Here we report the second case of new-onset anti-PR3, C-ANCA vasculitis and the fourth case of AAV following COVID-19 infection in the pediatric population. The gold standard for diagnosing childhood vasculitis is with either histopathology from tissue biopsy or by characteristic lesions detected by imaging studies. Multiple studies in adults have found that more than half of biopsies reveal only non-specific inflammation with necrosis,15–17 which is what the lung biopsy of our patient showed. Different classification criteria have been proposed to diagnose GPA in children.5,18−20 The mostly commonly used classification system in pediatrics is the European League Against Rheumatism/Pediatric Rheumatology International Trials Organization/Pediatric Rheumatology European Society (EULAR/PRINTO/PRES) classification scheme; it requires three of the following six features to diagnose GPA: abnormal urinalysis with hematuria or proteinuria; nasal sinus inflammation; granulomatous inflammation on biopsy; subglottic, tracheal or endobronchial stenosis; abnormal chest x-ray or CT; PR3-ANCA or C-ANCA positivity.5,18,21 Most patients (> 80%) have a positive ANCA, and GPA is primarily associated with PR3-ANCA.22,23 Approximately 90% of patients with GPA have ENT manifestations such as rhinosinusitis, otitis media, earache, conductive and/or sensorineural hearing loss, persistent rhinorrhea, purulent or bloody nasal discharge.24–26 Our patient meets criteria for AAV and her clinical presentation—nasal sinus inflammation, upper airway and middle ear involvement, abnormal CT showing cavitary lesions, and PR3 and C-ANCA positivity—is most consistent with GPA.18
With the present report, we identified three cases of pediatric-onset ANCA-associated vasculitis (PAAV) and the table includes an update of the published cases (Table 1). A review of the literature found three cases of PAAV following COVID-19 infection. A total of four cases were included in this review.27–29 Of the four patients (including ours), two (50%) were male; the mean age was 15.5 +/- 2.1 years.27–29 Two of the patients had no prior comorbidities while two had pre-existing asthma.29 Immunological tests showed positive C-ANCA in two cases27 and P-ANCA in two.28,29 Two patients had anti-PR3 antibodies,27 and 2 patients had anti-MPO antibodies.28,29 Pulmonary imaging studies showed multifocal cavitary pulmonary nodules in 2 patients;27 diffuse alveolar hemorrhage in two patients;28,29 dense patchy infiltrates in 2 patients.28,29 Two patients had normal kidney function at the time of presentation27 while two patients had necrotizing glomerulonephritis on renal biopsy.28,29 All four patients were treated with glucocorticoids. Three patients received rituximab therapy27,28 and one patient received plasmapheresis;29 for maintenance therapy, two were treated with cyclophosphamide,28,29 one was treated with mycophenolate, and one did not continue therapy.27 All four patients had symptomatic and radiographic improvement at follow up.27–29
There have been six reported cases of adults developing AAV following COVID-19 infection.30 Similar to our findings, half of the adult patients had C-ANCA vasculitis with anti-PR3 antibodies. The most common lung findings were bilateral cavitary lesions, pulmonary infiltrates, and alveolar hemorrhage which were similar to the findings in children. Kidney involvement was more severe in the adults who developed AAV.30–33 All adult patients (6) had either crescentic or necrotizing glomerulonephritis on renal biopsy, active urinary sediment, and high creatinine levels. Two patients had kidney failure that required hemodialysis.30–33 The pediatric patients who developed renal involvement had necrotizing glomerulonephritis on renal biopsy but neither required hemodialysis.28,29 Two had normal creatinine levels and renal function at presentation.27 Studies from the NIH report that glomerulonephritis is present in only 18% of patients at presentation.24 However, 77 to 85% of patients subsequently develop glomerulonephritis, usually within the first two years of disease onset.24,34
The treatment strategy was similar in adults and children with all 10 patients receiving high dose systemic corticosteroids.27–33 Glucocorticoids have been the standard of care for chronic vasculitis in children.35,36 Half of the patients (5) received rituximab27,28,31 and half (5) received cyclophosphamide.28–30, 32 Cyclophosphamide is often added for patients with more severe disease.37 Other immunosuppressive medications, such as methotrexate and azathioprine, as well as biologic agents (e.g., TNF-inhibitors, rituximab, and tocilizumab) are increasingly being used to treat chronic vasculitis in the pediatric population.36,38
The clinical outcomes following treatment were generally favorable in both adult and pediatric patients: all patients had symptomatic and radiographic improvement; the patients with renal involvement had improvement or resolution of their hematuria, proteinuria and creatinine levels at follow-up; none of the patients required long-term dialysis; Two patients (one pediatric patient and one adult patient) had bilateral hearing loss as part of their initial presentation.30 Unfortunately, both continued to have profound hearing loss with the need for hearing aids or cochlear implants.30
Our case presentation and review of the pediatric and adult literature show that AAV may be another autoimmune-mediated sequela of COVID-19. We report the tenth case of AAV following COVID-19 infection. In general, patients who develop AAV post COVID-19 have few, if any, comorbidities, and show marked radiographic and symptomatic improvement after treatment.
Autoimmunity may be generated by a combination of genetic, hormonal, and environmental factors in susceptible people.39,40 One such environmental trigger is viral illness. Studies have suggested a causal relationship between viral infections and the onset of autoimmune disease with molecular mimicry, hyperstimulation and dysregulation of the immune system being proposed mechanisms.10 Epstein-Barr virus, cytomegalovirus, and human immunodeficiency virus are examples of viruses that have an established association to multiple autoimmune diseases.41–43 There is increasing evidence that SARS-CoV-2 is another virus that can lead to dysregulation of the immune system and the development of autoimmune disease in children and adults.11 A recent study found that children with a history of COVID-19 infection were at an increased risk of developing type 1 diabetes mellitus than those without a history of COVID-19.9 Antecedent viral infections have been implicated in the development of PAAV including GPA.44 Our report and review of the literature suggest that COVID-19 may be another viral trigger for the development of AAV in children and adults. More research is needed to better understand how SARS-CoV-2 may act as a precipitating trigger of autoimmunity and autoimmune disease in children. Our case highlights the importance of considering AAV in a pediatric patient presenting with pulmonary and renal disease following a recent COVID-19 infection because timely treatment may improve clinical outcomes.44