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].