We finally confirmed EGPA in the patient because his clinical course adhered to the items in the Japanese Ministry of Health and Welfare diagnostic criteria for “allergic granulomatosis with polyangiitis/Churg–Strauss syndrome,” which is now known as EGPA[5]. The following criteria were met: bronchial asthma, allergic rhinitis, eosinophilia, fever, and purpura. Treatment with methylprednisolone (48 mg/day) and amethopterin (10 mg weekly) was initiated. His symptoms improved, and some abnormal imaging manifestations on the chest CT disappeared within one month (Fig. 1).
Differential diagnosis
Conventionally, differential diagnosis of EGPA primarily focused on vasculitic disorders such as GPA and MPA; however, based on this case report, there is no doubt that asthma should also be considered for differential diagnosis.
Asthma is a common chronic inflammatory disease of the airways with symptoms including cough, wheeze, shortness of breath, and chest tightness[6], which presently impacts more than 300 million individuals worldwide; roughly 250,000 asthma-related deaths are reported annually[7; 8]. Notably, the prevalence of asthma is increasing rapidly in developing countries like China[9].
Both EGPA and asthma, which can be concluded as “adult-onset eosinophilic airway diseases,” are characterized by prominent peripheral blood eosinophilia. Eosinophils contain granules that are toxic to bronchial epithelial cells and play a vital role in the symptoms of asthma[60]. Hence, similar pathogenesis makes distinguishing between these two diseases difficult. In fact, whether asthma is a symptom or disease should be considered for each patient with asthma.
Mechanisms/pathophysiology
The exact aetiology and pathogenesis underlying the development of EGPA remains unknown[10]. EGPA has features of eosinophil infiltration and ANCA-induced endothelial damage, thus it is classified among the small-vessel vasculitides associated with ANCAs and hypereosinophilic syndromes (HESs)[11; 12]. Clinical manifestations of EGPA tend to fall into one of two major disease subsets dominated by vasculitic and eosinophilic manifestations, and ANCA can be used to differentiate between these two subsets. One genome-wide association study (GWAS) examining EGPA demonstrated that EGPA is comprised of two genetically distinct subtypes: MPO-ANCA+ EGPA and ANCA–EGPA, which align with observed clinical differences among patients[13; 14]. Mendelian randomization revealed an increased risk of eosinophilia underlying susceptibility to EGPA. Meanwhile, it has been suggested that various of environmental factors such as allergens, infections, vaccinations, and medications are potential triggers of EGPA[15; 16]. To some extent, there are shared genetic associations which influence both eosinophil numbers and asthma[10].
Asthma symptoms have strong associations with airway inflammation, which is characterized by the infiltration and activation of immune cells including dendritic cells, eosinophils, neutrophils, lymphocytes, innate lymphoid cells, and mast cells, which gradually leads to mucus production, remodelling of the airway wall, bronchial hyperresponsiveness (BHR), and airway obstruction. Currently, asthma phenotypes are usually classified into type 2 or non-type 2 asthma based on its mechanistic pathogenetic processes[17]. Non-type 2 asthma, which is usually associated with obesity, aging, and smoking, is characterized by infiltration of Th1cells, Th17 cells, and neutrophils, the presence of type I interferons, and NLRP3 inflammasome activation[6; 18; 19]. Type 2 asthma is usually observed in the clinic as early-onset allergic asthma, late-onset eosinophilic asthma, or exercise-induced asthma, accompanied by recurrent and chronic rhinosinusitis, allergies to common aeroallergens, high eosinophil numbers in the airways, increased periostin, and high exhaled nitric oxide[20; 21]. Additionally, asthma is characterized by variable airflow obstruction, airway inflammation, and remodelling[22].
In a study of bronchoalveolar lavage fluid (BALF) in patients with EGPA and bronchial asthma, patients with EGPA had a much stronger Th2-type response compared to those with bronchial asthma [23].
Clinical presentation
EGPA is considered to be an idiopathic condition[24]; the mean age at onset is 38 to 54 years[25; 26]. As a type of AAV, EGPAs present with manifestations relating to small vessel vasculitic lesions and organ dysfunction. Asthma is a near-universal feature often present for years before the onset of eosinophilia and eosinophilic tissue inflammation, and it is difficult to control even after EGPA treatment [10]. The presence or absence of ANCA in patients distinguish between EGPA’s two subtypes. Compared with the ANCA-negative subset that features myocardial involvement, lung infiltrates, and gastrointestinal symptoms, ANCA-positive patients are more likely to display peripheral neuropathy, glomerulonephritis, and purpura (which are due to small-vessel vasculitis) [13; 14; 27]. In general, asthma symptoms, eosinophilia greater than 10%, mononeuropathy (including multiplex) or polyneuropathy, non-fixed pulmonary infiltrates on CT, paranasal sinus abnormalities, and biopsy containing a blood vessel with extravascular eosinophils are cardinal characteristics of EGPA[59].
The symptoms of asthma are non-specific, inclusive of episodic wheezing, dyspnoea, chest tightness, and cough[28; 29]. Expiratory wheezing which may be heard on auscultation is the most noteworthy characteristic of asthma. No gold standard exists for diagnosis of asthma, and diagnosis is typically made using a two-pronged approach, including a careful review of medical history to include review of the nature of symptoms, timing, triggers, and response to treatment[30] in addition to objective measurements of variable expiratory airflow limitation, forced expiratory volume in 1 second (FEV1), and forced vital capacity (FVC)[9].
Examination
Histopathology of EGPA has revealed necrotizing small-vessel vasculitis and an abundance of eosinophils. More accurately, eosinophilic infiltrates (but no necrosis) are present in tissues or blood vessel walls in the early stages of EGPA. In later stages of the disease, the epithelioid cells within granulomas are surrounded by eosinophils and necrosis is present. Blood tests may show anaemia and eosinophilia as well as increases in C-reactive protein (CRP), lactate dehydrogenase (LDH), creatine kinase (CK), rheumatoid factor (RF), and platelets. In practice, the degree of eosinophilia elevation is typically at least 30% at the onset of vasculitis. A marked growth in total serum IgE level may be found in two-thirds of cases; meanwhile, the positivity rate of MPO-ANCA (P-ANCA) is only present in 30–40% of cases[31]. In addition, > 75% of patients with EGPA have been reported to have pulmonary parenchymal lesions on imaging, including GGO, peribronchial or centrilobular nodules, and bronchial wall thickening.[61; 63]
Sputum eosinophilia is the most useful biomarker for asthma diagnosis[32]. Although there is no standardized cut-off, an asthma diagnosis may be considered with a blood eosinophil count more than 300 cells/µL or sputum eosinophilia increases over 1–2% of the normal range[33]. Pulmonary function tests such as FEV1, FVC, FEV1/FVC% and peak expiratory flow (PEF) are also necessary to make an asthma diagnosis. Accounting for reversible airflow obstruction, guidelines such as the Global Initiative for Asthma (GINA) suggest that a bronchial dilation test (BDT) should be completed to assess airway hyperresponsiveness for suspected asthma cases without contraindications[34]. A 20% decrease in FEV1 after challenge with a standard dose of methacholine defines the positive result of bronchial provocation test (BPT)[30]. Following the use of a bronchodilator, an increase in FEV1 of more than 12% that is greater than 200 mL above the normal range is an indicator of airflow obstruction reversibility[35; 36]. However, a negative test does not rule out asthma. Although it is present in many other conditions, airway hyperresponsiveness is a key feature of asthma. Lastly, a chest CT can be used to visualize airway wall thickness and obstruction of airways by mucus, which may contribute towards an asthma diagnosis[37; 38].
Treatment
Treatment strategies for EGPA vary according to disease manifestations and severity. Treatment regimens may consist of corticosteroids (CS), immunosuppressants, intravenous immunoglobulins, plasma exchanges, and targeted biotherapies[39]. There is no doubt that concomitant manifestations of asthma should be managed aggressively. Locally administered treatments can often alleviate asthma and ENT manifestations. As for systemic therapies, corticosteroids are considered first-line treatment for EGPA. Immunosuppressive drugs such as cyclophosphamide function indirectly by reducing high glucocorticoid requirements[40]; these are typically recommended as a combination treatment, especially in severe cases with poor response to CS treatment and in patients with a poor prognosis[31]. Treatments targeting cytokines, such as humanized monoclonal antibodies mepolizumab and reslizumab, are additional therapeutic options that bind to and block the function of circulating IL-5, preventing binding between IL-5 and its receptor, which has demonstrated effects on airways and allergic manifestations[31; 41]. A randomized clinical trial illustrated that mepolizumab was useful in the majority of patients with asthma and chronic sinusitis due to its ability to maintain sustained remission, reduce relapse rates, and substantially reduce the dosage or duration of glucocorticoid therapy[42]. A study showed a 64% reduction in the corticosteroid dose after mepolizumab therapy[43]. Notably, rituximab is usually not considered as the first choice for treatment because its efficacy is less well established for ANCA– patients. Furthermore, patients with asthma and chronic sinusitis frequently experience relapses despite continuous use of rituximab[44].
Treatment strategies for asthma include environmental control, inhaled glucocorticoids (ICS), long-acting β-agonists (LABA), leukotriene antagonists, anticholinergics, and targeted biologic therapies[45]. These treatments have varying mechanisms of action which impact their suitability for different treatment scenarios. For patients experiencing acute stage asthma, the first actionable step is to distance the patient from known allergens. ICS may improve disease control and reduce asthma exacerbations by reducing the number of airway eosinophils[46; 47; 48; 49]. However, if ICS alone is not effective, the addition of a LABA such as formoterol may have significant benefits[50]. Leukotriene antagonists are best for treating asthma exacerbations in children[51; 52], and the anticholinergic tiotropium could reduce the frequency of asthma exacerbations[53]. The most widely used targeted biologic therapies include anti-IgEs, such as omalizumab, and anti-IL-5s, such as mepolizumab and reslizumab. Omalizumab is a humanized monoclonal antibody directed against IgE that has the ability to reduce the risk of asthma exacerbations in allergic asthmatic patients[54; 55; 56; 57; 58]. Since IL-5 leads to airway eosinophilic inflammation, anti-IL-5 agents are generally reserved as maintenance therapies for patients with uncontrolled persistent eosinophilic asthma.
According to this Case
Although the patient in this case report first developed wheezing in 2018, they did not meet the diagnostic criteria for EGPA based on initial examination. The patient was aware of his 3-year history of asthma, however, his EGPA status during this period remained in question.
The development of EGPA on chest CT has not yet been reported. Here, we report a case of a patient with EGPA who underwent thoracic CT six times in 4 years and had dynamic changes on CT (Fig. 1), which included the premorbid period of the disease, the period of the disease, and the period after the treatment. According to his follow-up visits, varying degrees of absorption of the lesion were observed on the patient’s chest CT. Consequently, we consider that the imaging manifestations of EGPA on chest CT might be reversible. Meanwhile, early diagnosis and treatment may prevent disease progression. Furthermore, imaging manifestations on chest CT could be regarded as an evaluation index to evaluate the therapeutic effect in patients with EGPA.
Asthma exacerbations are widely treated with inhaled CS. To relieve the recurring asthma symptoms, we administered intermittent short-term CS treatment to our patient. There are hormones available to ease the symptoms of EGPA; however, hormone treatment alone is insufficient to prevent recurrent symptoms in our patient. We considered the controversial notion that maintenance therapy is justified once remission is achieved. Ultimately, we adhered to the 2016 European Alliance of Associations for Rheumatology guidelines for AAVs to advise a combination of glucocorticoids and either methotrexate or mycophenolate mofetil[62]. To date, the patient remains in good condition, and re-examinations were normal.
EGPA has shifted from being a disease with high mortality to a chronic condition requiring lifelong management by specialists. However, despite this substantial progress, additional collaborative studies and continued interactions between basic and clinical researchers are needed to develop a gold standard for EGPA diagnosis and treatment.
The patient was finally diagnosed with EGPA after treatment for asthma for 3 years; therefore, EGPA should be considered a differential diagnosis in patients with asthma. To some extent, the abnormal manifestations on thoracic CT gradually returned to normal. We further speculated that the imaging manifestations on chest CT of EGPA might be reversible. Meanwhile, early diagnosis and treatment may prevent disease progression. Furthermore, imaging manifestations on chest CT could be regarded as an evaluation index to evaluate the therapeutic effect in patients with EGPA. Finally, low-dose CS is available to ease the symptoms of EGPA although it would be better to use a combination of glucocorticoids and either methotrexate or mycophenolate mofetil to control disease relapse.