Novel insights into diagnosis and management of hyperreactivity: a narrative review

Introduction

Body reactivity refers to the ability of individuals to respond appropriately to external or internal stimuli, which is regulated by factors such as age, gender, and genetic background, as well as immune and neuroendocrine status (1). However, clinical observations indicate that many patients exhibit exaggerated and persistent local or systemic responses after surgery, lung transplantation (LT), or coronavirus disease 2019 (COVID-19) infection, even in the absence of definite antigen exposure, suggesting the presence of an underrecognized pathophysiological mechanism beyond classical immune hypersensitivity or acute stress responses (2-4).

In recent years, a non-antigen-specific “threshold reduction and amplitude enhancement” model has been proposed to describe a state of hyperreactivity (HR), which arises from imbalances within the neuro-endocrine-immune-microenvironmental axis (5). HR is characterized by three key features: thoroughness, reflected in the simultaneous activation of multiple physiological systems; early onset or persistence, involving the premature or sustained release of damage-associated molecular patterns and cytokines; and variation and dysregulation, manifested as marked heterogeneity across organs and individuals and strongly influenced by genetic susceptibility (6). Although HR has been identified in conditions such as chronic cough, lung transplant dysfunction, and severe COVID-19, its conceptual definition, classification framework, and dynamic monitoring indicators remain incomplete. Consequently, HR continues to be underrecognized in clinical practice, leading to fragmented diagnostic approaches and inconsistent management strategies.

In this context, the present review systematically delineates the definition, mechanisms, and disease spectrum of HR, and elucidates its intrinsic links with postoperative complications, transplant-related immune dysregulation, and severe viral infection. This work aims to bridge the current knowledge gap in the field of non-immune hypersensitivity overreactions and to provide a theoretical foundation for developing biomarker-based early warning and hierarchical management frameworks. We present this article in accordance with the Narrative Review reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-1929/rc).

Methods

Search strategy and selection criteria

This review was designed as a conceptual review focusing on the concept, mechanisms, and clinical implications of HR. A comprehensive literature search was conducted to collect publications related to HR, its physiological and pathological mechanisms, and its associations with conditions such as COVID-19, LT, postoperative inflammation, and chronic cough. Electronic searches were performed in PubMed, Web of Science, Scopus databases and China National Knowledge Infrastructure (CNKI). The search strategy combined Medical Subject Headings (MeSH) and free-text terms, including “hyperreactivity”, “body reactivity”, “stress reactivity”, “neuroendocrine”, “immune regulation”, “lung transplantation”, “surgery”, “COVID-19”, and “chronic cough”. The search covered the period from January 01, 1968, to November 01, 2025. Reviews, meta-analyses, randomized controlled trials, non-randomized trials, observational studies, human or animal studies related to HR mechanisms or clinical manifestations were included. Case reports, letters, conference abstracts, editorials and non-peer-reviewed materials were excluded. A summary of the search strategy is presented in Table 1.

Physiological foundations of body reactivity

Adaptation

Adaptation helps organisms maintain homeostasis through intracellular, biochemical, and metabolic regulations (7). Shaped by natural selection, it modifies morphology, metabolism, and function via neural and humoral pathways. Common adaptive forms include tissue remodeling, atrophy, hyperplasia, hypertrophy, and epithelial-mesenchymal transition (EMT) (8-11).

Stress

Stress is a physiological response to physical, psychological, or physicochemical stressors (12), primarily mediated by the sympathetic-adrenomedullary (SAM) system and the hypothalamic-pituitary-adrenal (HPA) axis (13). The initial stress phase activates locus coeruleus-noradrenergic neurons and the SAM system (1). The HPA axis releases corticotrophin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and cortisol (1). The stress response has three stages: alarm, resistance, and exhaustion (14). Initial SAM activation enhances adrenocortical hormone secretion, while subsequent adaptation increases metabolism and reduces inflammation. Prolonged stress elevates ACTH and decreases glucocorticoid (GC) receptor activity, leading to allostatic overload and organ dysfunction (15-17).

Immune response and hypersensitivity

The immune response protects against pathogens through antibody production, innate immunity activation, and cytokine release (18). Hypersensitivity represents an immune-mediated overreaction, classified into four types (19,20): Type I (anaphylactic) involves IgE-antigen binding and histamine release; Type II (cytotoxic) results from IgG or IgM binding leading to cell destruction; Type III (immune complex) arises from antigen-antibody deposits activating complement; and Type IV (delayed) is mediated by T cells and lymphokines, causing allergic or contact dermatitis.

Osmoregulatory responses

Organisms maintain osmotic homeostasis despite external variations (21). Osmoregulatory mechanisms regulate water absorption, ion concentrations, and the production of osmo-protective compounds (22). These adjustments preserve cellular integrity and organismal viability under osmotic stress (23,24).

Other responses

Sensory and pain responses represent two other distinct categories of physiological reactions. Sensory responses enable organisms to perceive and react to external stimuli (25), while pain responses address perception and reaction to harmful stimuli (26). These responses are crucial for adaptation and survival.

HR: an underrecognized physiological response

Concept of HR

HR differs from hypersensitivity in that it involves a reduced threshold and an enhanced response amplitude. It represents a non-immune-system-mediated state of heightened responsiveness. In addition to the aforementioned physiological responses, HR refers to an underrecognized response pattern characterized by increased sensitivity to various stimuli in humans (27) (Table 2). This heightened reactivity, short of allergic responses, is linked to intense reactions influenced by genetics, environment, and development. HR controls the interaction of the nervous, endocrine, and immune systems, forming a highly responsive state. While helpful in moderate conditions, HR can lead to stress-related illnesses (17,28-30).

Properties of HR

Thoroughness and exhaustiveness

HR is distinct from stress, which is mediated by neuroendocrine regulation and characterized by the alert, resistance, and exhaustion phases of an adaptive response (12). It also differs from hypersensitivity, an immune-mediated reaction that produces inflammatory storms and exudation while the nervous and endocrine systems remain relatively passive (18). Moreover, HR is typically associated with more intense immediate reactions to stimuli, rather than with the cumulative effects of allostatic load, which represents the long-term consequences of repeated activation of the body’s stress response systems, including the nervous, endocrine, and immune systems (17). In contrast, HR reflects the dynamic interplay among these systems, highlighting their intricate interconnections in stress physiology.

Premature response or long-term continuity

HR individuals may respond to stimuli earlier and more intensely, reflecting increased responsiveness (27). Unlike the transient alert phase observed during stress, HR induces sustained elevations of damage-associated molecular patterns, senescence-associated secretory phenotype, cytokines, and chemokines, particularly monocyte chemoattractant protein 1, both locally and systemically (31,32). Various immune cells, including monocytes, neutrophils, dendritic cells, B cells, T cells, and natural killer lymphocytes, infiltrate the body while regulatory T cells decrease, resulting in a prolonged alert state (6,33). Consequently, immune tolerance decreases, and sensitivity to stimuli increases, causing strong responses to weak stimuli. Fibroblast-like cells in inflammation activate type II EMT, aiding tissue reconstruction and post-inflammatory repair, but chronic EMT activation can lead to organ fibrosis (34).

Variation and dysregulation

HR varies based on the reaction site and triggering stimulus, affecting the nervous, endocrine, and immune systems. This variability can lead to imbalances in inflammation and different disease outcomes. HR occurs in LT and surgeries; after transplantation, immune infiltration may cause graft rejection through fibroblast-mediated EMT, often associated with neurological and vascular issues (35). Post-surgical HR is triggered by the neuro-humoral system, with gradual immune involvement depending on the site (33,36). Typical manifestations include fever, erythema, edema, exudation, and pain. Catecholamine release increases circulation, vascular permeability, cellular infiltration, and pro-inflammatory mediator production, creating a feedback loop that perpetuates and amplifies HR (37,38).

Inter-individual variability and genetic predisposition

Genetic susceptibility reflects the tendency to develop disease due to genetic and environmental factors. HR exhibits variable susceptibility depending on the affected site and population. Airway hyperresponsiveness (AHR) is often hereditary, with genetics accounting for 60–70% of its development. Genes on chromosomes 5q and 11q regulate AHR by influencing IgE and airway inflammation (39). ADAM33 gene expression by fibroblasts and smooth muscle cells contributes to airway remodeling and HR. ADAM33 single-nucleotide polymorphisms (SNPs) and haplotypes are linked to asthma susceptibility in Caucasian and Korean populations (40). These findings suggest that HR across different organ systems may share common genetic and molecular bases, predisposing individuals to heightened physiological reactivity.

Pathophysiological mechanisms underlying HR

HR represents an external manifestation resulting from imbalances among the nervous, humoral, immune, and microenvironmental systems.

Nervous system

The development of HR involves complex nervous system interactions, including nerve conduction, neurotransmitter activity, and neuroendocrine regulation (41). Specifically, regions of the central limbic system such as the cortex, amygdala, hippocampus, and pontine locus coeruleus are closely involved in this process (42). The HPA also plays a role in HR, as CRH-secreting neurons in the paraventricular nucleus of the hypothalamus are connected to ACTH, resulting in increased GC secretion (43).

Nervous system activation alters the humoral-endocrine and immune systems through mediators like acetylcholine, norepinephrine, and calcitonin gene-related peptide (CGRP), affecting muscle contraction and vasomotion (36).

The non-adrenergic non-cholinergic system in some tissues and the trachea is divided into excitatory nonadrenergic noncholinergic (e-NANC) and inhibitory NACA (i-NANC) systems (44). The e-NANC releases neurotransmitters like P and CGRP, promoting inflammation and muscle contraction (44). On the other hand, the i-NANC releases vasoactive intestinal peptide (VIP) and nitric oxide (NO), which can relax smooth muscle. However, in airway inflammation, VIP can be inactivated, leading to increased reactivity. Endogenous NO has different effects on different sites and may be associated with different isoforms (45).

Endocrine-humoral interaction

HR involves widespread neuroendocrine alterations. Activation of the locus coeruleus-noradrenergic neurons and the sympatho-adrenomedullary system elevates catecholamine levels, influencing heart rate and vasodilation. Additionally, the HPA axis stimulation raises CRH and ACTH, leading to GC secretion. GC enhances gluconeogenesis, glucagon, catecholamine, lipid mobilization, and cardiovascular sensitivity. Furthermore, humoral-endocrine changes include elevated antidiuretic hormone (ADH) levels, decreased gonadotropin-releasing hormone (GnRH) levels, increased glucagon, and decreased insulin and thyroid hormone levels (46).

The regulation of the humoral-endocrine system is crucial in local HR, as oxidative stress from reactive oxygen species (ROS) disrupts the oxidative/antioxidative balance, leading to immune cell activation, cytokine release, and enzyme regulation, causing muscle spasms and worsening ischemia-hypoxia responses (47,48).

Immune system

The immune system plays a central role in HR neuromodulation. Immune cells express neurotransmitter receptors like acetylcholine and dopamine receptors, emphasizing neuro-immunity. Sympathetic stimulation suppresses immunity, whereas parasympathetic stimulation enhances it. Autonomic dysfunction contributes to inflammation, as autonomic nerves influence lymphoid organ function and regulate immune responses (49).

The humoral-endocrine system mediates immune activation in HR, modulating the activation and differentiation of immune cells (50). Both innate and adaptive immunity are involved, with contributions from the monocyte-macrophage system, B-cell humoral immunity, and T-cell cellular immunity. Antigen recognition, signaling, cell differentiation, and mediator release rely on humoral pathways. Immune molecules, including antibodies, cytokines, inflammatory mediators, and complement components, are key effectors in HR (41).

Eosinophils produce over twenty cytokines, including interleukin-3 (IL-3), IL-5, and granulocyte-macrophage colony-stimulating factor (GM-CSF), which promote hematopoietic progenitor cell maturation and prevent apoptosis. IL-4 stimulates B cell IgE production, and transforming growth factor-beta (TGF-β) promotes fibroblast collagen synthesis. Eosinophils also release cytotoxic proteins, oxides, neuropeptides, and lipid mediators, which induce histamine release from mast cells and damage respiratory tract epithelium. Neuropeptides like P and VIP cause smooth muscle contraction, mucosal edema, vasodilatation, and mast cell degranulation (51,52).

Mast cells are critical effectors in HR and immediate hypersensitivity (53). Upon stimulation, mast cells degranulate and release mediators that induce airway smooth muscle contraction, mucus hypersecretion, vascular leakage, and inflammatory exudation, enhancing airway HR (54). Lymphocytes, including T, B, and innate lymphoid cells (ILCs), further amplify these responses. T helper 1 (Th1) cells secrete IL-2, interferon-gamma (IFN-γ), and tumor necrosis factor-beta (TNF-β) to activate macrophages, while Th2 cells release IL-4, IL-5, IL-9, and IL-13, driving IgE synthesis, eosinophil proliferation, mast cell differentiation, and mucus production (55,56). ILCs, lacking antigen receptors, respond to epithelial danger signals by producing type-2 cytokines and contribute to allergen- and infection-induced airway HR independently of adaptive immunity (57).

Hyperreactive microenvironment

Structural elements such as blood vessels, muscle tissues, basement membrane, mesenchymal cells, and fibroblasts play crucial roles in the formation of a hyperreactive microenvironment. Angiogenesis, driven by endothelial cells, is a key process (58). Angiogenic factors such as cytokines, growth factors, proteolytic enzymes, and plasminogen activators bind to receptors on endothelial cells and activate pathways like tyrosine kinase. Various cytokines, such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor, hepatocyte growth factor (HGF), TGF-β, IL-6, IL-8, and platelet-derived growth factor (PDGF), can stimulate angiogenesis directly or indirectly. Under hyperresponsive conditions, VEGF is released, leading to cell reprogramming and inflammation in the affected areas, which can contribute to the development of various diseases, including pulmonary hypertension, asthma, fibrosis, and cancer (59).

Additionally, epidermal growth factor receptor (EGFR) transactivation modulates the effects of angiotensin II, endothelin-1, and catecholamines, which are linked to local high blood pressure, vascular inflammation, and arteriosclerosis in a hyperresponsive environment (60). Upregulation of EGFR can enhance sensitivity to ERK1/2 mitogen-activated protein kinase (MAPK) activation, leading to increased oxidative stress and inflammation, ultimately exacerbating the harmful effects of angiotensin II, endothelin-1, or aldosterone (61).

In airway HR, microenvironment changes lead to airway wall thickening, epithelial damage, thickening of the reticular basement membrane (RBM), also known as subepithelial fibrosis, mucus transformation, and proliferation and hypertrophy of myofibroblasts (62). In response to tissue injury or immune infiltration, there is a local response that involves the activation of fibroblasts, secretion of inflammatory mediators, and synthesis of extracellular matrix (ECM) components such as collagens and fibronectin (63). This response, known as the callus response, is initiated to promote tissue repair (63). However, when injury is severe or recurrent, persistent ECM accumulation leads to structural damage, organ dysfunction, or failure (64).

Diseases with hyperreactive pathophysiology

HR denotes an exaggerated bodily response, varying in intensity, timing, and location. It can be acute or chronic, localized or systemic, and affects multiple organ systems. Acute HR manifests as fever, fatigue, shock, inflammatory storms, or local symptoms such as rash, swelling, pain, fluid exudation, and bronchospasm. Chronic HR may result in persistent cough, post-lung transplant fibrosis, ongoing intestinal inflammation, stenosis, or even cancer. In the context of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and LT, HR underlies many of the severe complications and clinical outcomes observed.

SARS-CoV-2 and HR

SARS-CoV-2, first identified in December 2019, primarily infects the lungs via the angiotensin-converting enzyme 2 (ACE2) receptor, although ACE2 is expressed in multiple organs (65-67). Infection manifests with fever, cough, dyspnea, fatigue, myalgia, gastrointestinal symptoms, anosmia, and ageusia. Severe cases can lead to pneumonia, ARDS, systemic HR, thrombosis, multi-organ injury, and sepsis (68). Severe COVID-19 is often accompanied by lymphopenia, neutrophilia, reduced interferons, and elevated antibodies and pro-inflammatory cytokines such as IL-6, TNF, and TGF-β (69). These exaggerated responses, or HR, can drive immune cell recruitment, vascular leakage, hypoxia, thrombosis, and multi-organ inflammation, potentially leading to disseminated intravascular coagulation and multi-system inflammatory syndrome (70-72). Properly regulated responses are crucial for viral clearance, whereas uncontrolled HR worsens disease severity and clinical outcomes.

The mechanism of systemic HR caused by SARS-CoV-2

Patients infected with SARS-CoV-2 may develop systemic HR through multiple interconnected mechanisms, including nervous system involvement, humoral-endocrine dysregulation, impaired immune tolerance, and tissue HR (Figure 1).

Figure 1 The mechanism of COVID-19 and HR. Individuals infected with SARS-CoV-2 may experience an intense systemic response, often referred to as HR. This state can be influenced by a host of factors, encompassing not only involvement of the nervous system, but also changes within the humoral-endocrine system, diminished immune tolerance, and hyper-responsiveness of various tissues. COVID-19, coronavirus disease 2019; HR, hyperreactivity; IFN, interferon; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Nervous system

One line of evidence uncovers the neurologic manifestations of COVID-19 and potential routes of neuroinvasion (73). The lungs are innervated by sensory, sympathetic, and parasympathetic fibers. Sympathetic innervation from the upper thoracic spinal cord provides noradrenergic input to bronchial vessels and submucosal glands, while parasympathetic pathways induce bronchoconstriction and mucus secretion via muscarinic M3 receptors. Presynaptic cholinergic M2 receptors inhibit acetylcholine release, modulating airway tone (74,75). SARS-CoV-2 infection may disrupt these neural pathways, priming the body for exaggerated “fight or flight” responses. Studies also indicate close neuro-immune crosstalk, with nerve fibers influencing immune cell recruitment and function during viral infections (76-78). P2RY1⁺ neurons, innervated by vagal and laryngeal nerves, mediate protective airway reflexes, emphasizing neural contributions to HR (5).

Immune system

Upon viral infection, the immune response is activated, involving the innate immune system through antiviral signal reactions from receptors like Toll-like and NOD-like receptors (79). Transcription factors, including interferon regulatory factor 3 and nuclear factor kappa-B (NF-κB), are activated, leading to type I interferon and pro-inflammatory cytokines like IL-1, TNF-α, and IL-6 (80). Neutrophils and monocytes are key mediators of hyperinflammation, and their infiltration into the airway drives airway HR, excessive mucus production, smooth muscle hyperplasia, airflow restriction, and lung tissue damage (77,81). Furthermore, Wen et al. (82) found that during SARS-CoV-2 infection, inflammatory monocyte expansion activates cytokines like interleukin-1β (IL-1β), colony-stimulating factor 1, and IL-6, thereby increasing inflammation. Adaptive immunity involves antigen presentation to T cells, with IL-12 promoting Th1 differentiation and IFN-γ production to activate macrophages, also inducing chemokine transcription (83). Th0 cells differentiate into Th1, Th2, and Th17 subsets, while IL-6 drives CD8⁺ T cell cytotoxicity. B cells, stimulated by antigens and Th2 cells, proliferate into plasma cells producing antibodies, with IgM providing an early response followed by long-term IgG immunity (84). Overall, innate and adaptive responses work together to clear the virus but may contribute to HR when excessive.

Humoral endocrine mechanism

COVID-19 can disrupt glucose homeostasis, with severe inflammation exacerbating insulin resistance and hyperglycemia through cytokine storms and hormonal dysregulation (85). Inflammatory cells may impair skeletal muscle and liver function, reducing glucose uptake and gluconeogenesis (86). These organs are crucial for insulin-mediated glucose uptake and gluconeogenesis, and inflammation-related dysfunction may lead to hyperinsulinemia and hyperglycemia. COVID-19 also affects the thyroid. Chen et al. (87) conducted thyroid function tests on 50 COVID-19 patients and found that 64% had abnormal thyroid function after three months. Fifty-six percent had reduced thyroid-stimulating hormone levels, with many also showing decreased triiodothyronine compared to healthy controls. Muller et al. (88) found a higher prevalence of hyperthyroidism in COVID-19 patients (15.3%) versus 1.3% in pneumonia recovery controls, noting a significant correlation between thyrotoxicosis and increased IL-6 levels (89). The proposed mechanism is that SARS-CoV-2 directly damages the thyroid due to high ACE2 expression in thyroid tissue. Thyroid injury may also occur indirectly through immune mechanisms like cytokine storms (85).

Highly reactive microenvironment

COVID-19 can cause severe symptoms persisting for months after hospital discharge. In a study by Munblit et al. (90), many patients displayed symptoms during 6–8 months of follow-up, with chronic fatigue and dyspnea being the most common; 12% reported dyspnea. Severe inflammation leads to lung damage, requiring ventilation support, which increases lung and trachea HR (91). The vagal nerve (5) may mediate virus-induced HR, aggravating dyspnea and respiratory failure due to neuroimmune crosstalk in the lungs. Respiratory distress in COVID-19 patients is linked to HR or cellular responses mediated by airway stretch receptors. Changes in vagal nerve activation can cause sneezing, coughing, hypersecretion of mucus, and bronchoconstriction (5). In a cytokine storm context, fibrogenic factors can promote tissue remodeling and pulmonary fibrosis, further impairing gas exchange (91). Enhanced Th2 or impaired Th1 or IL-10 responses can lead to airway HR, where T-cell responses enhance lung inflammation (92), promote IgE production, activate eosinophils and mast cells, and enhance AHR through chemokines and cytokines (93). COVID-19 sequelae may relate to mast cell activation syndrome, where over-activated mast cells contribute to fibrotic diseases (94). Serum levels of anti-novel coronavirus S1 protein-specific IgE (SP-IgE) were significantly increased in critically ill patients, indicating potential hypersensitivity during COVID-19 pathogenesis, lasting into recovery (68).

LT and HR

Over the past three decades, about 70,000 adult lung transplants have been performed, significantly improving survival and quality of life for patients with end-stage lung disease (95). Since the 1980s, LT has become an established treatment for advanced pulmonary conditions, including interstitial lung disease, chronic obstructive pulmonary disease (COPD), cystic fibrosis, non-cystic fibrosis bronchiectasis, pulmonary arterial hypertension, pulmonary lymphangioleiomyomatosis (PLAM), thoracic malignancies, and acute respiratory distress syndrome (96). The proportion of recipients with diabetes has nearly tripled, and those with prior malignancy increased from 2.7% to 7.9% (95).

Mechanism of LT HR

Despite advances in organ acquisition, preservation, post-transplant management, and therapies improving survival rates, unresolved complications remain, such as lung post-transplant malignancy, infection, acute rejection, and chronic allogeneic lung dysfunction (CLAD). Infection and rejection are the most frequent issues post-transplant. Complications from infections or acute rejection and CLAD can trigger, activate, or sustain HR, leading to increased morbidity and mortality (97). Factors contributing to HR after LT include denervation-related mechanical issues, lymphatic drainage disruption, anastomotic complications, impaired ciliary clearance, infections, alloimmune reactions, and immunosuppressive drug use (98-100).

Acute rejection induces a hyperreactive state

Lung transplant mucosal biopsies show various immune cells, including activated memory CD4⁺ T cells, follicular helper T cells, γδ T cells, M1 and M2 macrophages, and eosinophils (101). Vagal nerve-associated neurons trigger protective responses to airway irritants (5), releasing acetylcholine through neurohumoral modulation. Muscarinic M2 and M3 receptors (102) on pulmonary macrophages allow for direct modulation of lung macrophage activity, influencing inflammation.

Surgical trauma, even if sterile, causes acute inflammation by releasing inflammatory cytokines and damage-associated molecular patterns (DAMPs) (103). This local response attracts immune cells, like neutrophils and monocytes, to the injury site and can trigger systemic inflammation, damaging other tissues (33). Pattern recognition receptors (PRRs) on activated monocytes and high mobility group box-1 (HMGB1) activate NF-κB (104), increasing cytokine transcription, further activating NOD-like receptor thermal protein domain associated protein 3 (NLPR3) and promoting IL-1 production (105). IL-1 induces monocyte chemoattractant protein-1 (MCP-1) expression, facilitating C-C motif chemokine receptor 2 positive (CCR2⁺) monocyte entry into the cerebrospinal fluid, causing inflammation and neuropathies (106,107), resulting in HR.

Lung transplant patients may lose neuroimmune unit (NIU) function due to decreased vagal activity and immuno-monitoring. Post-surgery infections increase the likelihood of inflammation storms. The airway vagal nerve connects nerves and airway macrophages, facilitating communication via acetylcholine and neuropeptides (108). Nerve- and airway-associated macrophages (NAM) regulate immune responses and prevent infection-induced inflammation, a relationship known as NIU (109). After LT, NIU function weakens due to reduced vagal activity, making NAM activation challenging. Consequently, infections may trigger intense immune responses, leading to excessive cytokine release and cytokine storms, ultimately causing HR.

The infection triggers an HR state

After LT, lungs are exposed to pathogens, increasing infection risk and HR. Patients with pre-existing conditions like diabetes, renal insufficiency, and malnutrition are especially vulnerable to hyperreactive symptoms, potentially causing acute renal injury (97,110), systemic inflammation (111), or death (112).

Infection leads to alveolar macrophages, mast cells, and neutrophils to engulf pathogens and trigger inflammatory responses, resulting in high reactivity. It also makes airway receptors sensitive to inhaled stimuli, enhancing reactivity through vagal mediation (113). Additionally, infections stimulate the hypothalamus-pituitary-adrenal axis, causing tachycardia, vasoconstriction, and hyperglycemia. Immunosuppressants like cyclosporine A limit activated T cell expansion, reducing rejection risk but increasing neurological complication risks in LT recipients (114). Infections stimulate dendritic cells to present antigens to T cells, activating T cell-mediated immune responses (115). They also damage airway epithelium and release cytokines, exacerbating inflammation.

LT can trigger an exaggerated innate immune response, leading to inflammation (116). Various cell death forms occur, including apoptosis and regulated necrosis (necroptosis, ferroptosis, pyroptosis), inducing inflammatory reactions (116). Ischemia-reperfusion injury related to transplantation can cause inflammatory cell death in grafts and recipients, releasing DAMPs.

Bacterial infections during or after surgery can release pathogen-associated molecular patterns (PAMP) (117,118). These signals activate the complement and coagulation systems, inducing leukocyte and receptor signal transduction, generating immediate immune responses (116). Severe infections or injuries can cause overly strong innate immune responses (119,120), prolonging white blood cell life and releasing autoimmunity and inflammatory cytokines, leading to excessive inflammation. These changes can worsen hypoxia and bacterial invasion, damage cell barriers, and increase DAMP and PAMP levels, creating a vicious cycle of the innate immune response and ultimately causing HR (120,121).

Persistent HR caused by CLAD

CLAD is a significant obstacle in LT, presenting more challenges than infection due to its sterile nature and high reactivity (122). CLAD comprises two phenotypes: bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS) (123), with BOS being more prevalent (124). significantly contributes to incidence and mortality post-LT (125).

BOS primarily affects the airways, damaging small airway epithelial cells and subepithelial structures, disrupting fiber expansion, epithelial regeneration, and tissue repair (126). Airway epithelial cells are both targets and effectors in BOS. Bronchial epithelial injury leads to activation, inflammation, fibrosis, and airflow limitation, resulting in HR in BOS patients (127).

The immune mechanisms in BOS need further clarification. BOS etiology may involve alloimmune reactions from preexisting antibodies against human leukocyte antigens (HLA) and non-HLA molecules (128), autoimmune reactions to autoantigens in airway epithelial cells (129), exposure to external stimuli like bacteria and viruses, and airway ischemia (130). These injuries trigger inflammation in the small airways, damaging the epithelium and tissues, which can amplify the immune response, creating local HR. Long-term fibrosis and obstruction of the small airways lead to structural remodeling termed fine occlusive bronchitis, while other lung areas remain relatively unaffected (131).

BOS post-LT can cause chronic lung inflammation by increasing vascular permeability, resulting in persistent vascular infiltration and HR (132). Increased pulmonary vascular permeability is regulated by Rho and Cdc42/Rac pathways (133). The Rho pathway increases focal cell adhesion junctions (AJs), raising permeability (132), while the Cdc42/Rac pathway stimulates linear junction production, inhibiting focal AJ production and reducing permeability. The balance between these pathways affects BOS development and can be disrupted by inflammation, leading to blood and protein leakage, chronic inflammation, and a hyperreactive lung state (Figure 2).

Figure 2 The mechanism of LT and HR. HR after LT can arise due to a multitude of factors. These can include issues associated with the mechanical defense systems due to denervation, disruption in lymphatic drainage, complications at the surgical junction (anastomosis), compromised ciliary function leading to poor mucus clearance, infections from external sources, immune responses directed against the transplanted lung (alloimmune reactions), and side effects from the use of immunosuppressive medications. APC, antigen-presenting cell; CR, complement receptor; DAMP, damage-associated molecular pattern; HR, hyperreactivity; LT, lung transplantation; MHC, major histocompatibility complex; NAM, airway-associated macrophages; NIU, neuroimmune unit; PAMP, pathogen-associated molecular pattern; TLR, Toll-like receptor.

Surgical site redness, swelling, drainage and HR

Surgical site HR arises when the normal inflammatory processes required for tissue repair become excessively amplified after surgical trauma. This overactivation of innate and adaptive immune pathways transforms a localized physiological response into a pathological cascade, marked by persistent redness, swelling, pain, and excessive exudation. Understanding the mechanisms underlying surgical site HR is essential, as these processes not only determine local wound healing but may also propagate systemic inflammation, influencing postoperative recovery and complications.

Mechanism of surgical site HR

Tissue injury releases alarmins or DAMPs, which are recognized by Toll-like receptors (TLRs) at the surgical site. This recognition activates MyD88 and TRIF pathways, triggering MAPK and IκB kinase (IKK) cascades. Subsequently, cytokines such as TNF, IL-1β, IL-6, and IL-18 are produced through activation of AP-1 and NF-κB (134). Surgery causes cell destruction, releasing mediators like potassium, prostaglandins, and chemokines (135). The ensuing inflammatory response causes vasodilation, increased vascular permeability, and interstitial fluid accumulation, leading to congestion, hyperemia, and altered hemodynamics. Plasma protein leakage, leukocyte exudation, and neovascularization further amplify local inflammation. Neuropeptides such as substance P and CGRP sensitize nociceptors, producing inflammatory pain and establishing local HR characterized by redness, swelling, and heat (136).

During reperfusion after lung ischemia/reperfusion (I/R) injury, alveolar macrophages release pro-inflammatory cytokines, exacerbating inflammation against damaged vascular endothelium and airway epithelium. This activates neutrophils, worsening injury, with chemokines like CXCL1 (GRO1) and CXCL8 (IL-8), facilitating neutrophil activation and infiltration. Adhesion molecules (CD18, ICAM-1, P-selectin) upregulate after I/R, enhancing neutrophil response and increasing capillary permeability and surgical wound exudate (137). After pulmonary I/R, pro- and anti-inflammatory cytokines are rapidly released, including TNF-α, IFN-γ, CXCL8, IL-1β, IL-10, and IL-12. Many of these cytokines are primarily derived from resident and circulating/infiltrating leukocytes and mediate inflammatory responses, such as leukocyte activation and chemotaxis. Given the significant resident population of alveolar macrophages in the lung, these cells will likely be rapidly stimulated after I/R to initiate an inflammatory cascade response, together with alveolar type II cells (138). The depletion of alveolar macrophages reduces I/R injury (IRI) by lowering the expression of pro-inflammatory cytokines and chemokines (139). TNF-α may promote inflammation by increasing the secretion of pro-inflammatory cytokines and chemokines by alveolar epithelial cells and affecting neutrophil recruitment (138).

Surgical site exudate triggers a systemic response, affecting the thermoregulatory center through endogenous pyrogens like IL-1 and TNF, raising the thermoregulation point and causing fever. During the postoperative period, monocyte-derived IL-6 is the primary inflammatory cytokine that activates acute-phase response proteins such as C-reactive protein (CRP) and calcitoninogen. Additionally, IL-6 mobilizes neutrophil progenitors, granulocytes, and GM-CSF in the bone marrow, leading to peripheral agranulocytosis with high reactivity (140).

Furthermore, pro-inflammatory cytokines and acute-phase proteins rise due to surgical stress, activating the HPA axis, increasing counterregulatory hormones (cortisol, growth hormone, glucagon, catecholamines) (141), leading to tachycardia, vasoconstriction, and hyperglycemia. Cortisol release may be heightened during systemic inflammation (142). Additionally, surgery inhibits mitochondrial activity, decreases adenosine triphosphate (ATP) levels, and increases inflammation, which produces ROS, damaging lipids, proteins, and DNA and impairing vascular permeability. The hypothalamus releases ACTH, with impaired permeability potentially increasing surgical wound exudate (Figure 3).

Figure 3 The mechanism of redness, swelling, drainage, and HR at the surgical site. The high reactivity of the surgical site is reflected in the surgical incision and drainage fluid, which is actually an excessive inflammatory response and abnormal immune regulation of the nervous system, as well as a large amount of exudation of inflammatory cells, blood and fibrin. After the surgery, high reactions at the surgical site should be addressed in advance, including not only wound dressing changes and drainage issues but also preventive use of drugs to reduce inflammation and immune regulation. ACTH, adrenocorticotropic hormone; ADH, antidiuretic hormone; DAMP, damage-associated molecular pattern; GH, growth hormone; HR, hyperreactivity; MAC, membrane attack complex; MBL, mannose-binding lectin; TSH, thyroid-stimulating; T3, triiodothyronine; T4, thyroxine.

Chronic cough after the operation, late cold, and vaccination

Cough is a fundamental defense reflex that clears the airways of secretions and foreign material (143). The mucociliary system helps transport these secretions toward the central airways for expulsion (144). According to the American College of Chest Physicians, cough lasting more than eight weeks is classified as chronic (145). Chronic cough is one of the most common respiratory complaints, significantly impairing quality of life and increasing healthcare burden (146). When the cough reflex becomes excessively sensitive or persistently activated, it manifests as hyperreactive chronic cough, reflecting an overamplified neuroimmune response of the airways that underlies many postoperative, post-infectious, or vaccine-related conditions.

Mechanism of chronic cough

Mechanistically, chronic cough in HR involves neural, humoral-endocrine, immune, and microenvironmental dysregulation that together amplify cough sensitivity. Joad et al. (147) showed that guinea pigs exposed to cigarette smoke for five weeks developed enhanced citric acid-induced cough HR, which was markedly reduced by the substance P antagonist SR140333, suggesting a role for substance P released from the nucleus tractus solitarius in mediating cough HR. Transient receptor potential vanilloid 1 (TRPV1), a non-selective cation channel, is a key mediator of the cough reflex (148). Groneberg et al. (149) found that TRPV1 expression in the bronchial epithelium was significantly elevated in patients with chronic cough, correlating with capsaicin-induced HR.

Boulet et al. (150) conducted a study on chronic cough patients and found increased inflammatory cells in the bronchoalveolar lavage fluid. Biopsies revealed epithelial shedding and monocyte infiltration, with leukotrienes enhancing airway responsiveness (151). Additionally, Driessen et al. (152) confirmed that chronic cough involves neuroinflammation, with glial cells regulating cough via neural systems, increasing neuroplasticity and nerve sensitization, and inflammatory stimuli activating glial cells to release neurotransmitters, altering cough sensitivity. Patients may experience chronic cough due to high reactivity after various triggers (Figure 4).

Figure 4 Post-operative, late-stage colds and vaccination cause the mechanism of chronic cough. Chronic cough is intricately associated with heightened reactivity of multiple bodily systems. This includes the nervous system, which can result in overstimulation of the cough center. This humoral-endocrine system can lead to the activation of the transient receptor potential pathway and a diminished immune tolerance, which can cause inflammation in the airways and an overall reactive microenvironment. These elements are thought to play a role in initiating and progressing a cough that displays HR. COPD, chronic obstructive pulmonary disease; GERD, gastroesophageal reflux disease; HR, hyperreactivity; URTI, upper respiratory tract infections.

Hyperreactive cough after the operation

Surgery is critical despite other treatment advances. Postoperative stress and lung diseases can raise airway susceptibility, causing pulmonary issues and HR (153). Airway inflammation and injury are central to HR. The imbalance, particularly increased Th2 or decreased Th17, enhances humoral immunity and IgE production (154). Adhesion molecules cause leukocyte aggregation and airway inflammation. Smooth muscle contraction, bronchial congestion, and increased secretions raise effusion and drainage. Severe inflammation can lead to systemic HR, with fever, hemogram changes, and organ dysfunction. Anti-inflammatory immunosuppression can result in infections, sepsis, and tumor growth, impacting recovery and prognosis (155). Postoperative hyperreactive cough in lung cancer patients presents as sudden, repeated dry coughs, with chest tightness and wheezing in severe cases (156).

Hyperreactive cough after a cold

Post-infectious cough (PCI) is a lingering cough after acute cold symptoms resolve, arising from non-specific airway inflammation. Some patients show airway HR linked to decreased immune tolerance. PCI patients exhibit increased cough HR, airway neurogenic inflammation, elevated vascular permeability, plasma extravasation, and tissue edema (157). Increased airway responsiveness likely results from unstable airway epithelial cell function, damaged cilia, and higher tissue permeability, allowing allergens and pathogens to reach smooth muscle and nerves, enhancing sensitivity (158). Chang et al. (159) found that leukotriene receptor antagonists can inhibit hyperreactive cough caused by airway inflammation infiltration, highlighting the role of immune infiltration in cough HR.

Hyperreaction cough after vaccination

SARS-CoV-2 caused over a million deaths in the first six months (160). The development of an effective vaccine is considered crucial in reducing morbidity and mortality (161). However, vaccination can induce HR, leading to localized and rare systemic adverse reactions, including severe allergies (162). This HR is linked to reduced immune tolerance, altering airway structure. Unstable patients may show neuropathic inflammation, decreased lymphocyte counts, lower oxygenation indices, and increased inflammatory indices. Chest imaging may reveal unilateral or bilateral ground-glass opacities and patchy infiltrates, typically near the pleura and vascular bundles, with late-stage fibrosis impacting gas exchange. Airway stenosis from fibrosis worsens HR (163).

Management and outlook

Advantages and disadvantages of HR and treatment

Advantages of HR

HR refers to an excessive local or systemic response to external stimuli, serving a protective function by fighting infections and removing harmful factors and damaged tissues. Additionally, HR can increase glucose synthesis. Qing et al. (164) found that acute stress enhances sympathetic drive, leading to IL-6 production from brown adipocytes in a beta-3-adrenergic-receptor-dependent manner, boosting hepatic gluconeogenesis and causing hyperglycemia to provide energy reserves.

Disadvantages of HR

HR often manifests as excessive allergic reactions or activation of neurofeedback and endocrine systems. Acute-phase symptoms include fever, weakness, shock, rash, redness, swelling, heat, pain, drainage, and bronchospasm, causing significant discomfort. A cytokine storm can occur, where the immune system overreacts to viruses or infections, leading to tissue damage. For example, SARS-CoV-2 can infect monocytes and macrophages, triggering a cytokine storm that results in severe lung damage (165).

On the other hand, Chronic symptoms of HR include chronic cough after lung cancer surgery (166), pulmonary fibrosis after LT (167), irritable bowel syndrome due to brain-gut axis inflammation (168), and intestinal stenosis from inflammatory bowel disease (169). These symptoms may stem from increased nervous system activity and the release of transmitters that enhance muscle contraction, vascular remodeling, or fibroplasia.

The role of HR

Potential markers for HR

External stimulation can trigger HR symptoms like fever, leukocytosis, and increased CRP. CRP activates the complement system and enhances phagocyte activity, a sensitive indicator of tissue damage or inflammation from pathogens (170). IL-6 is a critical pro-inflammatory cytokine that regulates immune cell proliferation and differentiation, making it an early marker of tissue damage and involved in immune and nervous system modulation (170). TNF-α is produced by monocytes/macrophages and regulates immune functions, massively released in response to trauma (171). IL-1β is critical in autoimmune diseases and cellular activities, aiding tissue repair and pathogen defense, associated with pain, inflammation, and autoimmunity (172). Thus, CRP, TNF-α, IL-1β, and IL-6 can indicate acute-phase HR (6), but no clear markers exist for chronic-phase HR (6).

In addition, a variety of potential biomarkers have been proposed to reflect hyperreactive status. These include cytokines and immune mediators, such as IL-1, IL-2 (173), IL-4 (174), IL-6 (164), IL-8 (175), NO, tumor necrosis factor-α (171), CRP (170), and myeloperoxidase; endocrine hormones such as testosterone, cortisol (176), epinephrine, and norepinephrine; and oxidative stress metabolites including malondialdehyde, thiobarbic acid, ascorbic acid, 4-hydroxy-2-nonenal, and 8-hydroxy-deoxyguanosine (177). Other relevant indicators involve phagocytic activity-related factors, such as granulocyte colony-stimulating factor (178), myeloperoxidase, macrophage chemotactic protein-1, and neutrophil chemotactic factor; markers of myocardial and DNA injury including cardiac troponin I, creatine kinase, and CK-MB (179); coagulation proteins such as fibrinogen, prothrombin, factor VIII, and plasminogen (180); complement components (C1s, C4, C2, C3, factor B, C5); as well as heat shock proteins, blood glucose, and lactate levels. Biomarker monitoring enables assessment of HR severity and treatment response, emphasizing dynamic trends over absolute values and highlighting the need for molecular trajectory models to guide precision management.

Therapeutic approaches to HR

The mechanisms underlying HR include activation of the sympathoadrenal medulla system by surgical stimulation, releasing catecholamines (181); activation of neutrophils and macrophages by inflammatory mediators and cytokines (182); and hormone level changes from HPA system activation (183). Since HR is closely related to allergic immune reactions, neurofeedback stimulation, and endocrine activation, treatment strategies should focus on these aspects.

Inflammation and immune regulation therapy

This category encompasses interventions targeting excessive inflammatory cascades and immune hyperactivation, the key drivers of HR. Non-steroidal anti-inflammatory drugs and cholinergic inhibitors serve as foundational anti-inflammatory agents in trauma and severe infection by mitigating immune dysfunction caused by excessive inflammatory mediators. GCs exert potent anti-inflammatory and immunosuppressive effects by suppressing immune cell activity and reducing excessive immune responses in infections and autoimmune diseases; for example, early corticosteroid use decreases migration of neutrophils, monocytes, and lymphocytes in acute respiratory distress syndrome, while also lowering serum and bronchoalveolar lavage fluid levels of IL-6, IL-10, and TGF-β1 to alleviate pulmonary inflammation induced by the SARS-CoV N-protein (83,184). In the context of SARS-CoV-2-related HR, which is characterized by cytokine storms resulting from massive immune cell infiltration and elevated pro-inflammatory cytokines and chemokines (86), GCs help correct excessive immune responses and inflammatory stress. Cytokine antibodies and receptor antagonists directly target pro-inflammatory cytokines to reduce systemic HR. For instance, TNF-α antibodies significantly improved survival in animals with lethal Escherichia coli infection (from 9 hours in controls to 7 days in treated groups) (185), while IL-6 antibodies, given IL-6’s central role in cytokine storms through IL-6R binding and gp130 dimerization, have shown efficacy in animal models of septicemia (186). Antihistamines alleviate allergic-type HR by competing with histamine for effector-cell receptors. Activation of histamine H1 receptors, which are expressed in capillaries, bronchopulmonary tissue, and intestinal smooth muscle, mediates mast-cell-derived symptoms such as vasodilation, extravasation, pruritus, urticaria, and bronchospasm (187). Second-generation H1-antihistamines, such as loratadine, effectively mitigate these responses (188).

Neuro-endocrine regulation therapy

Neuro-endocrine regulation therapy aims to correct HR-related dysregulation across the nervous, endocrine, and immune systems by interrupting maladaptive signaling loops. Nerve block techniques, which involve injecting local anesthetics near neural structures such as ganglia, roots, trunks, plexuses, or nerve endings, or using physical methods to inhibit nerve conduction, effectively disrupt the “pain-muscle spasm-ischemia-pain” cycle, thereby reducing neurogenically mediated inflammation and HR (189). In parallel, modulation of the renin-angiotensin system through ACE inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) provides an additional therapeutic strategy. Angiotensin II promotes vasoconstriction and inflammation, while agents such as captopril and losartan suppress pro-inflammatory cytokine production and vascular reactivity, collectively exerting anti-inflammatory and vasoprotective effects that mitigate HR-associated pathophysiological responses (190).

Vascular function improvement therapy

Focused on mitigating vascular hyperpermeability, a common contributor to local and systemic HR manifestations. Yuan et al. (191) showed that the angiogenic inhibitor Pazopanib improves pulmonary vasculature stability through the myeloid MAP3K2/MAP3K3-p47phox pathway, enhancing pulmonary barrier function and reducing acute lung injury risk.

Collectively, these therapeutic approaches highlight the multi-dimensional management of HR, encompassing neuroimmune, inflammatory, and endocrine regulation. Based on these mechanisms, a hierarchical management framework for different HR types is summarized (Table 3).

Tailored treatment plans

Treatment for HR after LT

Post-LT HR commonly manifests as acute or chronic rejection. Acute cell-mediated rejection (ACR) occurs when recipient T cells recognize donor major histocompatibility complex, increasing the risk of allograft failure (192). Symptomatic grade A1 and ≥ A2 ACR are typically managed with GC pulse therapy, while refractory cases may require optimization of maintenance immunosuppression (e.g., switching from cyclosporine to tacrolimus) (193); anti-thymocyte globulin to deplete cytotoxic T cells (194), alemtuzumab to reduce severity via antibody-dependent lymphocytolysis (195), anti-CD3 monoclonal antibodies to deplete circulating T lymphocytes, cyclophosphamide to inhibit DNA synthesis (192), or in vitro phototherapy to modulate T cell immunity (196).

Antibody-mediated rejection (AMR) arises from donor-specific antibodies (DSA) against HLA molecules, ABO isoagglutinins, or endothelial antigens (197). Treatment focuses on reducing circulating DSA, using strategies such as plasmapheresis (198), intravenous gamma globulin to induce B-cell apoptosis and inhibit complement (199), rituximab to deplete peripheral B cells (200), bortezomib to target plasma cells (199); and other monoclonal antibodies like eculizumab or alemtuzumab as salvage therapy.

Chronic lung transplant failure, often resulting from chronic rejection, presents as BOS or RAS (201). Management includes optimizing immunosuppression (e.g., switching to tacrolimus), cautious use of GCs, azithromycin to reduce inflammation, ex vivo photochemotherapy for BOS with declining forced expiratory volume in one second (FEV₁), and total lymphatic irradiation in select cases. Maintenance therapy typically combines calcineurin inhibitors (cyclosporine, tacrolimus), cell proliferation inhibitors (mycophenolate mofetil, azathioprine), GCs (methylprednisolone, prednisone), and mTOR inhibitors (sirolimus, everolimus) (202). According to the 2018 International Society for Heart and Lung Transplantation (ISHLT) registry, the most common 1-year post-LT regimen was tacrolimus + mycophenolic acid + GC (37), and our center recommends adding pazopanib for quadri-combination therapy during acute HR phases (191).

Treatment for HR after thoracic surgery

Minimally invasive procedures such as video-assisted thoracic surgery (VATS) reduce surgical trauma, yet acute postoperative pain may still arise from incisions and nerve injury. Inadequate pain management can lead to chronic pain. Traditional opioid-based anesthesia carries side effects, including nausea, dizziness, delayed mobilization, and risk of dependence. To mitigate acute postoperative pain, perioperative nerve blocks should be performed prior to skin incision, reducing stress responses, nociceptive stimulation, and the likelihood of chronic pain (203). Multimodal analgesia, including patient-controlled analgesia pumps, helps maintain stable drug levels and enables patient self-management (204). Early extubation, nutrition, and mobilization are also encouraged.

Outlook

HR, a frequently underappreciated mode of body response, is characterized by the exhaustive thoroughness of its response, a tendency towards premature or sustained reactivity, and marked variability, dysregulation, and a distinct inter-individual and genetic predisposition. Presenting as an overt external reaction, the character of HR varies in accordance with the reaction site and the stimulus that triggers it. This indicates a profound underlying imbalance within the orchestration of various systems, including the nervous, humoral, immune, and microenvironmental systems. This incongruity is observable in a multitude of hypersensitivity responses linked to various diseases such as LT, surgery, COVID-19, and chronic cough.

HR individuals exhibit heightened sensitivity to low-dose endocrine-disrupting chemicals (EDCs), such as bisphenol A and phthalates. This suggests potential compensatory alterations in detoxification pathways (CYP450 enzyme activity) and genetic polymorphisms in biotransformation genes, collectively lowering toxicity thresholds (205). For physical exposure, noise and airborne particulate matter (PM_2.5/PM₁₀) may enhance systemic inflammatory reactivity, possibly mediated by overexpression of TLR signaling pathway and dysregulation of epigenetic network (206). Psychosocial stressors further exacerbate neuroendocrine-immune crosstalk, where enhanced GC receptor sensitivity promotes exaggerated cytokine storms via bidirectional HPA-immune communication (207). Build an HR oriented dynamic exposure group monitoring model that integrates wearable sensors with multi-time point biological sample collection. Constructing a dynamic exposure group monitoring model guided by HR, integrating wearable sensors with multi-time point biological sample collection, providing new insights for personalized detection of HR.

Our paper evaluates the potential advantages and challenges inherent in using HR as a tool for disease diagnosis and personalized patient management. Deepening our understanding of the nature and variants of HR can pave the way for more efficacious strategies to manage and treat patients suffering from conditions marked by underrecognized HR. This approach offers a unique opportunity to facilitate more precise, patient-centric therapeutic interventions. In the future, clinical indicators (lung function), serum inflammatory cytokine groups, and environmental exposure data can even be combined through unsupervised learning (such as t-SNE clustering) to identify subtypes. This will lay the foundation for targeted therapy.

Conclusions

HR represents a critical yet underrecognized physiological and pathological paradigm that transcends traditional disease boundaries. Our synthesis elucidates that HR is a distinct clinical entity, characterized by a decreased threshold and an amplified response amplitude, primarily driven by dysregulation of the neuroendocrine-immune-microenvironment axis rather than antigen-specific immunity. The manifestations of HR—ranging from postoperative sequelae and chronic lung allograft dysfunction to severe COVID-19 and persistent cough—highlight its profound clinical relevance. Recognizing HR as a common underlying mechanism provides a transformative lens for reinterpreting complex patient presentations. Moving forward, future efforts must focus on validating specific biomarkers for HR, establishing dynamic monitoring models, and developing personalized, mechanism-driven management frameworks. By integrating these insights into clinical practice, we can advance towards more precise, proactive, and patient-centered care, ultimately improving outcomes for individuals experiencing these exaggerated reactive states.

Acknowledgments

We would like to acknowledge The First Affiliated Hospital of Guangzhou Medical University and the State Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory Disease for providing access to the necessary resources for conducting this study.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-1929/rc

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-1929/prf

Funding: This study was supported by the Science and Technology Plan Project of Guangzhou (No. 202206080013 to J.H.), the China National Science Foundation (Nos. 82022048 & 81871893 to W.L.), the Key Project of Guangzhou Scientific Research Project (201804020030 to W.L.), and the National Natural Science Foundation of China (No. 82404093 to X.L.).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-1929/coif). J.H. received funding from the Science and Technology Plan Project of Guangzhou (No. 202206080013). W.L. received funding from the China National Science Foundation (Nos. 82022048 & 81871893), and Key Project of Guangzhou Scientific Research Project (No. 201804020030). X.L. received funding from the National Natural Science Foundation of China (No. 82404093). J.P.T. serves as Chief Scientist at Biosyngen and Chairman of Scientific Advisory Board at BioSyngen Pte Ltd. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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