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DOI: 10.1055/a-2501-5886
Severe Manifestation of Granulomatosis with Polyangiitis in an Adolescent with Respiratory, Hemorrhagic and Vascular Occlusive Complications
Schwere Manifestation einer GPA bei einer Jugendlichen mit respiratorischen, hämorragischen und vaskulär-okklusiven Komplikationen
For two weeks, the 17-year-old female adolescent suffered from productive and hemorrhagic coughing, sneezing, and fever up to 39.7°C (103.5°F) which did not respond adequately to antipyretic medication. Over the next few days, shortness of breath and multiple episodes of epistaxis occurred. A perforation of the nasal septum was suspected and treated with antibiotics. Previous history revealed no serious infectious diseases, asthma or suspected autoimmune disorders, but recurrent epistaxis for about 2 years.
The patient was admitted due to shortness of breath and discoloration on distal fingers. A chest radiograph showed significant bilateral infiltrations, and an antibiotic therapy was initiated under the assumption of a community-acquired pneumonia. Due to clinical worsening and suspected autoimmune disease origin the patient was transferred to our clinic the next day.
At first presentation, the patient showed petechiae on both lower extremities, as well as livid discoloration on her distal fingers with pronounced pallor ([Fig. 1a, b]). Further, the patient showed signs of respiratory distress with orthopnea, tachypnea, and dyspnea. A chest radiograph revealed significant bilateral pulmonary consolidations ([Fig. 1c]). CT showed extensive bipulmonary consolidations with partial onset of cavitation and marginal enhancement, strongly suspected to be hemorrhagic and typical for vasculitis ([Fig. 1d]). The previously described nasal septum perforation could not be confirmed. Laboratory results showed elevated CRP with 228 mg/l (norm<5 mg/l) and normocytic normochromic anemia. Due to progressive worsening of respiratory symptoms requiring high-flow oxygen nasal cannulas (fiO2 max. 0.45; flow max. 50 l/min) over 11 days and intermittent non-invasive continuous positive airway pressure (CPAP) ventilation (with max. positive end expiratory pressure of 4,5 mbar) over 6 days, the patient was transferred to the intensive care unit the same day.
Despite initial thrombosis prophylaxis with heparin, a thrombosis of the right fibular vein developed, which could be controlled with heparin at a therapeutic dose and subsequently with factor Xa inhibitor therapy.
The patient showed mild proteinuria (protein/creatinine-ratio 397 mg/gCrea [<140 mg/gCrea] and microhematuria (24/µl erythrocytes) without impairment of kidney function (creatinine 0.52 mg/dl [0.5–0.9 mg/dl], cystatin C 0.91 mg/l [0.5–1 mg/l], eGFR 139 ml/min/1.73 m2). Urine sediment showed elevated numbers of round epithelial cells (7/μl [<1/μl]) and regular erythrocytes (24/μl [<23/μl]). These findings were interpreted as a sign of mild renal involvement. Highly elevated c-ANCA (proteinase 3 (PR3); [Fig. 2a]) were found with no detection of p-ANCA (myeloperoxidase (MPO)) which were in line with a suspected granulomatosis with polyangiitis (GPA). Complement factors were within normal range.
The patient fulfilled the following criteria of the new American College of Rheumatology/ European Alliance of Associations for Rheumatology (ACR/EULAR) classification of GPA (Robson et al., Arthritis Rheumatol 2022; 74: 393–399): bloody nasal discharge (+3), c-ANCA (+5) and cavitation on chest imaging (+2). The following other symptoms, which are negatively weighted in the score, were not present in the patient: positive test for perinuclear antineutrophilic cytoplasmic antibodies (p-ANCA) or anti-myeloperoxidase (anti-MPO) antibodies and blood eosinophil count≥109/l. As the cumulative score (10) was higher than the necessary 5 points for classification, the patient was classified to have GPA. Even though neither histopathology nor angiography was performed, the following 4 out of 6 Ankara 2008 classification criteria have been met: upper airway involvement (recurrent epistaxis), pulmonary involvement (pulmonary cavitation and infiltrates), ANCA (c-ANCA) and renal involvement (mild proteinuria and hematuria) (Ozen et al., Ann Rheum Dis 2010; 69: 798–806). Both classification criteria perform equally well for GPA in children (Kaya Akca et al., Rheumatology (Oxford) 2024; 63: SI122–SI128). The initial Birmingham vasculitis activity score (BVAS) was calculated with 30 points.
Following the current EULAR Guidelines, we initiated an immunosuppressive therapy with rituximab (RTX) in combination with intravenous methylprednisolone pulses (MP) followed by oral glucocorticoids (GC) (Hellmich et al., Ann Rheum Dis 2024; 83: 30–47). Due to the life-threatening nature and severe inflammation, avacopan (30 mg, 2x/d) was also administered off-label. While studies had not been available yet at the time of the Single Hub and Access point for pediatric Rheumatology in Europe (SHARE) recommendations (de Graeff et al., Rheumatology 2019; 58: 656–671), recent studies in adult patients have demonstrated that the use of this drug reduces therapy-associated toxicity and increases efficacy for maintenance of remission (Jayne et al., N Engl J Med 2021; 384: 599–609, Avacopan for the Treatment of ANCA-Associated Vasculitis (ADVOCATE) trial). As CRP continued to rise without signs of infections, mycophenolate mofetil (MMF) was temporarily added twice daily to the therapeutic regime, which is considered first-line for maintenance according to SHARE ([Fig. 2a]).
Under this immunosuppressant regime, the inflammation was controlled and disease activity regressive. Elevated blood pressure was treated with an ACE inhibitor for 7 months. MMF was discontinued 5 months after disease manifestation and oral GC were reduced according to the currently published tapering regimen, which suggests lower drug dosages compared to previous recommendations (Walsh, N Engl J Med 2020; 382: 622–631, Pivotal results of the Plasma Exchange and Glucocorticoids for Treatment of Anti-Neutrophil Cytoplasm Antibody (ANCA) - Associated Vasculitis study (PEXIVAS trial)).
Two weeks after disease onset the radiograph of the lung already showed clearly regressive infiltrates with mild residual findings, and at last visit the X-ray was uneventful ([Fig. 2b]). At that time lung function showed no signs of restrictive or obstructive ventilation disorder but a mildly reduced diffusion capacity for carbon monoxide (DLCO, 65%). Over the course of follow-up examinations, the necrosis on fingertips was regredient with discrete shortening and mild loss of sensitivity by the last follow-up 7 months after disease onset ([Fig. 2c, d]). Creatinine levels did not rise, urine protein/creatinine-ratio normalized (131 mg/gCrea at last follow-up). The BVAS at the last presentation was calculated with 0 points. Notably long-term GC side-effects such as cushing-like appearance or weight gain have been absent, which may be attributed to the reduced-dose regimen following new guidelines as well as the addition of avacopan. Serious adverse effects of medication regimen were not observed. MMF levels were monitored by AUC evaluation, avacopan tolerance by regular screening of liver toxicity, and RTX efficacy by levels of CD20+ B cells in peripheral blood.
Granulomatosis with polyangiitis (GPA) is a rheumatic systemic disease of the vascular system. It is characterized by necrotizing inflammation and ulcerating granuloma formation in blood vessels, particularly in the upper airway, kidney, and lower respiratory tract. It is a rare disease and mainly reported in adulthood, although it can occur at any age. Epidemiological data in childhood and adolescence are limited, with reported incidences ranging from 0.18 per 1 million (Sacri et al., Nephrol Dial Transplant 2015; 30: i104–12) to 6.39 per 1 million (Grisaru et al., The Journal of Rheumatology 2010; 37: 440–442). There have been several case reports in recent years, including cases with GPA mimicking tuberculosis (Arfaoui et al., Pan Afr Med J 2021; 38: 285) and a review considering lung involvement (Filocamo et al., Pediatr Rheumatol Online J 2017; 15: 28).
The pathophysiology of GPA is not well understood. It is assumed that anti-neutrophil cytoplasmatic antibodies which interact with proteinase 3 are responsible. These antibodies react with neutrophil granulocytes, activate them and increase their adherence to endothelial cells. This is further enhanced by C5a, a part of the complement system activated by this inflammatory process, which has been thought to act as chemoattractant and in priming neutrophils to be further activated by ANCA (Kallenberg et al., Mol Immunol 2015; 68: 53–56). Their degranulation leads to damage and ultimately destruction in vessel walls. Histopathologically GPA is characterized by necrosis, granulomas, and multinucleated giant cells.
Pulmonary involvement in minors with GPA is common, with a prevalence in a meta-analysis reported to be 61% (Iudici et al., Orphanet J Rare Dis 2016; 11: 141). The same meta-analysis found hemorrhage occurring in 16% of patients and lung nodules in 10%. Symptoms include shortness of breath, chronic cough, wheezing, hemoptysis, and alveolar hemorrhage (Cabral et al., Arthritis Rheum 2009; 60: 3413–3424), as well as rhinitis, sinusitis, nasal crusts, and epistaxis (Calatroni et al., Ital J Pediatr 2017; 43: 46). Radiological findings in GPA patients by chest radiograph or CT show nodules, fixed pulmonary infiltrates, cavitations, diffuse interstitial or alveolar opacities, and rarely fibrosis, septal thickening and pneumothorax. Pulmonary nodules consist of granulomatous inflammation with central necrosis. They vary in number (singular or multiple) and size (1 to 4 cm) and tend to increase on both criteria with progressing disease (Filocamo et al., Pediatr Rheumatol Online J 2017; 15: 28).
Plasmapheresis has been used as treatment option for GPA, however, a recent study in 352 adults with severe ANCA-associated vasculitis (PEXIVAS) has not found reduced rates of death or end-stage kidney disease for plasmapheresis in severe ANCA-associated vasculitis. Of note, the same study also identified noninferiority for a reduced-dose regimen of GC with respect to the same end points. Following this, updated EULAR recommendations suggest reduced amounts of GC in GPA and recommend plasmapheresis only as rescue therapy in severe active glomerulonephritis (Hellmich et al., Ann Rheum Dis 2024; 83: 30–47).
As a new therapy option, avacopan, a C5a-inhibitor, has emerged. It has been approved for use in adults with severe active GPA in combination with cyclophosphamide (CYC) or the B-cell depleting monoclonal antibody RTX. Additionally, the amount of GC used may be decreased when coadministering avacopan as shown in the ADVOCATE study. Here, noninferiority for use of avacopan together with a third of the standard GC dose compared with only standard GC was shown for remission at 26 weeks and superiority for remission after 52 weeks; both groups received RTX or CYC. No statement is made concerning the efficacy of avacopan being dependent on elevated or decreased complement factors in blood before starting the medication. This study did not involve children, and indeed only 3 case reports have been published to date on the use of avacopan in minors (Ennis et al., BMJ Case Rep 2020; 13: e236236; Zotta et al., Pediatr Nephrol 2023; 38: 4197–4201; Nishino et al., Pediatr Nephrol 2024; 39: 2919–2922).
In summary, a manifestation of a severe and life-threatening ANCA-positive complicated GPA with severe lung involvement is presented. Vasculitis-induced and hemorrhagic involvement of the lungs was predominant. Even though it is rare, GPA needs to be considered as differential diagnosis also in children and adolescent patients especially when pulmonary hemorrhage is present. The addition of avacopan can improve the disease outcome and help to reduce GC toxicity.
In brief, three main points of clinical significance are highlighted by this case:
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Consider GPA in minors with pulmonal hemorrhaging
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Consider avacopan as treatment option for GPA in minors
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Follow updated guidelines for reduced GC regime in GPA treatment
Publication History
Article published online:
03 February 2025
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