ANCA Associated Vasculitis
AAV are small- to medium- vessel vasculitis syndromes primarily affecting the blood vessels of the airways and the kidneys. They are generally divided into granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA) [131]. The incidence of pediatric AAV is not well established, with reported incidence ranging from 0.5 to 2 per million. The most common age of onset is in early teenage years, although some children present in infancy. Lung involvement, considered to be a hallmark of MPA and GPA, is associated with increased morbidity and mortality — in one cohort of 28 patients, half of children required ICU admission and one third of these admissions were for respiratory failure, with five patient requiring mechanical ventilation [131-133].
Of the AAVs, GPA is most common in children and classification criteria can include some of the following features: granulomatous inflammation on histopathology, renal disease, ANCA positivity and, from a pulmonary perspective any of the , upper airway involvement (chronic purulent or bloody nasal discharge, recurrent epistaxis/crusts/granulomata, nasal septum perforation or saddle nose deformity), laryngo-tracheo-bronchial involvement (subglottic, tracheal, or bronchial stenosis) and/or pulmonary involvement (chest x-ray or CT with nodules, cavities or fixed infiltrates) [134].
In pediatric GPA, pulmonary involvement can range from asymptomatic with radiographic abnormalities (a prior report noted 41% of radiographic abnormalities found in patients with pediatric GPA were observed in asymptomatic patients [135]) to presentation with fulminant DAH [133]. In the ARChiVe cohort, including 183 patients with pediatric GPA, 74% had pulmonary involvement, with 54% reporting chronic cough and 42% with massive hemoptysis or alveolar hemorrhage [136, 137]. PFTs may show abnormal DLCO (related to parenchymal disease or hemorrhage), restrictive lung disease, and/or obstructive disease (related to airway stenosis). CT findings may include nodular lung lesions (secondary to necrotizing, granulomatous inflammation, which may demonstrate cavitation and/or a “halo sign” related to adjacent hemorrhage), fixed pulmonary infiltrates, and more rarely (< 10% of cases), fibrosis, septal thickening and pneumothorax [133, 136]. Bronchoalveolar lavage (BAL) with serial aliquots can be useful in evaluation for pulmonary hemorrhage.
Data on pulmonary manifestations in pediatric MPA is more limited, with conflicting data. In a case series of 38 patients with AAV (in which MPA was the predominant AAV), MPA patients had higher prevalence of more severe pulmonary manifestations than GPA patients, with a subgroup of five patients experiencing recurrent pulmonary hemorrhage. MPA patients with early onset disease had worse pulmonary outcomes [138]. By contrast, in a retrospective review of 12 children with MPA, the majority of children (66%) had no respiratory symptoms at diagnosis with normal chest radiographs. Pulmonary manifestations at diagnosis were observed in four children, all with DAH. Among children without respiratory involvement at diagnosis, only one child developed DAH after 12 months [139].
Consensus guidelines and consensus treatment plans for treatment of pediatric AAV have been established by the SHARE initiative and Childhood Arthritis and Rheumatology Research Alliance (CARRA) ANCA vasculitis workgroup [140, 141]. For severe disease with multi-organ involvement, induction consists of cyclophosphamide and steroids (pulse or high dose oral) for 3 - 6 months. Other therapeutic options for treatment of pediatric AAVs can potentially be extrapolated from adult RCTs. The RAVE [142]and RITUXVAS [142] trials demonstrated non-inferiority of rituximab for induction therapy, which could be attractive for pediatric patients due the undesirable side effect profile (include effects on fertility) of cyclophosphamide. Without extensive pediatric data however, cyclophosphamide is generally considered first line therapy. In adults, a trial comparing mycophenolate mofetil to cyclophosphamide for induction, while non-inferior to inducing remission, had high rates of relapse [143]. Other therapeutics evaluated in the adult population, but with limited to no data in the pediatric population, include plasmapheresis for patients with severe disease and avacopan [144], an oral C5a receptor inhibitor thought to slow neutrophil trafficking. For patients with less severe or localized disease, oral steroids plus methotrexate or mycophenolate mofetil can be considered for induction. Trimethoprim-sulfamethoxazole has also been used for GPA limited to the upper airways [145]. For maintenance therapy, the three most used agents are methotrexate [146], azathioprine [147], and rituximab [148].