Pulmonary eosinophilic vasculitis with granulomas and benralizumab in children

Letter to the Editor,

Pulmonary eosinophilia represents a group of heterogeneous disorders consisting of lung disease and eosinophilia in the peripheral blood, alveoli, and/or pulmonary interstitium.¹ Subtype classifications include eosinophilic pneumonia (acute and chronic), allergic bronchopulmonary aspergillosis (ABPA), eosinophilic granulomatosis with polyangiitis (EGPA), drug or parasite-induced pulmonary eosinophilia, hypereosinophilic syndromes, and idiopathic pulmonary eosinophilia.¹ These classifications are based on adult populations, and therefore may not always be applicable to pediatric patients. As pulmonary eosinophilia rarely occurs in children and is largely described through case reports, its true incidence in pediatric populations is unknown. We report three cases of pediatric pulmonary eosinophilia identified at a single center within a 5-month period in 2019, all of which posed classification challenges. Benralizumab, an anti-interleukin-5 receptor alpha (IL-5Rα) monoclonal antibody, was used in all three cases under the impression of probable beneficial effect.

1 ∣. CASE SERIES

Medical records, imaging studies, and lung biopsy pathology of three patients were retrospectively reviewed from 2019 to 2020 for demographics and clinical course (Table 1).

TABLE 1.

Case descriptions

	Patient 1	Patient 2	Patient 3
Demographics
Date of diagnosis	Spring 2019	Summer 2019	Fall 2019
Age at diagnosis (years)	14	7	15
Sex	Female	Female	Female
Duration of symptom onset	Acute change × 1 month	7 months	7 months
Known history of asthmaa	Yes	Yes	No
First-hand inhalant exposure	No	No	Yes
Investigations
ANCA, MPO, and PR3 positivity	MPO+	Negative	p-ANCA+ and MPO+
Immunoglobulin E	5988 kUA/L (elevated)	Normal	Normal
Inflammatory markers
ESR	80 mm/h (elevated)	Normal	Normal
CRP	25 mg/dL (Elevated)
Infectious workup	Negative	Negative	Negative
Renal involvement	Self-resolved hematuria	No	Self-resolved hematuria
Peripheral eosinophilia	8% (AEC 0.71)	21% (AEC 3.77)	17% (AEC 2.50)
BAL eosinophils (%)	6	52	63
Diffuse alveolar hemorrhage	Yes	No	No
Chest CT
Ground glass opacities	Yes	No	Yes
Centrilobular nodulesb	Yes	Yes	Yes
Septal thickening	Yes	Yes	No
Bronchiectasis	No	Yes	Noc
Lung biopsy
Eosinophilic vasculitis	Yes	Yes	Yes
Granulomas	Yes	Yes	Yes
Pigment deposition	No	No	Yes
EGPA criteria
Revised CHC nomenclature	Yes	No	Yes
ACR classification criteria	Yes	Yes	Yes
Lanham diagnostic criteria	No	No	No
European respiratory society	Yes	No	No
Treatment
Duration of glucocorticoids	8 months	3 weeks	6 months
Steroid regimen	1 g IV methylprednisolone daily × 3 days, then 0.5 mg/kg prednisone twice a day tapered	1 mg/kg prednisolone twice a day × 7 days, then 1 mg/kg every other day × 2 weeks	1 g IV methylprednisolone daily × 3 days, then 40 mg prednisone daily tapered
Steroid-sparing agent(s)	Rituximab and benralizumab	Benralizumab	Benralizumab
Side effects of benralizumab	None	None	None

Abbreviations: ACR, American College of Rheumatology; ANCA, anti-neutrophil cytoplasmic antibody; BAL, bronchoalveolar lavage; CHC, Chapel Hill Consensus; EGPA, eosinophilic granulomatosis with polyangiitis; MPO, anti-myeloperoxidase antibody; PR3, anti-serine protease 3 antibody.

^aAsthma diagnosis is defined clinically by recurrent airflow obstruction that is reversible with a short-acting beta-agonist.

^bAll centrilobular nodules were subcentimeter in size.

^cBronchial dilation present.

1.1 ∣. Patient 1

A 14-year-old female with a history of asthma, pulmonary hypertension, factor VIII elevation with venous thromboses, and concern for ABPA presented to the hospital in pulmonary hypertensive crisis after 1 month of worsening dyspnea. Labs were notable for peripheral eosinophilia, elevated inflammatory markers, and positive myeloperoxidase (MPO) antibody testing. Infectious workup was unremarkable and she was escalated to bilevel positive pressure respiratory support. Baseline spirometry 2 months before presentation showed a forced expiratory volume in 1 s percent predicted (FEV₁%) of 73%. BAL revealed 6% eosinophils and copious red blood cells. Chest CT demonstrated massive pulmonary artery enlargement and diffuse pulmonary nodules (predominantly centrilobular), while lung biopsy revealed focal necrotizing granulomatous arteritis with eosinophils, thrombi, and pulmonary artery hypertrophy. She was treated with 1 g IV methylprednisolone for 3 days and quickly transitioned to nasal cannula oxygen support with normalization of inflammatory markers. She received 375 mg/m² rituximab weekly for four doses along with 30 mg benralizumab every 4 weeks for three doses, then every 8 weeks thereafter. She transitioned to 0.5 mg/kg prednisone twice a day that was tapered over 8 months and received maintenance 375 mg/m² rituximab at 6 months. At her 6-month follow-up, lung function, symptoms, and pulmonary hypertension treatment remained at baseline.

1.2 ∣. Patient 2

A 7-year-old female with a history of inadequately controlled asthma presented to pulmonary clinic with chronic hypoxemia and cough. Labs were notable for peripheral eosinophilia, normal inflammatory markers, and negative ANCA testing. Infectious workup was unremarkable. Spirometry revealed severe obstruction with an FEV₁% of 26%. BAL showed 52% eosinophils. Chest CT demonstrated multifocal mucus plugging, bronchiectasis, and tree-in-bud opacities, while lung biopsy revealed eosinophilic vasculitis with granulomatous inflammation. She responded to 1 mg/kg prednisolone twice a day for 7 days followed by 1 mg/kg every other day for 2 weeks before stopping. She successfully transitioned to 30 mg benralizumab every 4 weeks for three doses, followed by dosing every 8 weeks. Upon initiation of benralizumab, symptoms improved immediately per her mother's report and her FEV₁% improved to 63% in followup 7 months later.

1.3 ∣. Patient 3

A 15-year-old female presented to pulmonary clinic with 7 months of worsening cough, dyspnea, nasal congestion, and a 10-lb weight loss. Exposures included 1 year of vaping from a pod device multiple times per week. Labs were notable for peripheral eosinophilia, normal inflammatory markers, and positive MPO antibody testing. Infectious workup was unremarkable. Spirometry showed an FEV₁% of 29%. BAL revealed 68% eosinophils. Chest CT demonstrated diffuse bronchial dilatation originally described as bronchiectasis, centrilobular nodules, scattered larger nodules, and ground-glass opacities, while sinus CT demonstrated significant and diffuse paranasal sinusitis. Lung biopsy revealed eosinophilic vasculitis, granulomas, and black pigment deposits. Symptoms and spirometry improved with 1 g IV methylprednisolone for 3 days and benralizumab 30 mg every 4 weeks for three doses, followed by dosing every 8 weeks. She tapered off of 40 mg prednisone daily, had resolution of bronchial dilation on chest CT, and had normal spirometry with an FEV₁% of 96% at the 6-month follow-up.

2 ∣. DISCUSSION

We report three children with diverse presentations of pulmonary eosinophilia. A specific diagnosis for each case remains challenging due to the lack of pediatric-specific diagnostic criteria. While each patient had eosinophilic pulmonary vasculitis with granulomas and met the American College of Rheumatology classification criteria for EGPA, not all fit the EGPA clinical syndrome described by the European respiratory task force or Lanham diagnostic criteria (Table 1). Still, the presence of vasculitis may indicate the potential for the development of EGPA over time, including extrapulmonary manifestations and a significant risk of morbidity and mortality.

Additionally, Patient 3 had first-hand inhalant exposure through electronic nicotine delivery system (ENDS) use with corresponding black pigment deposition on lung biopsy in the setting of an atypical EGPA presentation (rapid symptom onset and lack of asthma). Epidemiologic studies have linked exposures to silica, high levels of dust, and heavy metals to the development of ANCA-associated vasculitis, all of which have been found in ENDS aerosol or marijuana smoke.^2,3 These cases highlight the need for improved differentiation of causes of pulmonary eosinophilia with eosinophilic vasculitis in children.

Despite their phenotypic diversity, this cohort represents the first peer-reviewed report of pediatric pulmonary eosinophilia successfully treated with benralizumab. Traditionally, treatment includes glucocorticoids with or without steroid-sparing agents specific to the suspected underlying etiology, such as azathioprine, cyclophosphamide, or rituximab. The duration of glucocorticoid therapy varies with each patient's response to treatment and the provider's preferred weaning schedule. While glucocorticoids induce apoptosis and downregulate eosinophil development, they are nonspecific and have significant adverse effects.

IL-5 is a key mediator in eosinophil differentiation, survival, and activation. Mepolizumab, an anti-IL-5 monoclonal antibody that primarily acts on circulating eosinophils, was previously FDA-approved for the treatment of severe eosinophilic asthma.⁴ It also demonstrated steroid-sparing effects and reduced relapse rates in adult EGPA.⁴ Benralizumab, which was FDA-approved in 2017 for severe eosinophilic asthma in patients 12 years and older, has the added mechanism of inducing eosinophil apoptosis in tissues through antibody-dependent cell-mediated cytotoxicity.⁵ Therefore, it exerts its effects on both peripheral and tissue eosinophils, making it an attractive medication for diseases with significant eosinophilic lung inflammation.⁵

This report is limited by its retrospective view of three patients at a single center and their concomitant immunosuppression treatment; thus, we are unable to draw firm conclusions between the use of benralizumab and the clinical improvement in patient symptoms and steroid discontinuation. However, given the risks associated with disease progression and traditional treatment approaches, the potential mechanistic benefits, side effect profile, and steroid-sparing effects of agents targeting IL-5/IL-5Rα warrant further study in pediatric pulmonary eosinophilia.