Pulmonary-renal Syndrome Caused by an Overlap Systemic Lupus Erythematosus/Antineutrophil Cytoplasmic Antibody-associated Vasculitis Syndrome in the Setting of Immune Complex-mediated Glomerulonephritis in a Patient with COVID-19 Infection

Abstract

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 continues to be a global public health issue. Kidney disease is common, mainly presenting as acute kidney injury. Glomerular diseases have been reported in COVID-19. We are presenting a case of immune complex-mediated glomerulonephritis in a patient with COVID-19 infection and probable superimposed systemic lupus erythematosus and antineutrophil cytoplasmic antibody-associated vasculitis overlap who developed a pulmonary-renal syndrome. The patient responded well with a combination of plasma exchange, rituximab, and glucocorticoid therapy. The treatment was successful with resolution of the diffuse alveolar hemorrhage and prevention of potential end stage kidney disease. We would like to add this case to the literature as another example of the long-ranging potential autoimmune/autoinflammatory complications associated with COVID-19 disease.

INTRODUCTION

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to be a global public health issue. COVID-19 can potentially affect any organ of the infected patient. Kidney disease is common, mainly presenting as acute kidney injury.[1,2] Glomerular diseases have been reported in COVID-19.[3] We are presenting a case of immune complex-mediated glomerulonephritis (GN) in a patient with COVID-19 infection with probable superimposed systemic lupus erythematosus (SLE) and antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) overlap who developed a pulmonary-renal syndrome.

CASE REPORT

A 60-year-old Caucasian woman with no significant prior medical history was admitted to our hospital due to symptoms of progressive lower extremity edema and dry cough. Admission blood work disclosed hemoglobin – 7.8 g/dL, white blood cells (WBC) – 7.4 th/uL, platelets – 253 th/uL, creatinine – 1.7 mg/dL, and estimated glomerular filtration rate (eGFR) (Cr) 38 mL/min/1.73 m². Six months before this admission, during an emergency department (ED) visit, her blood work disclosed a creatinine level of 0.86 mg/dL.

The patient was hypoxemic on room air and required to be started on supplemental oxygen. The chest X-ray disclosed evidence of bilateral patchy airspace disease and interstitial infiltrates. In the ED, she tested positive for SARS CoV-2/COVID-19.

The patient developed hemoptysis and an increase in oxygen requirement. She was transferred to the intensive care unit where she was intubated for acute hypoxemic respiratory failure. Urinalysis disclosed blood 3+, protein 1+, red blood cells too numerous to count/high-power field (HPF), and WBC 6–10/HPF. The patient underwent fiber-optic bronchoscopy. Serial bronchoalveolar lavage of the right middle lobe showed progressively increased blood return suggesting diffuse alveolar hemorrhage [Figure 1]. Laboratory results are presented in Table 1.

Figure 1.

Serial bronchoalveolar lavage of the right middle lobe showing progressively increased blood return

Table 1.

Autoimmune serology

Study	Value	Normal values
C3 (mg/dL)	44.0	82.0–185.0
C4 (mg/dL)	5.5	15.0–53.0
ANA	Positive	Negative
Antinuclear pattern	Nucleolar
Antinuclear titer	1: 160	<1:40
ANCA screen	Positive	Negative
ANCA titer	>1:320	<1:20
ANCA pattern	C-ANCA
Proteinase antibody, AI	<1.0	<1.0
Myeloperoxidase antibody, AI	1.9	<1.0
SSA antibody, AI	<0.2	0.0–0.9
SSB antibody, AI	<0.2	0.0–0.9
DNA antibody, units, IU/mL	46.5	<10
Histone DNA antibody, Units	0.6	<0.9
Centromere antibody, AI	<0.2	<0.0–0.9
Anti-glomerular basement membrane antibody, units	<0.2	0–20
Sm-RNP- antibody, AI	<0.2	0.0–0.9
Scleroderma antibody, AI	<0.2	0.0–0.9
Cryoglobulin >72 h	Negative	Negative

ANA: Antinuclear antibody, ANCA: Antineutrophil cytoplasmic antibody, SSA: Sjögren’s-syndrome-related antigen A, SSB: Sjögren’s-syndrome-related antigen B, Sm-RNP: anti-Smith/ribonucleoprotein, AI: Antibody index

Based on the clinical presentation suggestive of pulmonary-renal syndrome, the patient underwent computed tomography-guided left renal parenchymal biopsy for further evaluation. The renal biopsy showed a focal proliferative and crescentic GN associated with diffuse mesangial expansion and large deposits forming “wire loops” and hyaline pseudothrombi. By immunofluorescence, the large deposits showed near “full house” positivity with strong immunoglobulin (Ig) G, IgM, C3, and C1q mesangial and capillary loop staining. Frequent subendothelial and mesangial electron-dense deposits without substructure were present by electron microscopy. There were no endothelial tubuloreticular inclusions identified [Figure 2].

Figure 2.

Renal biopsy showing: (a) Focal glomeruli with cellular to fibrocellular crescents and segmental endocapillary hypercellularity (H and E, ×200). (b) Glomeruli with large, periodic acid–Schiff (PAS)-positive deposits forming “wire loops” (arrows) and hyaline pseudothrombi (PAS; ×400). (c) Diffuse glomerular mesangial and capillary loop granular staining by immunoglobulin G (fluorescein; ×200). (d) Frequent mesangial electron-dense deposits by electron microscopy (original magnification ×8000)

The patient was started on pulse dose intravenous (IV) methylprednisolone 1 g/day and was transitioned to daily prednisone. She was treated with one dose of cyclophosphamide and was initiated on plasma exchange (PLEX) therapy. She underwent five treatments of PLEX over a span of 10 days. After she completed her course of PLEX, she was treated with rituximab 1 g IV. After 14 days, she received a second dose of rituximab 1 g IV.

The patient was subsequently extubated after four sessions of PLEX with resolution of hemoptysis and improvement of hypoxemia. Her eGFR stabilized with a serum creatinine level of 1.3 mg/dL. The patient was discharged on oral prednisone 60 mg/day and atovaquone 1500 mg/day for Pneumocystis Jirovecii prophylaxis.

DISCUSSION

Our patient developed diffuse alveolar hemorrhage in the setting of immune complex-mediated focal crescentic GN after being diagnosed with COVID-19 infection. Immune complex-mediated GN is one cause of rapidly progressing GN (RPGN); crescentic lesions on renal biopsy are a hallmark of RPGN. RPGN can also be caused by antiglomerular basement membrane (GBM) antibody disease and pauci-immune ANCA-associated GN.[4] Immune complex-mediated focal crescentic GN is seen commonly in patients with underlying systemic autoimmune diseases (e.g. SLE) as well as other systemic conditions such as cryoglobulinemia and certain malignancies.

Patients with COVID-19 infection can present with various glomerular diseases. COVID-associated nephropathy is the most common diagnosis in native renal biopsies of patients with COVID-19 disease[5] and pathology is typically characterized by collapsing focal segmental glomerulosclerosis. Other glomerular diseases have been reported in patients with COVID-19 infection, including IgA nephropathy,[6] anti-GBM antibody disease,[7] as well as immune complex-mediated GN[8] and ANCA-associated GN.[9]

SARS-CoV-2 infection may be associated with autoimmunity.[10] The patient exhibited findings of a positive ANCA screen with c-ANCA pattern and a titer of >1:320, and instead of anti-PR3 antibodies, she was positive for anti-MPO antibodies. She also was found to have a positive ANA screen with a titer of 1:160, DNA Ab 46.5 IU/mL, and low C3 and C4 levels. We believe that our patient had a concomitant presentation of SLE/AAV overlap syndrome in the setting of an immune complex mediated process due to underlying COVID-19 infection. In addition, she responded very well to the combination of immunosuppression with rituximab, along with PLEX therapy. COVID-19 infection has been associated with a substantial risk for autoimmune and autoinflammatory connective tissue disorders.[11] During autoinflammatory and autoimmune syndromes, it has been hypothesized that triggering factors, such as viruses, drive the activation of an aberrant innate and acquired immune response, with increased synthesis of cytokines.[12] It is likely that immune dysregulation in the setting of COVID-19 infection may have unmasked this autoimmune process in our patient.

CONCLUSION

This patient with COVID-19 infection presented with a pulmonary-renal syndrome with evidence of diffuse alveolar hemorrhage and acute GN. Her glomerular disease was consistent with immune complex-mediated GN, likely with superimposed SLE/AAV overlap syndrome. She responded well with a combination of PLEX, rituximab, and glucocorticoid therapy. The treatment was successful with resolution of the diffuse alveolar damage and prevention of potential end stage kidney disease. We would like to add this case to the literature as another example of the long-ranging potential autoimmune/autoinflammatory complications associated with COVID-19 disease.

Research quality and ethics statement

The authors followed applicable EQUATOR Network (https://www.equator-network.org/) guidelines, notably the CARE guideline, during the conduct of this report.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that her name and initials will not be published and due efforts will be made to conceal her identity, but anonymity cannot be guaranteed.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.