Characteristics and Outcomes of COVID-19 in Patients with ANCA associated vasculitis

Abstract

The Coronavirus disease 2019 (COVID-19) pandemic has not only stressed medical systems with its acute presentations, but also has conferred an additional permutation to the management of various established diseases. This includes patients with autoimmune disease requiring immunosuppression. The optimal management of immunosuppression during the pandemic and in those with acute infection still remains a matter of debate. We recently reported significant disruption on the chronic care of patients with anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) as result of the pandemic, with a sizeable proportion of patients having their immunosuppression held and that the risk of disease relapse likely far outweighs the risk of COVID-19. 1 Also, with the use of protective equipment and adherence to social isolation restrictions, the incidence of COVID-19 in patients with AAV may be similar to that of the general population. The characteristics and outcomes of COVID-19 in patients with new and established diagnosis of ANCA remains largely unknown, with only few cases reported. We prospectively followed six patients with COVID-19 on a background of established diagnosis of AAV from our institution. Additionally, we conducted a literature search to for published cases of AAV patients with COVID-19, to report cumulative characteristics and outcomes of COVID-19 in this population. Results Four cases of AAV diagnosed at the time of acute presentation of COVID-19, along with 8 cases of patients with pre-existing diagnosis of AAV have been reported in the literature (in addition, we report 6 cases with established AAV from our institution; n=14). With respect to newly diagnosed AAV patients (n=4), median age was 41 years with male and proteinase 3 antibody (PR3) predominance. All patients had evidence of acute kidney injury (AKI; median creatinine 5.5 mg/dL) with evidence of crescentic necrotizing glomerulonephritis (GN) on kidney biopsy. All patients received pulse steroids with concomitant rituximab (RTX) administration in two and cyclophosphamide (CYC) administration. Two patients with severe alveolar hemorrhage required plasmapheresis (PLEX), with one patient dying (this patient did not receive immunosuppression). The remaining three patients who received immunosuppression for AAV demonstrated evidence of clinical recovery. In patients with established AAV presenting with COVID-19 (n=14), median age was 54 years with equal gender distribution and PR3 predominance (n=12). Duration of ANCA diagnosis had a disparate range of 0.5-396 months. Majority of patients (11/14) were on RTX and oral prednisone for maintenance therapy, with median duration elapsed since last administration of RTX being 60 days. All patients had evidence of bilateral interstitial/ground glass opacities on lung radiology, with only one patient requiring mechanical ventilation. Thirteen out of fourteen patients are in sustained clinical recovery, with one currently hospitalized with a positive clinical trajectory. Discussion This combined cases series review brings forward some pertinent aspects to characteristics and outcomes of patients with newly diagnosed and established AAV diagnosis in the setting of COVID-19 infection. It is unknown if SARS-CoV2 triggers autoimmunity. The emergence of pediatric multi-system inflammatory disease in temporal relation to SARS-CoV2 infection is an example of SARS-CoV2 triggering vasculitis. 2 In the newly diagnosed, the predominance of PR3 provides further evidence for infectious antigen stimulation leading to generation of autoimmunity, especially in the setting of PR3 AAV. 3 Additionally, both COVID-19 and AAV are associated with formation of neutrophil extracellular traps, providing further plausible mechanisms involved in development of autoimmunity in the setting of the acute viral infection. 4 , 5 Most importantly, these cases have provided possible strategies for management of immunosuppression in the time of a pandemic, where constant uncertainty regarding the same exists. In patients with new diagnosis of AAV, treatment with pulse steroids with either RTX or CYC shortly after acute presentation of COVID-19 led to overall sustained clinical recovery, with no worsening or recurrence of manifestations of infection. With respect to established AAV cases, the median duration elapsed since RTX administration being 60 days. Not only did all of these patients recover, but also, only one on RTX maintenance required mechanical ventilation. This in keeping with proposed theories that RTX may limit cytokine storm and prevent further worsening of clinical status. 6, 7, 8 Similar experience has been reported in utilization of B-cell depleting therapies in diseases such as multiple sclerosis and pemphigus vulgaris, along with other patients with other autoimmune diseases on biologic therapies. S1-S3 The only caveat is to recognize that patients previously treated with RTX may demonstrate prolonged viral shedding devoid of any symptoms. This may influence recommendations for duration of quarantine for this population of patients so as to prevent inadvertent exposure to other individuals. In conclusion, the use of immunosuppression in patients with COVID-19 in the setting of new and established diagnosis of AAV, may not be associated with deleterious outcomes. Induction immunosuppression could be used shortly after improvement of acute COVID-19 presentation to treat newly diagnosed AAV. On the other hand, maintenance immunosuppression has the potential to attenuate severe inflammatory effects of COVID-19 and may not be associated with worse outcome. Uncited Table Table 1 and 2 Table 1 Demographics, clinical characteristics and outcomes of patients with newly diagnosed ANCA associated vasculitis and COVID-19 Case report Age Gender Ethnicity Peak Creatinine (mg/dL) ANCA type Kidney Pathology Lung radiology ANCA Induction RRT Respiratory failure COVID-19 Treatment COVID-19 Outcome Comments Uppal S4 64 M African American 7.9 MPO Crescentic GN Bilateral patchy infiltrates Pulse steroids (MP 500 mgx3) + RTX (1g) iHD 10 L NRB mask Tocilizumab, convalescent plasma AKI in recovery Received only dose of RTX post negative COVID-19 PCR Uppal S4 46 M South Asian 4 PR3 Focal necrotizing GN Resolving peripheralGGOs Pulse steroids (MP 1gx3) + RTX (375 mg/m2) x2 No None HCQ, azithromycin AKI in recovery Completed both doses of RTX (one during hospital stay) Moeinzadeh S5 25 M NR 5.5 PR3 Crescentic proliferative GN Ground glass opacities resemble diffuse alveolar hemorrhage versus corona virusinfection Pulse steroids (MP 1gx3) + CYC + PLEX + IVIG No None HCQ, levofloxacin AKI in recovery PLEX given alveolar hemorrhageCommenced on CYC (day 10 post ANCA/COVID-19 diagnosis) after negative COVID-19 PCR Hussein S6 37 F Middle eastern NR PR3 - Patchy consolidation with a central and peripheral distribution, permeated by GGO and crazy paving pattern. Pulse steroids (prednisone 60mg) + PLEX + IVIG NR MV Ritonavir/lopinavir Patient died PLEX given alveolar hemorrhage NR- not reported, MPO- myeloperoxidase antibody, PR3- proteinase 3, GN- glomerulonephritis, GGO- ground glass opacities, RTX- rituximab, CYC- cyclophosphamide, PLEX- plasmapheresis, RRT- renal replacement therapy, iHD- intermittent hemodialysis, NRB- non-rebreather mask, HFNC- high flow nasal cannula, MV- mechanical ventilation, UA- urinalysis, HCQ- hydroxychloroquine Table 2 Demographics, clinical characteristics and outcomes of patients with COVID-19 on a background of established ANCA associated vasculitis Case report Age Gender Ethnicity Peak Creatinine (mg/dL) Duration of ANCA diagnosis (months) ANCA type Lung radiology ANCA maintenance Last IS to COVID diagnosis (days) RRT Respiratory failure COVID-19 Treatment COVID-19 Outcome Comments Guilpan 8 52 F NR NR 396 PR3 Bilateral interstitial pneumonia RTX 1 No MV Lopinavir/ritonavir; HCQ Recovered from respiratory failure; discharged on day 29 of admission Received RTX a day prior to COVID presentation Sharmeen S7 27 F Hispanic NR 1 PR3 Bilateral multifocal opacities RTX, prednisone (20 mg) 60 No NRB-15L HCQ, Tocilizumab Recovered On 20 mg prednisone at time of COVID diagnosis Schramm S8 25 M NR NR 2 PR3 Bilateral GGOs RTX, CYC (induction), prednisone (60 mg) 9 No Low flow 2L HCQ, lopinavir/ritonavir Recovered *Nosocomial infectionOngoing60 mg prednisone, 9 days after last of five cyclophosphamide infusions and 19 days after the last of four rituximab infusions Daniel 6 55 M NR NR 324 PR3 Bilateral GGOs (60% involvement) RTX, prednisone (4mg) 120 No None HCQ, azithromycin, lopinavir/ritonavir Recovered, discharged home after 23 days On 4 mg prednisone at the time of diagnosis Leipe S9 63 M NR 3.4 72 PR3 Bilateral GGOs RTX, prednisone (5mg) 14 No Face Mask-6L None Readmitted with worsening respiratory symptoms on Day 14; eventual recovery On 5mg prednisone at the time of diagnosis Shenavandeh S10 35 M NR NR 72 PR3 Multiple new left sided peripheral GGOs in addition to the pre-existing right-side cavitary lesion. RTX, AZA, prednisone (7.5mg) NR No None HCQ, azithromycin Discharged after 4 days; recovered On 7.5mg prednisone at the time of diagnosis Fallet S11 77 F NR NR 24 PR3 Scattered bilateral GGOs RTX, MTX, prednisone 5mg 30 No None None Discharged after 6 days; recovered - Suárez-Diaz S12 64 F NR NR 72 MPO NR Prednisone 5mg 90 No None None Recovered at home Treated for vasculitis relapse with RTX 90 days before COVID diagnosis Current study 74 F African American 1.5 108 MPO Scattered bilateral GGOs Prednisone 5mg - No MV Remdesivir Recovered Renal biopsy showed mild necrotizing GN; received MP 40 mg x 10; RTX 2 months after COVID diagnosis Current Study 48 F Hispanic 0.7 72 PR3 Diffuse peribronchovascular and peripheral GGOs RTX 500 mg, prednisone 8 mg 60 No HFNC Remdesivir, Dexamethasone Recovered - Current study 81 F African American 1.5 12 PR3 Scattered bilateral GGOs AZA, Prednisone 5mg - No HFNC None Recovered - Current study 45 M Asian 1.3 60 PR3 Scattered bilateral GGOs RTX, prednisone 5mg 120 No Low flow 2L Remdesivir Recovered - Current study 63 M Caucasian 1.2 0.5 PR3 Scattered bilateral GGOs See comments 7 No Low flow 6L Dexamethasone, remdesivir, convalescent plasma In-hospital Received RTX 1g and methylprednisone 500 mg x 3 for induction. Diagnosed with COVID a week after RTX and discharge from hospital. Current study 36 M Caucasian 1 54 PR3 - RTX 80 No None None Recovered at home - M-male, F- female, NR- not reported, MPO- myeloperoxidase antibody, PR3- proteinase 3, GN- glomerulonephritis, GGO- ground glass opacities, RTX- rituximab, CYC- cyclophosphamide, MTX- methotrexate, RRT- renal replacement therapy, iHD- intermittent hemodialysis, NRB- non-rebreather mask, MV- mechanical ventilation, UA- urinalysis, HCQ- hydroxychloroquine