Case 1
A 16-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. Upon presentation, he had hypertension with blood pressure ranges 120 – 166 / 44 – 92, hemoglobinuria (large) with RBC >100/hpf, proteinuria (100 mg/dL) with Protein to Creatinine ratio of 2.07, ESR 59 mm/hr, CRP 12.9 mg/dL, and hemoglobin 7.3 GM/dL. He was intermittently febrile with Tmax 38.8 degrees Celsius. His creatinine ranged between 0.79-0.98 mg/dL throughout his hospital stay. Due to persistent coughing and history of hemoptysis, he underwent chest CT which showed widespread bilateral ill-defined ground-glass opacities along the bronchovascular bundles (Figure 1). Rheumatology, Nephrology, and Infectious Disease were consulted. His ANCA pattern was positive for C-ANCA pattern 1:640 with PR3 812 AU/mL; his ANA was 1:80, with normal C3 and C4 and negative RNP, Smith, double-stranded DNA, antiphospholipid (cardiolipin IgG and IgM, beta-2 glycoprotein IgG and IgM, DRVVT and staclot) and anti-glomerular basement membrane antibodies. He underwent a thorough infectious workup that included serum testing for Tuberculosis, Histoplasmosis (both urine and serum), Coxiella burnetii, Bartonella henselae, Bartonella quintana and HIV, all of which was negative. His COVID-19 respiratory swab was negative. A bronchioalveolar lavage was completed for further infectious workup which was negative for AFB cultures and stain, fungal cultures and stain, and bacterial culture and stain. On hospital day 3, he underwent renal biopsy due to persistent hypertension and elevated protein/creatinine ratio. Renal biopsy showed focal necrotizing and crescentic glomerulonephritis with pauci-immune pattern on immunofluorescence staining. During his renal biopsy, he 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 as well as 1-2 small areas concerning for vegetation on the aortic valve with mild aortic regurgitation, as well as thickening of the anterior leaflet of the mitral valve with Ejection Fraction 60% (Figure 2). He was asymptomatic without palpitations, chest pain, or chest tightness. On hospital day 3, after completion of his echocardiogram, he had an acute ischemic event which resulted in left facial droop and left-sided hemineglect with abnormal sensations on his left side; Magnetic Resonance Angiogram (MRA) scan of the head 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. One bottle out of four returned positive >24 hours after collection growing coagulase negative Staphylococcus, a common contaminant. He was ultimately treated with 5 days of plasmapheresis and Rituximab 1000mg at week 0 and week 2 per ANCA-Vasculitis protocol as well as methylprednisolone pulse (30 mg/kg x 3 days, max 1000mg) followed by high-dose oral glucocorticoids 2mg/kg/day (18). He was initiated on lisinopril 10mg daily by cardiology for both hypertension and improvement in heart muscle function. Due to inability to rule out bacterial endocarditis based on one positive blood culture and findings on echocardiogram of valvular vegetations, he was also treated with four weeks of Ceftriaxone. He clinically did well, and four months post-induction with Rituximab he was asymptomatic and displayed normalization of inflammatory markers (CRP <0.5 mg/dL, ESR 2 mm/hr). He had no persistent neurological or cognitive deficits. He currently is in maintenance therapy with Rituximab (18 months post-hospitalization) with baseline creatinine 0.93 mg/dL, resolution of proteinuria and hematuria, baseline DLCO 90%, and resolution of his aortic valve vegetation with stable mild-moderate aortic valve regurgitation with perforation.
Case 2
A 16-year-old male presented to the Intensive Care Unit (ICU) due to acute hypoxic respiratory failure thought to be secondary to bacterial versus viral pneumonia. He had a history of stiff, painful knees and elbows three weeks prior that had resolved with NSAID use. He presented to an outside hospital a week before presenting to our ICU due to cough, congestion, fevers, and myalgias. He was tested for COVID-19 which was negative, although his chest X-ray was concerning for multifocal pneumonia. He was given Azithromycin, but his symptoms did not improve. He saw his primary care physician who re-tested him for COVID-19 (negative) as well as performed Influenza A testing (positive). He was given Amoxicillin and Doxycycline for 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 saturations of 65% while on room air. He had elevated white blood cell count to 18.5 k/cumm, hemoglobin 8.3 mg/dL, creatinine 1.21 mg/dL, BUN 31 mg/dL, PT 17.1 seconds with INR 1.41, D-dimer 4,224 ng/mL DDU, troponin 3.36 ng/mL, CRP 25 mg/dL, ESR 14 mm/hr. His urine was significant for large hemoglobinuria with 6-10 RBC/hpf. A repeat chest X-ray 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. He was then transferred to our center and placed on Venovenous (VV) extracorporeal membrane oxygenation (ECMO) due to severe respiratory failure secondary to pulmonary hemorrhage on day 2 of hospitalization; Bronchoalveolar lavage (BAL) completed on hospital day 2 was also consistent with pulmonary hemorrhage. An echocardiogram was completed on admission which 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. He was initiated on broad spectrum antibiotics (Cefepime, Gentamicin, Vancomycin) upon admission due to concern for overlying bacterial pneumonia and infectious endocarditis. Due to diffuse pulmonary hemorrhage, significant acute respiratory distress syndrome and requirement for VV ECMO, Pediatric ICU team began methylprednisolone 2mg/kg/day from day 2 – day 4 of hospitalization. Of note, while on 2mg/kg/day of methylprednisolone his creatinine improved from 1.21 mg/dL to 0.86 mg/dL, and then rose slowly after discontinuation of IV methylprednisolone; his VV ECMO settings were also able to be decreased while receiving methylprednisolone, with slow worsening of lung function after discontinuation. Rheumatology, Nephrology, and Infectious Disease were consulted on day 9, day 12, and day 6 of hospitalization respectively.
A thorough infectious workup ensued on day 6 of hospitalization. Serologies for Hepatitis A, B, and C, Bartonella henselae, Bartonella quintana, and HSV were sent and were negative. Multiple blood culture samples were sent throughout his hospital stay and were negative. PCR respiratory viral swabs for Parainfluenza, RSV, Bordetella parapertussis, Bordetella pertussis, Chlamydia pneumoniae, Mycoplasma pneumoniae, COVID-19, Human Metapneumovirus, Human Rhinovirus/Enterovirus, Adenovirus, Coronavirus 229E, Coronavirus HKU1, Coronavirus NL63, Coronavirus OC43, Influenza A and Influenza B were negative. BAL studies including AFB stain and culture, fungal stain and culture, bacterial stain and culture, and universal PCR were unremarkable. Of note, Aspergillus antigen in his BAL sample was slightly positive, with antigen Index in BAL 0.55 (normal <0.5), though our infectious disease team did not feel this was a true positive. His ASO and DNAse B were negative. 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, with consolidation likely representing a combination of atelectasis and edema although a component of hemorrhage or infection also possible. On hospital day 6, he developed splinter hemorrhages on examination, followed by scattered petechiae on hospital day 7 consistent with leukocytoclastic vasculitis confirmed by skin biopsy. Repeat echocardiogram on hospital day 8 re-demonstrated small mitral valve vegetation as well as likely perforation of the anterior leaflet near the medial annulus (Figure 2). 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 protein/creatinine ratio (now 3.72), pulmonary hemorrhage, leukocytoclastic vasculitis, overall negative infectious workup, and vegetations on echocardiogram with concern for an underlying rheumatologic disorder.
Rheumatologic evaluation showed normal C3 and C4, negative Double-Stranded DNA, anti-Smith/RNP, SSA, SSB, anti-Cardiolipin IgM and IgG, beta-2 glycoprotein IgM and IgG, anti-GBM, and ANA. His ANCA panel was sent on hospital day 9 and returned on hospital day 14 consistent with c-ANCA pattern 1:5120 with PR3 1542 AU/mL. By this time, his renal function had deteriorated to the point where he developed hyperkalemia and required continuous venovenous hemofiltration (CVVH) initiated on hospital day 11. He remained on VV ECMO which made obtaining a renal biopsy extremely dangerous due to risk of bleeding. On hospital day 11, given rapidly progressing rash, worsening renal function and hyperkalemia requiring CVVH, negative infectious workup thus far, pulmonary hemorrhage and inability to obtain biopsy given VV ECMO, he initiated pulse methylprednisolone 500mg q12 for a total of 3 grams. He also began a five-day course of plasmapheresis. Upon initiation of pulse methylprednisolone and plasmapheresis, 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 was obtained on hospital day 22 which was significant for segmental fibrinoid necrosis without crescent formation and pauci-immune pattern on immunofluorescence, further supporting the diagnosis of Granulomatosis with Polyangiitis. When stabilized, he underwent a CT scan of his chest which showed diffuse symmetric ground glass opacities bilaterally as well as 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 (Figure 2).
For Granulomatosis with Polyangiitis, he received high-dose pulse glucocorticoid for 3 days (hospital day 11-13) followed by high-dose oral glucocorticoids (prednisone 30mg twice daily), plasmapheresis for 5 consecutive days (hospital day 11-15), and ultimately Rituximab 375 mg/m2 every week (first dose on hospital day 30) for a total of four doses per protocol followed by 1000mg every 6 months (18). Due to inability to completely rule out infectious endocarditis despite negative blood cultures, he also completed 4 weeks of IV Ceftriaxone therapy. He did initiate treatment for Aspergillus due to positive Aspergillus antigen in BAL and known need for immunosuppression with B-cell depleting therapy. Due to persistent hypertension, proteinuria, and risk of cardiac remodeling, he was initiated on lisinopril 10mg daily per cardiology and nephrology recommendations. He is now 10 months post-hospitalization and is in maintenance therapy with Rituximab 1000mg every 6 months, with baseline creatinine around 1.5 mg/dL and resolution of hematuria and proteinuria, improved lung function with most recent DLCO at 74% (lowest value prior to discharge from the hospital 42%), and resolution of mitral valve vegetation with stable mild mitral regurgitation with persistent perforation within the anterior mitral valve leaflet.