ANCA vasculitis is a rare disease, especially in the pediatric setting. Most case reports describing the use of ECMO in ANCA vasculitis focus on the adult population [7,8,9,10]. There are very few case reports, especially within the pediatric population, described in the past 10 years detailing a patient’s hospital course with successful use of ECMO [11]. This is the third report of its kind describing a pediatric patient whose treatment involved multiple immunosuppressive medications and ECMO promoting his survival from a disease with a high mortality [11, 12].

In a case series of eight patients on ECMO from various causes of pulmonary hemorrhage (i.e., GPA, sepsis, systemic lupus erythematosus, and autoimmune hepatitis), two patients had GPA and were also successfully treated with ECMO, plasmapheresis, systemic steroids, and cyclophosphamide. One patient was treated with veno-arterial ECMO (VA-ECMO) and the other seven with VV-ECMO [13]. Another case report describes a similar patient scenario of a 13-year-old male with MPA, requiring VA-ECMO and continuous renal replacement therapy, in addition to plasmapheresis, corticosteroids, cyclophosphamide, and rituximab [11], which is similar to the treatment received by our patient.

These case studies suggest that patients with ANCA vasculitis who also have pulmonary hemorrhage may benefit from additional respiratory support while waiting for the full effects of inductive immunosuppressive agents. Some clinicians have found success utilizing ECMO specifically in the management of diffuse alveolar/pulmonary hemorrhage secondary to ANCA vasculitis [8,9,10]. Utilizing ECMO provided the support our patient needed to survive while awaiting the improvement in arteritis, which was the underlying etiology for the pulmonary hemorrhage and ensuing respiratory failure. This support also allowed for a therapeutic bronchoscopy to be performed safely. The bronchoscopy enabled the removal of significant blood clots from his airways, which was necessary for recovery of native lung function. It is also interesting to note that in the case series with eight patients mentioned above [13], seven out of the eight patients were treated with VV-ECMO and not VA-ECMO. This is significant because VV-ECMO is easier to manage without systemic anticoagulation, which is clearly a benefit in patients, such as ours, with active bleeding. The same case series also did not report any bleeding complications. However, even in one case report involving a patient with active pulmonary hemorrhage where initially no systemic coagulation was added but subsequently involved heparinizing the circuits due to active clots being formed, resolution of bleeding occurred by day three of ECMO, which suggests that ECMO can be safe in smaller children with active pulmonary hemorrhage as well [9]. In addition, VV-ECMO carries less risks than VA-ECMO, such as stroke. The patient was on ECMO for a total of 16 days, like previous patients described, survived decannulation, extubation, and was discharged home. In our case, we were able to use adult sized cannulas and circuits, which minimized the need for anticoagulation and mitigated the risk for continued pulmonary hemorrhage. Although the cases above describe success with ECMO therapy, ECMO remains a rescue therapy for both pediatric and adult patients with pulmonary hemorrhage due to the concern for bleeding complications associated with ECMO itself, as well as the risk of infection in immunocompromised patients. Prospective studies are needed to quantify the risk in our specific pediatric population.

Immunosuppressive treatment for ANCA vasculitis mainly involves two stages: induction therapy for the first 3–6 months to induce remission followed by maintenance therapy for the next 2–4 years with the aim of preventing relapses [14]. For patients with ANCA vasculitis with rapidly progressive glomerulonephritis or alveolar hemorrhage, pulse steroid treatment with IV methylprednisolone is often used for three days, as done with our patient. Previously, the standard of care for induction therapy involved glucocorticoids in combination with cyclophosphamide. However, given the toxicity profile of cyclophosphamide, rituximab has been studied as an alternative agent in adults and is increasingly being utilized and preferred (dose: 375 mg/m2 of body surface area per week for 4 weeks) [9, 15]. In particular, two important randomized control trials have been conducted: the RAVE and RITUXIVAS trials. The RAVE trial enrolled patients with new and relapsing ANCA vasculitis [16]. One arm received cyclophosphamide and the other received rituximab [16]. The end point was tapering off steroids by 6 months. Rituximab was found to be non-inferior to cyclophosphamide in reaching this goal. However, this study did not include patients requiring renal replacement therapy [16]. The RITUXIVAS trial only included patients with newly diagnosed ANCA vasculitis and included those with renal involvement [17]. Patients received either glucocorticoids plus rituximab with two IV doses of cyclophosphamide or IV cyclophosphamide for three to six months followed by azathioprine [17]. The end points were sustained remission rates at 12 months and severe adverse events [17]. Once again, rituximab was not found to be inferior [17]. Thus, rituximab is now often preferred in patients with relapsing disease, refractory disease, and contraindications to cyclophosphamide [15]. In addition to rituximab, there are several other induction treatment options being examined such as mycophenolate mofetil [18], combining cyclophosphamide and rituximab [19], and utilizing complement inhibitors [20]. As described above, our patient received rituximab in addition to glucocorticoids as part of his induction therapy. Although the PEXIVAS study demonstrated that plasmapheresis has not been shown to reduce the incidence of death or end stage renal disease, given our patient’s acute decompensation, the decision was made to proceed with plasmapheresis [21]. Plasmapheresis, cyclophosphamide, and IVIG were subsequently added given his ongoing clinical decline, as others have done in severe renal/life-threatening disease.

Cyclophosphamide used to be the cornerstone of maintenance therapy as well, with the goal of maintenance therapy being to prevent relapse rates. However, again, other options have been evaluated given the toxicity of cyclophosphamide. Given that we initially started with IV methylprednisolone, rituximab, and plasmapheresis, we only chose to use cyclophosphamide after our patient continued to further decompensate and required ECMO. Currently, azathioprine and/or rituximab are preferred forms of treatment [15]. The MAINRITSAN trial found that in patients who achieved remission after induction therapy with rituximab, when given rituximab infusions every six months patients had less major relapse at month 28 compared to the group of patients who only received azathioprine [22].

In pediatric cases of ANCA vasculitis, much of the current treatment regimens are extrapolated from adults as there are no pediatric randomized control trials evaluating treatment for pediatric ANCA vasculitis. Given the paucity of data in pediatrics, there are guidelines from various organizations. The SHARE (Single Hub and Access point for Pediatric Rheumatology in Europe) initiative, which has provided the only pediatric specific guideline, recently developed clinical care guidelines for the management of pediatric vasculitis [23]. Guidelines for induction focus on corticosteroids and cyclophosphamide as the main agents, as was common in adults. Rituximab, unlike in adults, was not discussed to be a first line induction agent but rather as second or third line. Plasma exchange therapy, while not commonly used in adult patients, was considered as an induction agent for pediatric patients if primary induction agents fail [14]. Although rituximab is thus far not mentioned as first line agent in induction or maintenance therapy, it is used more frequently in treating ANCA vasculitis [23].

This case report demonstrates the aggressive nature of ANCA vasculitis. Although this is a rare disease, modern immunosuppressive agents have been successfully used. Most importantly, our case report demonstrates and corroborates similar findings to those of other reports, which demonstrate that ECMO can be used as a life supporting therapy in pediatric patients with pulmonary hemorrhage from ANCA vasculitis. We hope that the information presented here about our patient may be useful to other patients and providers.

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