202013 - DOI - PubMed
1. Hekking PW, Wener RR, Amelink M, Zwinderman AH, Bouvy ML, Bel EH. The prevalence of severe refractory asthma. J Allergy Clin Immunol. 2015;135(4):896‐902. 10.1016/j.jaci.2014.08.042 - DOI - PubMed
1. von Bülow A, Kriegbaum M, Backer V, Porsbjerg C. The prevalence of severe asthma and low asthma control among Danish adults. J Allergy Clin Immunol Pract. 2014;2(6):759‐767. 10.1016/j.jaip.2014.05.005 - DOI - PubMed

Grants and funding

AstraZeneca S.A. Greece

LinkOut - more resources

Full Text Sources
Miscellaneous
- NCI CPTAC Assay Portal

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

T2-low severe asthma clinical spectrum and impact: The Greek PHOLLOW cross-sectional study

Affiliations

T2-low severe asthma clinical spectrum and impact: The Greek PHOLLOW cross-sectional study

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Grants and funding

LinkOut - more resources

Full Text Sources

Miscellaneous