The diagnostic difficulty of EGPA is attributed to its diverse manifestations of symptoms that may impact different organ systems [19]. Wheezing, coughing, and shortness of breath are common asthmatic symptoms that patients first encounter and may even come on before systemic indications. Skin involvement can include ulcers, livedo reticularis, palpable purpura, and skin nodules. Sensory and motor compromise is a common feature of peripheral neuropathy, and mononeuritis multiplex may range from mild to severe. Respiratory involvement is common in EGPA and ranges from sinusitis and nasal polyps to severe manifestations such as pulmonary infiltrates and exacerbations of asthma. Furthermore, the likely vascular nature of the disease increases its multisystemic involvement, which may include cardiovascular complications such as myocarditis and pericarditis. Someone else may have diarrhea or other stomach symptoms, such as abdominal pain [20]. Considering the wide range of symptoms [21]. EGPA requires a multidisciplinary approach for efficient treatment to enhance patient outcomes and reduce the course of the disease [22].

EGPA has a polyorgan systemic involvement [13]. The most recognized system involved is the respiratory system, with the lungs being one of the most commonly involved organ systems. Respiratory symptoms can worsen if not treated quickly and may progress from mild asthma-like symptoms to severe eosinophilic pneumonia and diffuse alveolar hemorrhage, which can ultimately lead to respiratory failure [23]. In addition to the lungs, skin has a role in the majority of cases of EGPA with nodules, livedo reticularis, and palpable purpura, all signs consistent with small-vessel vasculitis. The cardiovascular involvement of EGPA may include coronary artery disease, myocarditis, or pericarditis, all of which have the potential to be serious complications [24]. Neurological features include peripheral neuropathy or mononeuritis multiplex, which represent peripheral nerve changes/damage due to vasculitis. Involvement can occur in other organ systems as well, with vasculitic changes in the gastrointestinal tract (GIT) and kidneys [25].

EGPA has an impact on several organs, such as the lungs, kidneys, heart, and GIT [22]. Before the vasculitic phase, asthma is frequently a respiratory problem in EGPA patients. Sinusitis and allergic rhinitis are frequent conditions that can develop either before or after asthma [26]. A frequent cause of morbidity and death in EGPA is myocarditis. Arrhythmias or heart failure might manifest as a result. Pericarditis: Chest discomfort and pericardial effusion can result from inflammation of the pericardium. One possible cause of myocardial ischemia or infarction is coronary vasculitis [27]. Peripheral neuropathy is a prevalent symptom that frequently appears as a broader polyneuropathy or as multiple sclerosis. Less frequent indications of CNS involvement are strokes, headaches, and encephalopathy [28]. Lower limbs are typically affected by palpable purpura. In the integumentary system, cutaneous vasculitis causes nodules or ulcers [29–31].

Cardiac function is not standard and can be fatal in EGPA patients, but it can also have serious outcomes. Endomyocardial biopsy showed eosinophilic aggregations in the sub-endocardium, suggesting injury to the ventricular endothelium, which can lead to thrombus formation [32–34]. Although rare, this multisystem vasculitis may cause important cardiac complications [35]. Ocular manifestations occurring in EGPA may include orbital myositis, conjunctival nodules, and blockage of the central retinal vein or artery, ptosis, ischemic optic neuropathy, and dacryocystitis [36]. Chronic or acute inflammation of the sinus and nasal mucosa, accompanied by abnormal mucus production, can be the result of many stressors that can influence the normal functioning of the immune system and/or the vascular tone, both locally and systemically. In certain situations, the inflammatory state of the lower respiratory tract can also be influenced by the upper respiratory tract [37]. The course of EGPA can progress through three distinguishing phases: prodromal, eosinophilic, and vasculitic phases. Each phase is characterized by a separate but closely linked group of manifestations and pathophysiology. The prodromal phase usually begins with sinusitis and asthma. The late phase of EGPA is marked by the development of heart failure, gastrointestinal involvement, and pulmonary infiltrates after 8 to 10 years [22, 38], representative of eosinophil-induced cardiomyopathy. The vasculitic phase of EGPA is characterized by patients with manifestations of glomerulonephritis, palpable purpura, and neuropathy [39].

Mucin may promote the proliferation of eosinophils. Mucus pathobiology is also expected to involve mast-cell activation, eosinophil-independent IL-13 production, and non-type 2 (T2) cytokines. Such as non-steroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disorders, eosinophilic bronchiolitis, asthma with an eosinophilic phenotype, and eosinophilic chronic rhinosinusitis (ECRS) [41]. Though occasionally more than one illness develops concurrently or sequentially, most of the NSAIDs have an adult onset. When given systemic corticosteroids (CS) as an initial therapy, mast cells respond well to them [42] and generate precursors of eosinophils. As a chemotactic agent, IL-5 helps eosinophils migrate from bone marrow into the circulation and enhances their survival in tissue. The only cells that express the IL-5R are mast cells, basophils, and eosinophils [43].

ANCA vasculitis is associated with the most frequent systemic involvement of small vessel vasculitides. A predetermined list of cases was utilized to identify individuals with ANCA-associated vasculitis (Figure 1), including those with microscopic polyangiitis (MPA), EGPA [44]. The relationship between interstitial lung disease (ILD) and MPO-ANCA-associated vasculitis (AAV) is widely acknowledged. The diagnosis of AAV is associated with a poor prognosis and might happen simultaneously, post-, or even before pulmonary fibrosis [45]. AAV is an autoimmune-mediated inflammation of tiny blood arteries in several organs, including the kidneys [42]. In contrast EGPA is driven by an eosinophilic mechanism characterizsed by the excessive production of eosinophils, as well as elevated levels of IL-5. The resulting tissue damage is mainly caused by the accumulation of inflammation, chronic rhinosinusitis with eosinophilia and nasal polyps, toxic granules, and pro-inflammatory cytokines. This process leads to inflammation and the formation of granulomas (Figure 2).

The pathophysiology of EGPA is hypothesized to have a genetic basis and environmental factors, which ultimately result in dysregulation of the immune system and a consequent inflammatory response. Genetically, some cases of EGPA are linked with certain variants of the HLA genes, indicating a genetic predisposition for this disorder. These genetic factors could mediate the regulation of the immune system, as well as promote an abnormal response to certain environmental factors [46].

In susceptible individuals, environmental factors are thought to act as triggers for EGPA. For instance, exposure to some medications has been linked to the change of EGPA in some individuals; these drugs include those used to treat asthma, such as leukotriene receptor antagonists. Infections have also been suggested as potential triggers, but this could be because they provoke an autoimmune response. Environmental allergens could also be involved in EGPA’s increased eosinophils, since such cells are frequently increased in allergic reactions [47]. The interaction between these genetic and ecological factors, therefore, induces the onset of the immune response, which then leads to eosinophilia production, ultimately leading to vasculitis affecting multiple organs. This complexity in pathophysiology highlights the possibility that genetic predisposition and environmental exposure converge to promote both initial eosinophilic proliferation as well as progression of EGPA [48].

Currently, there are no accepted diagnostic criteria for EGPA. The proposal from 1984 stated that, in addition to eosinophilia and asthma, the patient should have systemic vasculitis of two or more organs. In 1990, the American College of Rheumatology (ACR) created six criteria classifications for EGPA. Criteria included asthma, eosinophilia greater than 10%, neuropathy, and paranasal sinus abnormalities, nonfixed biopsy-revealed lung infiltrates, and extravascular eosinophils. The categorization standards to distinguish the various vasculitides were also established by the ACR [12, 49]. The ACR criteria, however, may only be used to describe the kind of vasculitis in individuals who have been diagnosed with it, as they were developed for categorization (rather than diagnostic) purposes. In individuals who did not use prednisone, the association between laboratory tests was somewhat significant, but was dramatically decreased when prednisone was used [50]. Every patient at every study visit had the following tests performed at the Vector Control Research Center (VCRC) sites, and standard techniques were used to measure the eosinophil count, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR). As previously mentioned, ELISA was used to measure the serum levels of TARC (Thymus and Activation-Regulated Chemokine, also known as CCL17) and eotaxin-3, and total IgG and IgG4 content were examined using nephelometry [51].

Extravascular granulomas, eosinophilic infiltrates, and small and medium-sized vessel vasculitis are the most common histological findings in EGPA. An eosinophilic necrotic matrix, including interstitial and vascular granulomas, is encircled by large cells and palisading lymphocytes. The primary foci of the vasculitic process are tiny and medium-sized vessels, particularly small arteries. whether granulomas or eosinophils are present or not [45]. Fibrinoid necrosis of the arterial cell wall characterizes the systemic process, which may occur in small and medium vessels, particularly smaller veins, and is often related to or occurs apart from granulomas and eosinophilic infiltrates [13].

Recent studies have suggested that patients with seronegative EGPA might show ANCA activity in their sputum. This activity is associated with sputum eosinophilia and more severe respiratory symptoms. Sputum ANCA testing is being studied both as a way to reveal a separate subset of patients as well as a potential way to diagnose serum ANCA-negative EGPA [6]. It is essential to conduct a complete pulmonary and respiratory symptom evaluation, which will include pulmonary function testing and baseline imaging of the chest. At the same time, all patients should undergo chest X-rays; CT will allow for a more detailed assessment of pulmonary abnormalities. Confirmation of pulmonary eosinophilia can be made via bronchoscopy and evaluation of inflammatory cells in the bronchoalveolar lavage fluid (BALF). Assessing cardiac involvement, given the poor prognosis in sepsis with the cardiac participation at both diagnosis and relapse, is key; therefore, all patients should undergo a cardiological assessment at baseline. At a minimum, this would include an electrocardiogram (ECG), echocardiogram (ECHO), and recording of serum cardiac biomarkers, specifically BNP and troponin. A 24-hour symptom monitor can help detect arrhythmias that may not be seen with the resting ECG [52]. The differential diagnosis of EGPA involves mostly other eosinophilic disorders and small-vessel vasculitides. Microscopic polyangiitis GPA can generally be differentiated based on clinical presentation and histopathology. Still, at least some patients with EGPA may present with PR3-ANCA positivity and features of granulomatous vasculitis or eosinophilia. Peripheral or regional eosinophilia, although rare, can occur in EGPA [22, 53].

A number of drugs have been developed for the treatment of EGPA with their unique mechanisms of action and indications (Table 1). EGPA management uses induction treatment with rituximab (RTX) or CYC. CYC is preferred more specifically when there is cardiac involvement. Maintenance treatment (with azathioprine, methotrexate, or mepolizumab, etc.) is initiated approximately two weeks after induction therapy and planned for 18 to 24 months to reduce relapse recurrences and glucocorticoid toxicity. Mepolizumab is currently a first-line option, while glucocorticoid monotherapy is used in mild disease. Interferon-α is rarely used since it has limited benefit compared to the risk of adverse effects, and also poor results in treating patients experiencing severe relapses.

EGPA is a very uncommon condition; current treatment approaches are primarily based on research addressing other, more common AAVs. Asthma and ENT symptoms should be treated with topical medications first since they have a poor effect on the quality of life of the patient, may be effectively managed with general treatments, and often progress independently of systemic vasculitic manifestations. MPA, GPA, and EGPA treatment with systemic involvement must be phased in throughout the induction and maintenance phases [68–70]. It is reported that nearly 90% of EGPA patients attained remission, 18% relapsed, and 25.3% had flare-ups of either asthma or ENT, which supports continued GC usage [71, 72]. potential toxicity is a serious worry, particularly for young children who may require therapy for a long time, often their whole lives [73]. Before the availability of rituximab, CYC was used almost ubiquitously for initial induction therapy for severe vasculitis. There is a growing body of evidence across various patient groups that provides evidence for the use of the CYC induction regimen. The CYCLOPS study showed that patients treated with bolus IV of CYC experienced a safer induction than those treated orally daily and found fewer side effects because they had a reduced cumulative dose [74, 75]. The CYC regimen was suggested by the CORTAGE study, which included 14 EGPA patients. With regard to effectiveness, there were no important changes compared to the conventional regimen, but there were fewer adverse effects [76]. A total of six infusions, or three infusions every two weeks and three infusions every three weeks, make up the real dosage of 0.5–0.7 g/m². In light of the growing experience with different AAVs, the recently released ACR recommendations recommend that patients with severe EGPA be administered RTX or CYC for the induction of remission. Because of its better clinical experience, individuals with a worse prognosis and active cardiac involvement should take CYC preferentially. In any case, it is still uncertain how well CYC and RTX work in comparison to EGPA induction regimens. To lessen dose-related CYC toxicity [71], RTX is also advised as an induction protocol for recurrent illnesses, regardless of the method chosen. Relapse rates in the absence of maintenance medication vary from 73.8% to 85.7%, depending on the length of CYC therapy time duration in 6 to 12 months [77]. It is suggested to begin maintenance therapy two weeks after the last CYC course. Again, there are no randomized controlled trials (RCTs) comparing the current maintenance therapy for EGPA or stating how long it should be continued. However, in RCTs, AAVs were found to be better than mycophenolate mofetil, and azathioprine and methotrexate are equal [71, 78, 79]. However, the recently published ACR recommendations urge this inclusion to reduce GC toxicity. Mepolizumab is now a part of first-line treatment with RCT evidence [30, 80, 81]. No RCT has evaluated methotrexate, azathioprine, or mycophenolate mofetil in EGPA patients. For recurrent disease, alternate immunosuppressants should be used. Glucocorticoid monotherapy can be used in select patients [67]. Interferon-α has demonstrated a potential to induce remission in EGPA patients and reduce eosinophil counts, but is limited in its clinical use because of significant side effects and poor efficacy in high-degree relapses [71, 82, 83].

Vasculitis, asthma-directed therapies, and pathways toward remission exacerbation and maintenance increasingly depend on new biologics, especially in relapsed or treatment-resistant EGPA, with some shared similarities in asthma, eosinophilic disorders, and systemic AAV [84, 85]. An improved understanding of the EGPA pathophysiology has revealed a target-rich landscape within the Th2 IL activation pathway and eosinophils. Agents have been developed targeting eosinophil biology, most importantly, mepolizumab, an anti-IL-5 monoclonal antibody. The role of the B-cell compartment in EGPA is unclear; however, rituximab has been studied in other AAVs and is being investigated for this purpose in EGPA [86].

Treatments for EGPA that target IL-5, a cytokine that is intimately linked to eosinophils, have shown promise [113]. Anti-IL-5 medications, such as mepolizumab, can be used as a steroid-sparing therapy and have demonstrated effectiveness and safety in individuals with refractory or recurrent EGPA [114].

There are multiple compelling pathways of research into therapeutic targets for EGPA to ultimately improve treatment success and lessen the burden of this multifactorial disease. Eosinophils are integral to the pathophysiology of EGPA, and targeting eosinophils might be the ideal therapeutic direction. Mepolizumab and benralizumab, two biological therapies that specifically target IL-5 or IL-5R, have been shown to reduce eosinophil counts and improve clinical outcomes in some patients. IgE is another possible target because it is important for the eosinophils and mast cells. The anti-IgE monoclonal antibody omalizumab has shown promise in the treatment of severe asthma. EGPA: More data will be needed to confirm this. In addition to this, future research could explore targeting pathways that are involved in eosinophil recruitment, activation, and survival (e.g., CCR3 antagonists or inhibitors of eosinophil survival determinants such as IL-5 and GM-CSF). In addition, a fresh understanding of the pathophysiology of EGPA and mechanisms of T lymphocytes and their cytokines, especially involving Th2 and Th17 responses, may lead to new therapies that target these immunological pathways. It is hoped that as the complex mechanisms of EGPA, such as the processes involving T lymphocytes, are unravelled, these specific strategies may shift therapy paradigms and improve outcomes of patients living with this challenging vasculitis.