European Respiratory Society
Eosinophilic Lung Diseases

A great deal of knowledge about eosinophilic lung diseases has been gained in the last few years, but unanswered questions concerning eosinophil biology still remain. It is in this context that this Monograph was developed. Broad in scope, the book bases its approach to the management of eosinophilic lung diseases on a fundamental understanding of eosinophil biology in health and disease. State-of-the-art reviews written by world-leading authorities and up-and-coming stars in the field take the reader on a journey through the different eosinophilic lung diseases. This Monograph will ensure the practicing clinician is better equipped to recognise and treat patients with eosinophilia, as well as appreciate the advances coming in the near future.

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  1. Page v
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  4. Page 1
    Steven J. Ackerman (

    Eosinophils participate in a broad range of both normal and pathological processes. Results from both animal models and human studies suggest that eosinophils regulate aspects of normal tissue and organ homeostasis in health, in addition to their more traditionally considered contributions to host defence against parasites (mainly helminths), pathological roles in inflammation, induction of tissue damage and remodelling in eosinophil-associated allergic and other immune-mediated diseases, as well as newly reprised roles in responses to bacterial infection, viruses, and pro- and anti-cancer roles in malignancy and tumour immunology. Eosinophil-targeted therapies, particularly anti-cytokine (IL-5) and anti-receptor (IL-5, IL-13) biological therapies that partially or more fully deplete eosinophils have now been approved as add-on therapies for the treatment of eosinophilic asthma and other eosinophil-associated allergic and hypereosinophilic diseases. However, many unanswered questions remain in eosinophil biology, including a need to more fully understand the impact of eosinophil depletion on human health, disease pathogenesis and long-term safety.

    Cite as: Ackerman SJ. An introduction to eosinophils and their biology. In: Jackson DJ, Wechsler ME, eds. Eosinophilic Lung Diseases (ERS Monograph). Sheffield, European Respiratory Society, 2022; pp. 1–18 [].

  5. Page 19
    Brian D. Kent (

    Pulmonary eosinophilic disorders are a heterogeneous group of diseases, which range in incidence from the very common to the extremely rare, and in severity from asymptomatic to life threatening. They are defined by the presence of airway or parenchymal eosinophilia, often accompanied by peripheral blood eosinophilia. Important causes of pulmonary eosinophilia include asthma, parasitic infection, exposure to drugs or toxins, and autoimmune disorders, but a defined cause is often not identified. Diagnostic approaches and therapeutic approaches are dictated by the clinical presentation and suspected diagnosis, but many pulmonary eosinophilic disorders are highly sensitive to corticosteroid therapy. Advances in understanding of eosinophil biology have led to the development of a family of eosinophil-targeting biological agents, which may facilitate reduced corticosteroid exposure and toxicity. Prognosis is significantly informed by the underlying diagnosis, but most cases of pulmonary eosinophilia have good clinical outcomes if appropriately identified and treated.

    Cite as: Piggott LM, Gill CM, Kent BD. Differential diagnosis of pulmonary eosinophilia. In: Jackson DJ, Wechsler ME, eds. Eosinophilic Lung Diseases (ERS Monograph). Sheffield, European Respiratory Society, 2022; pp. 19–36 [].

  6. Page 37
    Celeste Porsbjerg (

    Biomarkers of eosinophilic inflammation have become increasingly clinically relevant with the advent of targeted biological treatments for severe asthma, but also for guiding the choice of inhaled steroids in the management of COPD. Measuring airway eosinophils in induced sputum is the gold standard for detecting and quantifying eosinophilic airway inflammation, but requires a specific set-up for immediate processing, thus is only available in highly specialised clinics. The blood eosinophil level may be used as a surrogate marker, as well as FENO. Eosinophilic biomarkers may be used for different purposes in the clinical setting: inflammatory phenotyping, predicting future risk of exacerbations, predicting response to treatment, assessing the response to treatment, assessing adherence and adjusting treatment. With the advent of biologics, an increased focus on biomarkers reflecting activation of specific pathways can be expected, such as FENO as a marker of IL-13 activation. Finally, other biomarkers of eosinophilic inflammation may become more relevant in the future, for assessing eosinophilic activation status.

    Cite as: Porsbjerg C, Björnsdóttir U. Biomarkers of eosinophilic inflammation. In: Jackson DJ, Wechsler ME, eds. Eosinophilic Lung Diseases (ERS Monograph). Sheffield, European Respiratory Society, 2022; pp. 37–50 [].

  7. Page 51
    Salman Siddiqui (

    Advances in imaging have yielded novel insights into the basic mechanisms of eosinophil-mediated diseases and responses. For example, intra-vital imaging in EPX-Cre specific eosinophil mouse models has identified that eosinophils exhibit a range of local context-dependent behaviours, such as patrolling of tissue eosinophils under homeostatic conditions. A novel positron emission tomography ligand, zirconium-89-oxine, has been used to identify the mechanism of rapid eosinophil depletion in vivo following OCS administration. Clinical imaging studies have identified quantitative structural and functional biomarkers of eosinophilic lung disease, including bronchial wall thickening, airway luminal narrowing, mucus plugging and functional small airways disease, which may be suitable as end-points in clinical trials. Beyond CT imaging, hyperpolarised gas magnetic resonance imaging (MRI), dynamic contrast-enhanced MRI and technetium-99m-labelled autologous eosinophils coupled with single-photon emission CT (SPECT) plus CT imaging offer the potential for multimodality imaging approaches. Future studies deploying quantitative imaging biomarkers in clinical trials will yield new insights into the integrated tissue response in eosinophil-mediated diseases.

    Cite as: Bell A, Siddiqui S. Imaging. In: Jackson DJ, Wechsler ME, eds. Eosinophilic Lung Diseases (ERS Monograph). Sheffield, European Respiratory Society, 2022; pp. 51–72 [].

  8. Page 73
    Hitasha Rupani (

    Asthma is a heterogenous disease with diverse pathophysiological mechanisms, clinical characteristics, comorbidities and treatment responses. Eosinophilic asthma is characterised by increased airway or peripheral blood eosinophils. Longitudinal sampling and multicomponent clinical algorithms suggest that most patients with difficult-to-treat and severe asthma have underlying eosinophilic inflammation. Uncontrolled eosinophilic inflammation is associated with poor asthma outcomes related to increased risk of exacerbations and persistent airflow limitation. Identification of eosinophilic asthma is essential for therapy optimisation and provision of targeted therapies such as biologics, which effectively reduce exacerbations and improve lung function.

    Cite as: Rupani H, Gates J, Kavanagh JE, et al. Eosinophilic asthma. In: Jackson DJ, Wechsler ME, eds. Eosinophilic Lung Diseases (ERS Monograph). Sheffield, European Respiratory Society, 2022; pp. 73–99 [].

  9. Page 100
    Daiana Stolz (

    Eosinophils play an important role in the host response in COPD and despite the fact that their role is yet to be fully elucidated, it is accepted that eosinophils can be used to influence clinical decisions, being a treatable trait in COPD. Blood eosinophils during stable COPD can be used to predict the risk of mortality and exacerbation; in contrast, eosinophil counts during the onset of an exacerbation can be used to identify patients at risk of worse outcomes and predict risk of hospital re-admission, length of hospital stay, response to ICSs and mortality. Patients with COPD and elevated blood eosinophils have more exacerbations and ICSs appear to be beneficial in reducing them, as the clinical response to ICSs is enhanced with increasing eosinophil concentrations. In this chapter, we briefly summarise the eosinophilic inflammatory profile of COPD, as well as its response to treatment, while at the same time exploring the potential role of blood and sputum eosinophilic count as a biomarker in the management and treatment of COPD.

    Cite as: Karakioulaki M, Stolz D. Eosinophilic COPD. In: Jackson DJ, Wechsler ME, eds. Eosinophilic Lung Diseases (ERS Monograph). Sheffield, European Respiratory Society, 2022; pp. 100–118 [].

  10. Page 119
    Shigeharu Ueki (

    The respiratory tract is continuously exposed to fungi present in the indoor and outdoor environment. Among the various fungal species, some thermotolerant fungi can colonise the human airways. Fungi colonising tenacious mucus can induce robust type I hypersensitivity and severe eosinophilic inflammation, both of which are hallmarks of allergic bronchopulmonary mycosis (ABPM) and allergic fungal rhinosinusitis (AFRS). The accumulating eosinophilic mucus in ABPM and AFRS expands to cause irreversible pathological changes. Disease concepts and treatment strategies remain controversial because of the diverse host responses against a variety of germinated fungi. Further studies are required to understand their precise pathophysiology, which may lead to reduced refractory disease burden, thus avoiding the unacceptable side-effects of systemic corticosteroids.

    Cite as: Ueki S, Fukutomi Y, Miyabe Y, et al. Allergic fungal diseases in the upper and lower airways. In: Jackson DJ, Wechsler ME, eds. Eosinophilic Lung Diseases (ERS Monograph). Sheffield, European Respiratory Society, 2022; pp. 119–140 [].

  11. Page 141
    Praveen Akuthota (

    Eosinophilic pneumonias are characterised by the presence of pulmonary infiltrates in the setting of peripheral blood eosinophilia, alveolar eosinophilia on BAL, or tissue eosinophilia on lung biopsy. AEP is an idiopathic lung-limited disease which often mimics acute respiratory distress syndrome and has an excellent and reliable response to corticosteroids. CEP usually occurs in patients with pre-existing asthma and is marked by presence of blood eosinophilia in association with peripheral pulmonary infiltrates. CEP responds well to corticosteroids and often requires a prolonged treatment course with a tendency to relapse when steroids are tapered. Many drugs and toxins are known to cause eosinophilic pneumonia. Endemic parasites such as Ascaris, Strongyloides and Wuchereria are associated with characteristic clinical syndromes, namely Löffler's syndrome, hyperinfection syndrome and tropical pulmonary eosinophilia, respectively. A detailed review of medications, toxin exposures and travel history are key to the differential diagnosis in eosinophilic pneumonia.

    Cite as: Gadre A, Akuthota P. Eosinophilic pneumonias. In: Jackson DJ, Wechsler ME, eds. Eosinophilic Lung Diseases (ERS Monograph). Sheffield, European Respiratory Society, 2022; pp. 141–152 [].

  12. Page 153
    Florence Roufosse (

    HES are a heterogeneous group of rare disorders characterised by hypereosinophilia and eosinophil-mediated organ damage and/or dysfunction. Although specific disease variants primarily involving myeloid or lymphoid cells exist, underlying pathogenic mechanisms remain unknown in most patients. Respiratory symptoms are frequent in HES, and the lungs are among the most commonly affected organs, especially in idiopathic and FIP1L1-PDGFRA+ myeloid variants. Pulmonary complications may occur in isolation, especially at presentation, or as part of a systemic disease affecting other organs. They vary in nature, and commonly consist of asthma and/or interstitial disease with presence of eosinophils both in the airway lining and parenchyma. Demonstration of eosinophils in BAL fluid and/or lung tissue is an important step in establishing the direct role of eosinophils in lung disease. Treatment should aim to reduce blood and tissue eosinophilia to reverse and prevent further damage. Although corticosteroids are often rapidly effective, targeted treatment options should be preferred, namely the tyrosine kinase inhibitor imatinib mesylate as first-line therapy for clonal eosinophilic variants and monoclonal antibodies targeting the IL-5 pathway as maintenance therapy for patients with non-clonal eosinophils.

    Cite as: Taton O, Bondue B, Roufosse F. Hypereosinophilic syndromes and lung involvement. In: Jackson DJ, Wechsler ME, eds. Eosinophilic Lung Diseases (ERS Monograph). Sheffield, European Respiratory Society, 2022; pp. 153–176 [].

  13. Page 177
    Alexandra M. Nanzer (

    Previously known as allergic angiitis with granulomatosis, or Churg–Strauss syndrome, EGPA is a complex, rare and potentially fatal disease characterised by asthma, eosinophilia, sino-nasal disease, pulmonary infiltrates and small-vessel vasculitis. Eosinophilic tissue infiltration may present with involvement of any organ system, but most often is identified by rash, peripheral neuropathy, renal impairment or cardiomyopathy. While eosinophils in the blood or on biopsy help establish a diagnosis, there are no other defining biomarkers, either for diagnosis or monitoring. Serum ANCA are detectable in less than half of patients, perhaps touching upon two distinct disease subtypes, in two distinct genetic environments. Dysregulated humoral immunity, including upregulation of TSLP, IL-4, IL-5, IL-13 and T-helper type 2 cells or ILC2s are believed to drive recruitment, activation and persistence of tissue eosinophilia with resultant release of cytotoxic granular proteins. While historical treatment with combinations of high-dose corticosteroids and immunosuppressants improved survival rates, relapses and drug-related adverse effects remained common. The last several years have seen the introduction of novel therapeutic options, which have improved outcomes in this challenging disease.

    Cite as: Nanzer AM, Wechsler ME. Eosinophilic granulomatosis with polyangiitis. In: Jackson DJ, Wechsler ME, eds. Eosinophilic Lung Diseases (ERS Monograph). Sheffield, European Respiratory Society, 2022; pp. 177–192 [].

  14. Page 193
    Matthew Drake (

    Eosinophils cause excessive bronchoconstriction in asthma by inducing airway nerve dysfunction. In humans with asthma and in experimental animals exposed to allergen, ozone and respiratory viruses, eosinophils potentiate parasympathetic nerve acetylcholine release, resulting in increased airway smooth muscle contraction. Chronic eosinophilia in asthma also increases airway sensory nerve density and heightens nerve sensitivity. Collectively, these eosinophil-mediated alterations in airway nerves potentiate airway responsiveness. A better understanding of eosinophil–nerve interactions may uncover new mechanisms and treatment strategies for asthma.

    Cite as: De La Torre U, Fryer AD, Jacoby DB, et al. Eosinophils and airway nerves in asthma. In: Jackson DJ, Wechsler ME, eds. Eosinophilic Lung Diseases (ERS Monograph). Sheffield, European Respiratory Society, 2022; pp. 193–203 [].

  15. Page 204
    Sebastian L. Johnston (

    Eosinophils are widely acknowledged as key cells in driving type 2 immune responses against parasitic infection and in mediating allergic disease. Advances in our understanding have suggested that eosinophils may play an important additional role in the host immune response against a range of respiratory virus infections in both health and disease. Eosinophils exert these effects through a diverse range of mechanisms spanning innate and adaptive immunity, including immune sensing via Toll-like receptors, acting as antigen-presenting cells and the secretion of potent antiviral molecules. Recent evidence that anti-IL-5/IL-5 receptor therapies markedly reduce asthma exacerbations in those with activated eosinophilic pathways indicates that eosinophils clearly play an important role in asthma exacerbation pathogenesis. The mechanisms of viral exacerbations in patients treated with biologics are not yet fully understood and further work is needed to assess the impact of eosinophil depletion in this patient cohort.

    Cite as: Dhariwal J, Padayachee Y, Johnston SL. Respiratory viruses and eosinophilic airway inflammation. In: Jackson DJ, Wechsler ME, eds. Eosinophilic Lung Diseases (ERS Monograph). Sheffield, European Respiratory Society, 2022; pp. 204–218 [].

  16. Page 219
    Manali Mukherjee (

    Given the lungs continual bombardment with extraneous agents, a breach of mucosal immunity is not uncommon. Loss of tolerance leading to autoimmune pathologies has been reported in the lungs, but seldom in the context of eosinophils. Several eosinophilic lung diseases, such as asthma, CRS, ABPA, etc., have reported autoimmune-like features but are rarely considered within the autoimmune domain due to their association with eosinophils. Eosinophils are multifactorial pleiotropic cells universally known for their role in parasitic and allergic diseases. While autoantibodies to eosinophil-specific antigens are limited, there is evidence of autoantibodies to common self-antigens in eosinophilic lung diseases. Evidence of common autoantibodies has been described in small cohort studies or as anecdotal evidence in several eosinophilic lung diseases that have been conferred an autoimmune disease status or have autoimmune-like features. Autoantibody-triggered eosinophil cytolysis leading to extensive histone-coated extracellular traps have been observed in several of these diseases, either as direct ex vivo or in vitro evidence. Here, we gather available reports of autoimmune responses in eosinophilic lung diseases, assess the evidence in the context of eosinophilic tissue-response and danger-associated molecular patterns, and construct the possibility of eosinophil-driven autoimmune pathologies that may contribute to the clinical severity indices and suboptimal-response to eosinophil-targeted therapies.

    Cite as: Mukherjee M, Nair P. Eosinophils as potential mediators of autoimmunity. In: Jackson DJ, Wechsler ME, eds. Eosinophilic Lung Diseases (ERS Monograph). Sheffield, European Respiratory Society, 2022; pp. 219–237 [].

  17. Page 238
    Ariel Munitz (

    Since the first characterisation of the eosinophil, it has been associated with various allergic diseases as well as parasitic infections. The ability to manipulate eosinophils levels in mice has led to new perspectives regarding the roles of these cells in multiple diseases from asthma to cancer, as well as in health including metabolism and innate immunity. With the penetrance of potent eosinophil-depleting therapeutic agents it is important to scrutinise these potential roles as predicted from experimental mouse models alongside clinical observations from eosinophil-depleted patients. In this chapter, we comprehensively compare these data. Although no clinically important homeostatic role has been observed, so far, from eosinophil-depleted patients, the roles of eosinophils in health and disease require further study.

    Cite as: Jackson DJ, Munitz A. Safety of eosinophil depletion. In: Jackson DJ, Wechsler ME, eds. Eosinophilic Lung Diseases (ERS Monograph). Sheffield, European Respiratory Society, 2022; pp. 238–252 [].

  18. Page 253
    Bart N. Lambrecht (

    Eosinophils have long been known to contribute to various airway, interstitial and vascular lung diseases. These cells are built to destroy large extracellular helminths, and are loaded with toxic mediators and enzymes to do so. Not surprisingly, eosinophils are also often seen as culprits of cellular damage and loss of homeostasis when they appear in a lung disease. Despite these century-old insights, it is still unknown if all eosinophil subsets have the same pathogenic functions, and it has even emerged that some eosinophils dampen inflammatory reactions. Recent developments in spatial and single-cell transcriptomics, together with availability of powerful biologicals that can deplete eosinophils almost completely in humans with eosinophil-associated lung diseases, are providing important new insights into the fascinating biology of these cells.

    Cite as: Lambrecht BN, Aegerter H, Schetters S, et al. Future prospects of translational and clinical eosinophil research. In: Jackson DJ, Wechsler ME, eds. Eosinophilic Lung Diseases (ERS Monograph). Sheffield, European Respiratory Society, 2022; pp. 253–262 [].