March 2022 Case

A male patient in his 60's with a history of hypertension, diverticulitis, prior heparin induced thrombocytopenia, and end stage renal disease presented with hemoptysis, shortness of breath, and weakness. COVID-19 testing was negative. CT angio chest showed findings consistent with pulmonary alveolar hemorrhage. He was anemic with a hemoglobin of 8.8 g/dL.

Over 8 years ago he was diagnosed with p-ANCA positive pauci-immune glomerulonephritis after a renal biopsy was performed for renal failure. He was treated with plasmapheresis (5 sessions), prednisone, and cyclophosphamide for 3 months. He required hemodialysis and has remained dialysis dependent ever since. After the initial diagnosis and treatment, he remained asymptomatic and did not receive any further therapy for p-ANCA vasculitis until this current episode. He had no previous report of any pulmonary involvement of vasculitis.

The transfusion medicine service was consulted for therapeutic plasma exchange for treatment of diffuse alveolar hemorrhage in the setting of p-ANCA vasculitis. Testing for p-ANCA was positive. The patient was treated with daily sessions of plasmapheresis for a total of 5 sessions, along with pulse steroids. Plasmapheresis was performed using full plasma as replacement fluid given the patient's ongoing hemorrhage. Following plasmapheresis, his hemoptysis significantly improved. He received one dose of rituximab and was discharged home.

Five days later, he developed recurrent hemoptysis and was found to be anemic with a hemoglobin of 7.5 g/dL during a dialysis session, prompting readmission. His respiratory status declined, and he was transferred to the ICU and intubated. COVID-19 testing was now found to be positive and he was given remdesivir. In addition, culture of a bronchoalveolar lavage specimen taken from a procedure performed during the previous admission was now positive for Mycobacterium avium intracellulare complex (MAC), and he was started on rifampin, ethambutol, and azithromycin. Given the recurrent hemoptysis, he received further treatment for p-ANCA vasculitis. Five additional sessions of plasmapheresis were performed at a frequency of one daily in conjunction with treatment with steroids. His hemoptysis resolved and he was extubated. His second dose of rituximab was held until he was deemed clinically stable and was given before discharge. He was stabilized and discharged with plans for follow up as an outpatient.

Anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis is an autoimmune disease characterized by inflammation and endothelial injury leading to a necrotizing vasculitis that predominantly affects small vessels [1,2]. ANCA-associated vasculitis can affect any organ, most commonly involving the kidneys (70%) and lungs (>50%). Lung involvement can range from asymptomatic pulmonary lesions to life threatening diffuse alveolar hemorrhage [1].

There are multiple different subtypes of ANCA-associated vasculitis based on clinicopathologic characteristics including microscopic polyangiitis, granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis, and renal-limited vasculitis, with overlapping features between these entities. ANCA may further be classified as c-ANCA or p-ANCA, which is localized more specifically to the perinuclear region of the neutrophilic cytoplasm in contrast to c-ANCA. ANCA specificities may also differ, with those of clinical relevance specific for myeloperoxidase (MPO) in p-ANCA and proteinase 3 (PR3) in c-ANCA [2].

Treatment is typically divided into two phases, induction of remission and maintenance of remission. Urgent initiation of treatment is required to prevent irreversible organ damage. Standard induction of treatment generally includes steroids, cyclophosphamide, rituximab, and possible therapeutic plasma exchange [1,2].

Diffuse alveolar hemorrhage in the setting of ANCA-associated vasculitis is considered a Category I indication for plasmapheresis, meaning that plasmapheresis is considered a first line therapy. This is a Grade 1C recommendation according to the Journal of Clinical Apheresis, meaning that this is a strong recommendation with low-quality evidence, with most studies on this subject being observational studies or case series [1]. The rationale for plasmapheresis is that the procedure removes circulating ANCA by removing the patient's plasma. ANCA is believed to have a pathogenic role contributing to localized vessel wall necrosis [1,2]. If diffuse alveolar hemorrhage is not present in an ANCA-associated vasculitis, recommendations for the role of plasmapheresis differs based on the specific diagnosis and renal status of the patient [1].

If diffuse alveolar hemorrhage is present, replacement with donor plasma is recommended to avoid additional bleeding risk. In cases without hemorrhage, replacement with 5% albumin may be satisfactory. Procedures may be performed either daily or every other day, and the reported median total number of procedures performed is 7 over a median of 14 days, with up to 12 procedures reported in patients with severe renal failure or diffuse alveolar hemorrhage [1]. The patient in this case required a total of 10 procedures.

Maintenance treatment usually entails low dose steroids plus an additional immunomodulatory therapy such as azathioprine, mycophenolate mofetil, or rituximab for 12-18 months [1,3]. In this patient's case, he received steroids and cyclophosphamide for 3 months during his first episode with renal failure but did receive any further therapy. Though his kidneys were irreversibly damaged requiring ongoing hemodialysis, he remained asymptomatic until recurrence over 8 years later. Relapses are common for ANCA-associated vasculitis, with increased risk seen in those who have anti-PR3 (c-ANCA), cardiovascular involvement, or those without renal impairment at the time of diagnosis [4].

Interestingly, the patient in this report initially did well with 5 sessions of plasmapheresis, steroids, and one dose of rituximab and was stable enough for discharge before contracting COVID-19. It is likely that the COVID-19 infection significantly contributed to his worsening respiratory status and recurrent disease. Steroids and rituximab have been shown to be associated with increased COVID-19 severity [5], and his second dose of rituximab was held until he was deemed clinically stable. In addition, he was found to have an ongoing MAC infection which may have also contributed to his worsening respiratory status. His recurrent hemoptysis and respiratory decline prompted further treatment for his p-ANCA vasculitis with an additional 5 sessions of plasmapheresis. This treatment, along with initiation of treatment for his infectious diseases, led to successful recovery of his diffuse alveolar hemorrhage and significant respiratory status improvement. He was able to receive a second dose of rituximab and was discharged on steroids with plans for follow up as an outpatient with rheumatology, as he will likely require maintenance treatment to prevent further recurrence.

1. Padmanabhan A, Connelly-Smith L, Aqui N, Balogun RA, Klingel R, Meyer E, Pham HP, Schneiderman J, Witt V, Wu Y, Zantek ND, Dunbar NM, Schwartz GEJ. Guidelines on the Use of Therapeutic Apheresis in Clinical Practice - Evidence-Based Approach from the Writing Committee of the American Society for Apheresis: The Eighth Special Issue. J Clin Apher. 2019 Jun;34(3):171-354. doi: 10.1002/jca.21705.
2. Domínguez-Quintana M, Alba MA, Hinojosa-Azaola A. Classification of ANCA-associated vasculitis: differences based on ANCA specificity and clinicopathologic phenotype. Rheumatol Int. 2021 Oct;41(10):1717-1728. doi: 10.1007/s00296-021-04966-5.
3. McClure M, Jones RB. Treatment of Relapses in ANCA-Associated Vasculitis. Clin J Am Soc Nephrol. 2019;14(7):967-969. doi:10.2215/CJN.06250519.
4. Walsh M, Flossmann O, Berden A, Westman K, Höglund P, Stegeman C, Jayne D; European Vasculitis Study Group. Risk factors for relapse of antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum. 2012 Feb;64(2):542-8. doi: 10.1002/art.33361.
5. FAI2R /SFR/SNFMI/SOFREMIP/CRI/IMIDIATE consortium and contributors. Severity of COVID-19 and survival in patients with rheumatic and inflammatory diseases: data from the French RMD COVID-19 cohort of 694 patients [published online ahead of print, 2020 Dec 2]. Ann Rheum Dis. 2020;80(4):527-538. doi:10.1136/annrheumdis-2020-218310.