Lung involvement in childhood onset granulomatosis with polyangiitis

Granulomatosis with polyangiitis (GPA), formerly known as Wegener’s granulomatosis [1], is an idiopathic vasculitis of medium and small arteries, characterized by necrotizing granulomatous inflammation of the respiratory tract with necrotizing, pauci-immune glomerulonephritis; vasculitis frequently involves also other organs. GPA is a member of a family of vasculitides associated with positive anti-neutrophil cytoplasmic antibodies (ANCA). In GPA, the pattern of autoantibody staining of ethanol-fixed neutrophils is typically cytoplasmic (c-ANCA), rather than perinuclear (p-ANCA), due to the presence of antibodies against proteinase 3, which is a constituent of the azurophilic granules of the neutrophil [2, 3].

The family of ANCA-associated vasculitides (AAV) also includes eosinophilic granulomatosis with polyangiitis (EGPA, previously known as Churg-Strauss syndrome) and microscopic polyangiitis (MPA). The clinical spectrum of vasculitides is broad; the lack of pathognomonic features and the presence of overlapping clinical manifestations makes diagnosis challenging, especially in discriminating one form from one another. In 1990 the American College of Rheumatology (ACR) published the classification criteria for seven vasculitides, including GPA and EGPA [4‐7]. However, because of the poor performance of ACR criteria in classifying children with vasculitis, the EULAR/PRINTO/PRES criteria were developed using pediatric data. The EULAR/PRINTO/PRES criteria for GPA (Table 1) showed improved sensitivity compared to the adult-based ACR criteria (93% vs 83%) [8‐10]. However, both classification criteria did not include MPA, which had its specific definition thanks to the Chapel Hill Consensuses Conference (CHCC) [11]. It is therefore possible that cases classified as GPA according to ACR criteria may be described as MPA using the CHCC definition. In 2007 the European Medicines Agency (EMA) endorsed a classification algorithm to classify patients with a mutually exclusive diagnosis (EGPA, GPA, MPA, or polyarteritis nodosa) [12]. The EMA classification algorithm showed to be a promising tool to uniquely diagnose children with either GPA or MPA [13].

GPA onset usually occurs between 45 and 60 years of age, with a peak in the sixth decade [2, 14, 15], but in a small proportion of cases (3.3–7%) it may affect also children and adolescents. Incidence of juvenile onset GPA is not well known but estimates range from 0.02 to 0.64 per 100,000 persons per year [16, 17]. Pediatric GPA is usually diagnosed in adolescence [18‐33], with a median age at onset of 11.6 years and a median age at diagnosis of 14 years, and presents a female predominance with a male to female ratio of 1:2.1 [18].

The most common clinical manifestations of childhood GPA at onset are related to upper airway involvement (82%), nephropathy (65%) and lower respiratory tract disease (61%). This characteristic triad is frequently associated with systemic symptoms (73%) [18]. Although the main aim of this review is to present lung involvement in GPA, upper airway disease is briefly summarized below in the next paragraph, as it affects respiratory findings in patients with GPA.

According to the EULAR/PRINTO/PRES criteria, upper airway involvement can be assessed in presence of chronic or bloody nasal discharge, recurrent epistaxis/crusts/granulomata, septal perforation or sinus inflammation [9]. Sinonasal disease is a common presenting feature of GPA in children, which should be distinguished from infectious or allergic rhinitis or rhinosinusitis [18, 24, 32]. Longstanding disease can damage nasal cartilage, leading to septal perforation and saddle-nose deformity. Other manifestations of ear, nose and throat involvement include otitis, mastoiditis, oral ulcers or granulomata, mucocele, hearing loss and subglottic stenosis [19, 21, 22, 24, 33]. Young patients under 20 years of age are more prone to develop tracheal involvement [34]; subglottic stenosis was reported to complicate childhood GPA five times as often as in adults [17]. Therefore, laryngo-tracheo-bronchial stenosis was included in the pediatric EULAR/PRINTO/PRES criteria [9]. In a cohort of 28 pediatric patient affected by GPA, airway stenosis was detected in 36% of patients at diagnosis and in 50% during follow-up, with involvement of the tracheobronchial tree in a third of cases [35]. The common symptoms caused by tracheobronchial involvement include hoarseness, cough, dyspnea, stridor, and wheezing [36‐38].

Treatment requires a remission induction phase, followed by maintenance therapy. Standard treatment of GPA has primarily consisted of glucocorticoids and cyclophosphamide. Several other immunosuppressive agents have been used, in monotherapy or in combination with glucocorticoids, including methotrexate, azathioprine, mycophenolate, cyclosporine, colchicines, etanercept, infliximab, adalimumab, rituximab. Remission induction is mainly based on the use of glucocorticoids and cyclophosphamide; cyclophosphamide can be administered either orally or with intravenous pulses and should be withdrawn when remission is achieved. Remission maintenance therapy, which should last at least 18–24 months, is usually based on the introduction of azathioprine or methotrexate, with concomitant tapering of glucocorticoids [18, 19, 21, 80‐84].

Other therapeutic strategies have been used in severe and refractory cases. Intravenous immunoglobulin administration has been used as adjunctive therapy in AAV patients with refractory or relapsing disease, even if 11,9% of patients presented serious adverse events [85]. In severe cases of alveolar haemorrage, together with aggressive immunosuppressive therapy, plasmapheresis has been used [86]. The use of plasma exchange in patients with creatinine levels > 5,8 mg/dl was proved to be more effective than intravenous methylprednisolone in preventing end-stage renal disease at 12 months, but no difference was observed in survival rates and incidence of adverse events [87]. Even if plasma exchange is usually reserved for refractory disease and life-threatening conditions, it has been proposed also for induction of remission in less severe cases [88]. The PEXIVAS study will better define the benefits of plasma exchange in AAV. [89] Kidney involvement may require dialysis and kidney transplant [90].

So far, no clinical trial has been conducted in the pediatric population and no pediatric specific recommendations are available. Pediatric guidelines for GPA will be hopefully developed by the SHARE project, whose aim is to provide recommendations for the care of children and young adults with rheumatic diseases, including vasculitis [91]. At the moment, therapeutic management is guided by data extrapolated from adult studies. Guidelines for the treatment of AAV in adult patients have recently been published [92, 93].

Of note, both British and EULAR recommendations include rituximab, an anti-CD20 monoclonal antibody, which has proved to be a promising new therapeutic option for AAV both in remission induction and in remission maintenance [92‐96]. The RAVE trial, which included AAV patients older than 15 years, showed that rituximab was not inferior to cyclophosphamide in achieving remission induction and was more effective for relapsing disease; better response to rituximab was observed in anti-PR3 positive patients [94]. Rituximab should be considered as a therapeutic option for remission induction also in children, since steroid sparing in pediatric age is mandatory and cyclophospahmide avoidance is especially desirable in young people at risk of infertility. In a pediatric series, 10 patients with primary systemic vasculitis, including 4 children with GPA, were treated with rituximab with a decrease in disease activity and in corticosteroid dose. Of 10 patients receiving rituximab, 3 presented adverse events: one patient with unclassified vasculitis had mild headache with second rituximab infusion; one patient with GPA developed paronychia 2 months after receiving rituximab treatment; one patient with GPA treated with both infliximab and rituximab presented, respectively 9 and 7 months after drug discontinuation, a Pseudomonas urinary tract infection and concurrent pneumonia, while he was also being administered concurrent immunosuppressive therapy with cyclosporine A for renal transplant [97]. At the moment, as long-term safety data on the use of rituximab in pediatric vasculitis are still missing, rituximab should be prescribed carefully, in refractory cases. A phase IIa international open-label trial is currently recruiting patients to evaluate the safety and pharmacokinetics of rituximab in children with severe GPA or MPA (PePRS study, NCT01750697), but mechanical ventilation due to alveolar hemorrhage represents an exclusion criterium for participation in the study. It should be noted that also the RAVE trial excluded patients with alveolar haemorrage requiring mechanical respiratory assistance upon enrollment [94].

A retrospective study analyzing a cohort of patients with alveolar haemorrage secondary to AAV, including also patients needing mechanical ventilation, showed that complete remission by 6 months was achieved in a higher proportion of cases with rituximab than with cyclophosphamide, even though the use of rituximab was not associated with a higher long-term survival rate. The same study could not demonstrate plasma exchange efficacy in addition to the standard remission induction therapy [47].

Lung disease can also necessitate the use of supportive measures. Pulmonary haemorrhage may require ventilator support in an intensive care unit setting or even extracorporeal membrane oxygenation [20, 98]. Akikusa and colleagues reported a median duration of intubation of 8 days in the subgroup of children requiring ventilation [22].

Airway lesions rarely respond satisfactorily to systemic therapy with cyclophosphamide, but rituximab appeared to be a more efficient therapy for tracheobronchial lesions [35, 99, 100]. In the presence of subglottic or tracheal involvement, surgical intervention is often needed to maintain a patent airway [101‐103].

Lung involvement is a common manifestation in children affected by GPA. Its severity is variable, ranging from asymptomatic pulmonary lesions to dramatic life-threatening clinical presentations such as diffuse alveolar haemorrhage. Several radiologic findings have been described, but the most frequent abnormalities detected are nodular lesions and fixed infiltrates. Nodular lung lesions tend to regress with immunosuppressive therapy, but lung disease may also require second line treatments. Rituximab may represent a promising treatment option also in pediatric patients, even if its efficacy and safety in children should be better studied. In cases of massive diffuse alveolar haemorrhage, ventilator support is crucial in the management of the patient.