Biomarkers for diagnosis and prediction of therapy responses in allergic diseases and asthma

Abstract

Modern health care requires a proactive and individualized response to diseases, combining precision diagnosis and personalized treatment. Accordingly, the approach to patients with allergic diseases encompasses novel developments in the area of personalized medicine, disease phenotyping and endotyping, and the development and application of reliable biomarkers. A detailed clinical history and physical examination followed by the detection of IgE immunoreactivity against specific allergens still represents the state of the art. However, nowadays, further emphasis focuses on the optimization of diagnostic and therapeutic standards and a large number of studies have been investigating the biomarkers of allergic diseases, including asthma, atopic dermatitis, allergic rhinitis, food allergy, urticaria and anaphylaxis. Various biomarkers have been developed by omics technologies, some of which lead to a better classification of distinct phenotypes or endotypes. The introduction of biologicals to clinical practice increases the need for biomarkers for patient selection, prediction of outcomes and monitoring, to allow for an adequate choice of the duration of these costly and long-lasting therapies. Escalating healthcare costs together with questions about the efficacy of the current management of allergic diseases require further development of a biomarker-driven approach. Here, we review biomarkers in diagnosis and treatment of asthma, atopic dermatitis, allergic rhinitis, viral infections, chronic rhinosinusitis, food allergy, drug hypersensitivity and allergen immunotherapy with a special emphasis on specific IgE, the microbiome and the epithelial barrier. In addition, EAACI guidelines on biologicals are discussed within the perspective of biomarkers.

Keywords: allergen immunotherapy; allergic rhinitis; asthma phenotypes and endotypes; biomarkers; food allergy.

FIGURE 1

Treatment based on molecular biomarkers for endotypes in asthma. Asthma can be subdivided into Type 2 (high) and non‐type 2 (or type 2 low) endotypes based on their underlying inflammatory pathways. For Type 2 high asthma, potential biomarkers could be serum‐specific IgE (sIgE), fractional exhaled nitric oxide (FeNO) and blood or sputum eosinophils, and in some more specialized centers periostin. Moreover, Type 2 cytokines (IL‐4, IL‐5 and IL‐13) and innate (epithelial) cytokines (IL‐25, IL‐33 and TSLP) can also be important biomarkers. The options to treat with biologicals emphasizing biomarkers of Type 2 high endotype have entered the market: IgE (omalizumab), IL‐5 (mepolizumab, reslizumab, benralizumab) and IL‐4/IL‐13 (dupilumab). In contrast, the diagnosis of Type 2 low asthma is difficult to establish as generally based on increased sputum neutrophils or paucigranulocytic with normal levels of other Type 2 markers, and non‐Type 2 cytokines (IL‐8 or IL‐17). There are still some associated indicators including obesity, smoking habits and psychological aspects. Therefore, therapeutic strategies for patients with Type 2 low asthma could be macrolides and bronchial thermoplasty

FIGURE 2

Microbiome Biomarkers in Asthma. Alterations in the gut and airway microbiota during childhood have been associated with asthma risk. The higher relative abundance of Veillonella and Prevotella and a switch from a Corynebacterium and Dolosigranulum cluster to a Moraxella cluster in the upper‐airways were associated with a higher risk of severe asthma exacerbation in children with asthma. The lower relative abundance of genera including Lachnospira, Veillonella, Faecalibacterium, Rothia, Bifidobacterium and Akkermansia in the gut during early life has been associated with the development of asthma. The increases in relative abundance of Gemmiger, Escherichia, Candida and Rhodotorula within the gut were also associated with the subsequent development of asthma

FIGURE 3

Immune cells and mediators as biomarkers in allergic rhinitis (AR). AR is associated with abnormalities in epithelial barrier function which is caused by exposure to exogenous proteases from allergens bacteria and viruses. These changes in epithelial barrier could contribute to the allergen absorption and disruption of epithelial tight junction. Activated dendritic cells (DCs) present allergen peptides to naive T cells and drive them to differentiate into Th2 cells and also allergen‐specific Th2A cells. Damaged epithelial cells release a high level of alarmin (TSLP, IL‐25, and IL‐33), which activate the group 2 innate lymphoid cells (ILC2s) as well as pathogenic memory T helper (Th) 2 cells. All these cells produce large amounts of proinflammatory mediators including IL‐4, IL‐5, IL‐9, and IL‐13. Besides, IL‐4 and IL‐13 are involved in IgE class switch in B cells. IgE binding to mast cells can trigger the release of mast cell‐associated mediators, such as prostaglandin D2 and leukotrienes, which could also activate the function of ILC2. PGD2 signaling could be a promising biomarker, as it can also activate eosinophils and basophils. Moreover, CD203c expression on basophils exhibits a time‐of‐day‐dependent variation, which could partly be responsible for temporal symptomatic variations in AR. IgG4 increased during allergen immunotherapy (AIT) is purported to be a blocking antibody by competing for allergen binding with IgE bound to Fcε receptors on mast cells and basophils. cysLT, leukotrienes; PGD2, prostaglandin D2

FIGURE 4

Biomarkers of viral infections in the exacerbation of AR. After the epithelial cells are infected with viruses, the replicating virus can cause cell lysis and direct damage to the epithelium, which causes deficiency in the production of antiviral interferon (IFN)‐β and IFN‐λ1. Together with the allergen‐induced cytokines IL‐25, IL‐33 and TSLP, ILC2s are activated and produce more Type 2 cytokines. Subepithelial plasmacytoid dendritic cells (pDCs) recognize virus antigens and present them to CD4⁺ T cells and CD8⁺ T cells through MHC class Ⅱ or Ⅰ and drive them toward a more Type 2 centric response. Excessive release of chemokines and cytokines can be triggered by infections such as respiratory–syncytial virus (RSV). Together with Type 2 cytokines, they could further promote the function of Type 2 macrophages, a small fraction of IL‐4‐secreting NK cells, IL‐4‐secreting NK‐T cells, neutrophils, eosinophils and mast cells and augment Type 2 responses in chronically inflamed airways. With the production of perforin and granzymes, CD8⁺ T cells can show cytotoxicity to virus‐infected epithelial cells and induce apoptosis. The viral RNA is released and detected by airway smooth muscle cells and stimulates the production of prostaglandins (PGs) in an autocrine manner

FIGURE 5

Biomarkers in food allergy diagnosis and treatment outcomes prediction. Conventional clinical approaches to diagnose food allergy include family history, skin integrity and the oral food challenge. Nowadays, expanded approaches focusing on genetic risk factors, allergen‐specific and nonspecific humoral and cellular biomarkers were explored. Genome, epigenome and mRNA linked to epithelial integrity and barrier (dys)function are linked to the development of food allergy. The measurement of IgE and IgG4 binding to linear or conformational epitopes could be more powerful to diagnose food allergy than conventional approaches. The soluble high‐affinity IgE receptor (FcεRI) may also act as a biomarker for IgE‐mediated pathologies in a less allergen‐independent way. Moreover, allergen‐specific Th2A cells and memory B cells have been discovered as new cellular biomarkers. Functional tests that simulate allergen exposure in vitro or ex vivo like the basophil activation test (BAT) and mast cell activation test (MAT) offer the possibility to assess allergen‐induced IgE cross‐linking

FIGURE 6

Mechanisms of immune‐mediated reactions to drugs. These reactions encompass immediate reactions (mediated by IgE) and nonimmediate reactions (mediated by T cells). In immediate reactions, drug‐induced polarization of Th2 cells from Th0 cells promotes B cells to produce specific IgE (sIgE). This sIgE binds to the FcεRI receptor on mast cells. In subsequent drug contacts, the simultaneous recognition by at least two sIgE initiates the degranulation and release of mediators. Nonimmediate reactions are generally characterized by a Th1 response with the increased secretion of IFN‐γ from Th1 cells and granulysin from NK cells

FIGURE 7

Mechanisms of cross‐reactive hypersensitivity reactions to NSAIDs. NSAIDs induce reactions relying on their COX‐1 inhibitory activity, i.e, activation of mast cells and other immune cells without involvement of adaptive immunity. During NSAID‐exacerbated respiratory disease (NERD), the administration of NSAIDs permits strong 5‐lipoxygenase (5LOX) activation and further generation of leukotriene E4 (LTE4). LTE4 induces the release of IL‐33 and TSLP, and consequent mast‐cell activation, with bronchoconstriction occurring as a result of the direct effects of leukotriene C4 (LTC4), prostaglandin D2 (PGD2) and other mast cell‐derived products. PGD2 recruits effector cells such as Th2 cells, group 2 innate cells (ILC2s), basophils and eosinophils to the airway. Consistently, in NSAIDs‐exacerbated cutaneous disease (NECD) and NSAIDs‐induced urticarial angioedema (NIUA), increased PGD2 can act on the skin epidermis. In addition, cross‐reactive hypersensitivity to NSAIDs may involve additional sources of inflammatory mediators, such as eosinophils and platelets. ILC2: innate lymphoid cells 2; LTE4/C4: leukotriene E4/C4; NSAID: nonsteroidal anti‐inflammatory drugs; PGD2: prostaglandin D2; TSLP: thymic stromal lymphopoietin; and 5LOX: 5‐lipooxygenase

FIGURE 8

Current view on mechanism and biomarkers in use to monitor AIT. A, Scheme of immune modulation by AIT, where low‐dose, repeated exposure to allergen is thought to occur with limited to no inflammation. As a result, Th skewing is balanced toward Th1 and Treg, which subsequently modify the B‐cell response. In particular, the production of IL‐10 is thought to drive IgG4 class switching. Thus, local and systemic memory is rebalanced, in both the T‐cell and the B‐cell compartments, and there is a strong increase in allergen‐specific IgG4 antibodies. Upon allergen challenge, IgG4 and potentially other soluble factors are thought to inhibit IgE‐mediated degranulation of target cells, i.e, desensitization. Together with the loss of Th2 skewing, this underlies the observed clinical tolerance. B, Laboratory biomarkers utilized in diagnostics and clinical trials for AIT (adapted from ²⁶⁷ ). Abbreviations: IgE‐FAB, IgE‐facilitated allergen binding; IgE‐BF, IgE‐blocking factor; BHR, basophil histamine release; DAO, diamine oxidase; Treg, regulatory T cell; Breg, regulatory B‐cell; DC, dendritic cell. Figure reproduced from ²⁶⁵