ANCA-associated vasculitis with cardiac valve vegetations in two teenage males: two case reports and a literature review

A 15-year-old male presented to our pulmonary service with a 6-week history of bloody noses, hemoptysis, cough, fatigue, weight loss, fevers, and dark urine. He denied cardiac symptoms and was without palpitations, chest pain, or chest tightness. He had hypertension with blood pressures in the range of 120–166 / 44–92 mmHg, hemoglobinuria (large) with red blood cells (RBC) > 100 per high-powered field (hpf), proteinuria (100 mg per deciliter (mg/dL)) with urine protein to creatinine ratio of 2.07, erythrocyte sedimentation rate (ESR) 59 mm per hour (mm/hr), C-reactive protein (CRP) 12.9 mg/dL, and hemoglobin 7.3 g per deciliter (GM/dL) (Table 2). He was intermittently febrile with a maximum body temperature of 38.8 degrees Celsius. His serum creatinine peaked at 0.98 mg/dL during his hospital stay. His chest CT showed widespread bilateral ill-defined ground-glass opacities along the bronchovascular bundles (Fig. 1). Rheumatology, Nephrology, and Infectious Disease services were consulted. Serum ANCA showed a cytoplasmic (C-ANCA) pattern with a titer of 1:640 and Proteinase-3 (PR3) value of 812 AU/mL. Additional rheumatologic laboratory tests returned normal/negative. A thorough evaluation for infection on admission was unremarkable (Table 2). On hospital day 3, he underwent renal biopsy due to persistent hypertension and elevated urine protein/creatinine ratio. The renal biopsy specimen showed focal necrotizing and crescentic glomerulonephritis (14/34 glomeruli with active lesions, see Fig. 2). Immune complex deposits were not seen in glomeruli by immunofluorescent and electron microscopy (i.e., pauci-immune), compatible with AAV. During his renal biopsy, he incidentally was found to have Mobitz II heart block on telemetry, which ultimately lead to his cardiac evaluation and cardiology consultation. Of note, he had an EKG on admission that was normal. His echocardiogram obtained on hospital day 3 showed thickened aortic valve leaflets with perforation within the right coronary leaflet, one to two small areas with vegetation on the aortic valve with mild aortic regurgitation and thickening of the anterior leaflet of the mitral valve with Ejection Fraction 60% (Fig. 3). He remained asymptomatic without palpitations, chest pain, or chest tightness. On hospital day 3, after completion of his echocardiogram, he experienced an acute ischemic event that resulted in left facial droop and left-sided hemineglect with abnormal sensations on his left side. Magnetic Resonance Angiogram (MRA) confirmed moderate-sized acute infarct involving the right insula, adjacent frontoparietal operculum and right parietal lobe with scattered foci of punctate infarcts bilaterally, suggesting thromboembolic phenomenon. Due to concern for bacterial endocarditis with newfound valvular lesions, blood cultures were drawn. Greater than 24 hours after collection, one bottle out of four grew coagulase-negative Staphylococcus, a common contaminant (Table 2). He received therapeutic plasma exchange for five days and was treated with Rituximab 1000 mg (mg) at week 0 and week 2 per ANCA-Vasculitis protocol, and methylprednisolone pulse (30 mg per kilogram (mg/kg) × 3 days, maximum 1000 mg) followed by high-dose oral glucocorticoids 2 mg/kg/day [18]. He was initiated on lisinopril 10 mg daily for hypertension, improvement in heart muscle function, and prevention of cardiac remodeling. Due to inability to exclude bacterial endocarditis based on one positive blood culture and findings on echocardiogram of valvular vegetations, he was also treated for 4 weeks with Ceftriaxone. Six months post-induction with Rituximab he was asymptomatic and displayed normalization of inflammatory markers and ANCA serology, resolution of proteinuria and hematuria, resolution of his aortic valve vegetation with stable mild-moderate aortic valve regurgitation with perforation, and no neurological or cognitive deficits.

A 16-year-old male was admitted to the Intensive Care Unit (ICU) due to acute hypoxic respiratory failure. He had a history of stiff, painful knees and elbows 3 weeks prior that had resolved with non-steroidal anti-inflammatory (NSAID) use. One week prior, he presented to an outside hospital due to cough, congestion, fevers, and myalgias. At this visit, his chest radiograph showed findings suspicious for pneumonia; however, his symptoms did not improve despite Azithromycin therapy. He was evaluated by his primary care physician who tested him for COVID-19 (negative) and Influenza A (positive). He was given Amoxicillin and Doxycycline due to concern for overlying bacterial pneumonia, however he then developed weakness and severe shortness of breath. He presented to outside emergency department where he was found to be febrile to 38.0 degrees Celsius and tachycardic, with blood oxygen saturations of 65% while on room air. He had elevated white blood cell count to 18.5 k/cumm, hemoglobin 8.3 mg/dL, serum creatinine 1.21 mg/dL, blood urea nitrogen (BUN) 31 mg/dL, mild coagulopathy, CRP 25 mg/dL, ESR 14 mm/hr. and urinalysis significant for hemoglobinuria with 6–10 RBC/hpf (Table 2). Chest radiograph showed the development of large bilateral pneumothoraces with pneumomediastinum and dense opacities in both lungs. He required high-flow nasal cannula but soon transitioned to Bilevel positive airway pressure (BiPAP) and ultimately intubation. On day 2 he was transferred to our ICU and placed on Venovenous (VV) extracorporeal membrane oxygenation (ECMO) due to severe respiratory failure secondary to pulmonary hemorrhage confirmed by bronchioalveolar lavage (BAL). An echocardiogram completed on admission showed a probable thrombus/vegetation on the mitral anterior leaflet near the septal attachment, trivial mitral regurgitation with normal tricuspid valve, and ejection fraction of 67%. Cardiology was immediately consulted. Due to clinical instability, a transesophageal echocardiogram was contraindicated. Repeat echocardiogram on day 8 of hospitalization confirmed the presence of the vegetation in addition to perforation of one of the anterior leaflets of the mitral valve. He was initiated on broad spectrum antibiotics (Cefepime, Gentamicin, and Vancomycin) upon admission due to concern for overlying bacterial pneumonia and infectious endocarditis. The Pediatric ICU team began methylprednisolone 2 mg/kg/day from day 2 through day 4 of hospitalization due to diffuse pulmonary hemorrhage, significant acute respiratory distress syndrome, and requirement for VV ECMO. While on IV methylprednisolone, his serum creatinine improved and his VV ECMO settings were decreased, though both renal and lung function slowly worsened after discontinuation of steroids. Infectious Disease, Rheumatology, and Nephrology services were consulted on days 6, 9, and 12 of hospitalization, respectively.

A thorough evaluation for infection ensued on day 6 of hospitalization, which was unremarkable aside from slightly positive Aspergillus antigen in his BAL (Table 2), though our Infectious Disease colleagues doubted this was a true-positive. On hospital day 6, a chest CT-Angiogram was completed to evaluate the extent of thromboembolic phenomenon given cardiac vegetations, which showed diffuse consolidation of both lungs without evidence of pulmonary arterial embolic disease. On hospital day 6, he developed splinter hemorrhages, followed by scattered petechiae on hospital day 7 consistent with leukocytoclastic vasculitis that was confirmed by skin biopsy. Repeat echocardiogram on hospital day 8 re-demonstrated small mitral valve vegetation and likely perforation of the anterior leaflet near the medial annulus (Fig. 3). Rheumatology was consulted on day 9 of hospitalization due to worsening hematuria (RBC on admission 6–10/hpf, hospital day 9 with RBC now > 100/hpf) with large hemoglobinuria and worsening urine protein/creatinine ratio (now 3.72), pulmonary hemorrhage, leukocytoclastic vasculitis, absence of a detectable source of infection (Table 2), and vegetations on echocardiogram with concern for an underlying rheumatologic disorder.

Rheumatologic evaluation was unremarkable aside from c-ANCA pattern with titer of 1:5120 and PR3 1242 AU/mL (Table 2). Results of his ANCA panel drawn on hospital day 9 were received on hospital day 14, by which time his renal function had deteriorated. He required continuous venovenous hemofiltration (CVVH) initiated on hospital day 11. He remained on VV ECMO, which precluded a percutaneous needle biopsy of the kidney due to risk of hemorrhage. Pulse methylprednisolone (500 mg q12 for a total of 3 g) and a five-day course of therapeutic plasma exchange were initiated on hospital day 11 due to rapidly progressing rash, worsening renal function and hyperkalemia requiring CVVH, negative testing for infection, pulmonary hemorrhage, and risk of renal biopsy. Upon initiation of pulse methylprednisolone and therapeutic plasma exchange, his lung function and kidney function improved. He was decannulated from VV ECMO on hospital day 20 and discontinued CVVH on hospital day 19. A renal biopsy specimen obtained on hospital day 22 showed focal necrotizing glomerulonephritis (1/23 glomeruli with activity, see Fig. 2) in the absence of detectable crescents. Immune complex deposits were not seen in glomeruli by immunofluorescent and electron microscopy (i.e., pauci-immune), compatible with AAV. When stabilized, he underwent a CT scan of his chest which showed diffuse symmetric ground glass opacities bilaterally and two well-defined solid appearing soft tissue density nodules in the right middle lobe and another nodule in the upper aspect of the major fissure of the left lung (Fig. 1). Collectively, these findings are consistent with GPA.

For GPA, he received high-dose pulse glucocorticoid for 3 days (hospital day 11–13) followed by high-dose oral glucocorticoids (prednisone 30 mg twice daily), therapeutic plasma exchange for 5 consecutive days (hospital day 11–15), and ultimately Rituximab 375 mg per meter-squared (mg/m2) every week (first dose on hospital day 30) for a total of four doses per protocol followed by 1000 mg every 6 months [18]. Due to our inability to exclude infectious endocarditis despite negative blood cultures, he completed 4 weeks of Ceftriaxone. Infectious disease team initiated treatment for Aspergillus due to detection of Aspergillus antigen in BAL and known need for immunosuppression with B-cell depleting therapy. Due to persistent hypertension, proteinuria, and risk of cardiac remodeling, we initiated lisinopril 10 mg daily per recommendations of Cardiology and Nephrology consultants. He clinically improved. At 6 months post-induction therapy he received maintenance therapy with Rituximab 1000 mg every 6 months, with baseline serum creatinine of 1.5 mg/dL, resolution of hematuria and proteinuria, improved lung function, and resolution of mitral valve vegetation with stable mild mitral regurgitation and persistent perforation within the anterior mitral valve leaflet.