De novo lupus nephritis after SARS-CoV-2 infection

Abstract

The relationship between viral infection and onset of autoimmune diseases such as systemic lupus erythematosus remains uncertain. During the COVID-19 pandemic, organ-specific and multisystemic autoimmune phenomena temporally related to the viral infection have been described. Immune dysregulation triggered by the SARS-CoV-2 virus leading to hyperactivation of both the innate and adaptive immune systems contributes to the excessive production of pro-inflammatory cytokines, autoantibodies, and subsequent autoimmune manifestations. We report two patients without known autoimmune diseases who developed lupus nephritis shortly after a documented mild SARS-CoV-2 infection. Together with other similar cases in the literature, the observation supports a viral trigger of the development of systemic lupus erythematosus in susceptible individuals.

Introduction

The coronavirus disease 19 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was declared a pandemic by the World Health Organization (WHO) in March 2020. While the majority of SARS-CoV-2 infection causes mild disease, some patients develop severe pneumonia that leads to acute respiratory distress syndrome (ARDS) and respiratory failure as a result of “cytokine storm” caused by massive release of pro-inflammatory cytokines. ¹ The persistent over-production of cytokines and inflammatory mediators contributes to organ damage and the post-COVID syndrome (PCS), which is an important cause of morbidity after the acute phase of COVID-19. ² Moreover, the activation of the innate and adaptive immune systems by the infection may trigger a number of autoimmune phenomena, presumably related to molecular mimicry.^3,4

The relationship between viral infection and onset of autoimmune diseases such as systemic lupus erythematosus (SLE) is complex and not fully elucidated. ⁵ There is growing evidence that COVID-19 may induce autoimmune features. In severe SARS-CoV-2 infection, anti-nuclear antibodies (ANA), anti-Ro antibody, rheumatoid factor, and lupus anticoagulant were detected in 11%–36% of patients.^6,7 Antibodies against type I interferon (IFN) could be found in at least 10% of patients with critically ill SARS-CoV-2 infection. ⁸ Moreover, organ-specific and multisystemic autoimmune manifestations, such as cutaneous vasculitis, immune thrombocytopenia, myelitis, demyelinating syndrome, systemic vasculitides, SLE, hemophagocytic lymphohistiocytosis (HLH), and multisystem inflammatory syndrome (MIS),^9–11 have been described after infection with the SARS-CoV2 virus.

Clinical flares of rheumatic diseases were reported in 41% of patients infected with SARS-CoV-2, ¹² which was at least 3-fold more common than non-infected patients. ¹³ However, these studies did not specifically report the incidence of disease flares in patients with SLE. Isolated cases of SLE flares involving various organ systems such as the kidneys and the central nervous system have been reported during or following SARS-CoV-2 infection.^14–19 In a retrospective series of 51 Italian SLE patients, flares of SLE developed in 5.9% of patients after a diagnosis of COVID-19. ²⁰ To our knowledge, only a handful of cases of de novo SLE, lupus nephritis or cutaneous lupus in otherwise healthy individuals after SARS-CoV-2 infection have ever been reported in the literature.^4,21–31 We hereby report two more cases of lupus nephritis which developed for the first time after the viral infection.

Report of Two Patients

Patient 1

A 38-year-old non-smoking Chinese woman with no known medical illnesses was admitted to our unit in December 2022 with dry cough, bilateral lower limb edema, and progressive dyspnea for several days. 10 days prior to the current presentation, she had upper respiratory tract infection symptoms and was diagnosed to have mild COVID-19 by a rapid antigen test. No specific anti-viral treatment was given by the primary care doctor. In the current admission, she had bilateral pitting edema of the lower limbs and raised blood pressure (systolic 170–190 mm Hg). A chest radiograph showed bilateral middle and lower zone infiltrates and pleural effusion. She developed intermittent fever shortly but microbiological investigations were negative, including a bronchoscopic alveolar lavage and culture of body fluids. She denied joint pain, skin rash, oral ulcers or alopecia. There was no family history of any autoimmune diseases. Her blood pressure remained high, which required treatment with multiple anti-hypertensive agents. She developed arterial hypoxia and was monitored in the intensive care unit with oxygen therapy. As her nasopharyngeal and throat swab for SARS-CoV2 polymerase chain reaction (PCR) was negative, no anti-viral therapy was given.

Laboratory tests revealed anemia (hemoglobin 9.5 g/dL; NR 11.6–15.5), lymphopenia (lymphocyte count 0.5 × 10⁹/L; NR 1.2–3.4), thrombocytopenia (platelet count 90 × 10⁹/L; NR 152-358), impaired renal function (serum creatinine 248 mmol/L; NR50-98), hypoalbuminemia (serum albumin 23 g/L; NR35-52), elevated C-reactive protein (34 mg/L; NR <5.0), nephrotic range proteinuria (urine protein/creatinine ratio [uP/Cr] 6.58; NR <0.2) and microscopic hematuria (but no active casts). Her ANA (titer 1/2560), anti-dsDNA (>800 IU/mL; NR <100), anti-Ro was positive, and so was the direct anti-globin tests. There was hypocomplementemia (C3 0.47 g/L; NR0.83–1.93 g; C4 0.05 g/L; NR0.15–0.57) but the antiphospholipid antibodies (anticardiolipin IgG and lupus anticoagulant) were negative. An echocardiography revealed mild pericardial effusion and normal left ventricular ejection fraction without evidence of pulmonary hypertension or infective endocarditis. A computer tomography (CT) scan of the thorax showed bilateral pleural effusion, pericardial effusion, and patchy ground glass opacities at the middle and lower zones of the lungs. A renal biopsy was subsequently done and showed ISN/RPS class IV lupus nephritis with a modified NIH activity index of 12/24 and chronicity index of 1/12.

In view of the absence of infective causes, a diagnosis of SLE was made, based on the presence of fever, thrombocytopenia, lymphopenia, hemolytic anemia, serositis, active nephritis, and the possibility of pneumonitis. Our patient was treated with high-dose glucocorticoids, hydroxychloroquine, and mycophenolate mofetil. The response was rapid, with subsidence of fever, hypoxemia, and stabilization of renal function after a week. There was gradual improvement of the serum creatinine and albumin level, together with reduction in proteinuria on follow-up 8 weeks later. Switching to cyclophosphamide or addition of the biological agents was discussed if no further improvement was observed in the next 1–2 months.

Patient 2

A 66-year-old Chinese woman was admitted to our unit in late December 2022 for intermittent fever, generalized myalgia and lethargy for several days. She had an unremarkable medical history except having essential hypertension, which was well controlled with a calcium channel blocker. There was no family history of autoimmune disorders. Her current symptoms started 7 days after a mild COVID-19 (upper respiratory tract symptoms) in which she received anti-viral treatment (nirmatrelvir/ritonavir) in an isolation facility.

In the current admission, she was relatively well with no abnormal physical signs elicited. Her initial chest radiograph showed mild left lower zone haziness and she was treated with antibiotics to cover for the possibility of post–COVID-19 bacterial pneumonia. Her blood tests were grossly normal. There was no evidence of sepsis on systemic review and blood tests. However, her fever persisted and there was a drop of hemoglobin to 10 g/dL (NR11.6–15.5) in the next week, with reticulocytosis (3.4%; NR <2) and positive direct and indirect anti-globulin tests. A CT of the thorax was performed for persistent fever and lung infiltrates, which showed bilateral pleural effusion, lower zone infiltrates, and multiple enlarged mediastinal lymph nodes. A subsequent bronchoscopic alveolar lavage was negative for microorganisms that included mycobacterium and pneumocystitis. Viral studies were negative. At this stage, her nasopharyngeal and throat swab was negative for SARS-CoV2 PCR.

The hemoglobin level of our patient further dropped to 7 g/dL, with the development of lymphopenia (0.5 × 10⁹/L; NR1.2–3.4) and neutropenia (1.0 × 10⁹/L; NR2.1–7.8). A bone marrow examination showed active erythropoiesis and megakaryocytic hyperplasia. Autoantibody screening revealed a positive ANA at high titer (1/2560), positive anti-dsDNA (>800 IU/mL; NR <100), and anti-La, with low complement C3 (0.68 g/L; NR 0.83–1.93) and C4 (0.11 g/L; NR 0.15–0.57) levels. Urine analysis showed significant proteinuria (uP/Cr 1.68; NR <0.2). Active urinary sediments were not present.

Our patient denied any skin rash, arthralgia, alopecia, oral ulcers, chest pain, or Raynaud’s phenomenon. In view of the positive ANA, elevated anti-dsDNA, low C3/C4 levels, proteinuria, hemolytic anemia, lymphopenia, and pleural effusion, which was not explained by alternative causes, a diagnosis of SLE with renal involvement was made. Unfortunately, our patient strongly declined a renal biopsy. She was treated with a moderate dose of oral prednisolone (0.8 mg/kg/day) along with mycophenolate mofetil. Resolution of clinical symptoms and improvement in hemoglobin (9.0 g/dL), cytopenia (normal total white cell and neutrophil counts), and uP/Cr (0.51) was observed after 8 weeks.

Summary of Patients Reported in the Literature

Table 1 summarizes the clinical characteristics of our two patients together with 10 others in the literature.^21–30 There were eight women and four men and the mean age at the time of COVID-19 was 39.7 ± 20.1 years (range 18–85). COVID-19 was confirmed by SARS-CoV2 PCR in eight patients and the rapid antigen test (RAT) in one patient. In two patients, the SARS-CoV2 PCR was negative but the SARS-CoV2 IgG antibody was positive, indicating a recent COVID-19 based on the presence of compatible respiratory symptoms. SARS-CoV-2 infection occurred concurrently with SLE manifestations in two patients while in the other nine patients, the mean time interval between SARS-CoV-2 infection and onset of SLE symptoms was 4.0 ± 2.7 weeks (range 1–8). Nine of the 12 patients were reported in the years 2020 and 2021, suggesting the non-omicron strains (alpha, beta, delta and gamma) of the SARS-CoV2 virus were involved based on epidemiological information, although the exact viral variants were not explicitly mentioned. The remaining three patients of COVID-19–induced SLE (our 2 patients and the one reported by Ali S et al.) ²⁸ presented in 2022 and 2023, which indicated that the omicron variant of SARS-CoV2 was responsible. The shorter interval between the infection and onset of SLE symptoms in these patients might suggest a more robust relationship between the omicron variant of SARS-CoV2 and autoimmunity.

Table 1.

Cases of New Onset SLE After COVID-19 Infection Reported in the Literature.

Patient Number	Author(s), Year	Sex	Age	SLE Manifestations	Autoantibodies, Complements	SARS-CoV2 Infection	Specific Anti-viral Treatment	Interval Between COVID-19 Infection and Onset of SLE Symptoms	Treatment and Outcome
1	Bonometti et al., 2020 21	F	85	Thrombocytopenia, pleural effusion, acute kidney injury with proteinuria, cutaneous vasculitis	ANA, low C3	SARS-CoV2 IgG positive	NIL	Not known	GC, HCQ
2	Slimani et al., 2020 22	F	23	Lymphopenia, thrombocytopenia, hemolysis, proteinuria, skin rash, pulmonary infiltrates	ANA, dsDNA, antiphospholipid antibodies, low complements	PCR confirmed	NIL	2–3 weeks	Respiratory failure due to worsening of pneumonitis and died
3	Cardoso et al., 2020 23	F	18	Fever, serositis, pericardial tamponade, acute kidney injury, lymphopenia, proteinuria, hematuria, deep vein thrombosis	ANA, dsDNA, LAC, aCL, low complements	PCR confirmed	NIL	Concurrent	Pericardiocentesis, mechanical ventilation, pulse methylprednisolone, HCQ, TCZ, plasma exchange; died on day 17
4	Ali et al., 2021 24	F	25	Facial and scalp rash, muscle weakness, oral ulcers, serositis, acute kidney injury, cytopenia (hemophagocytosis)	dsDNA, sm, U1RNP, Ro, LA	PCR confirmed	NIL	2 months	Pulse methylprednisolone, HCQ, MMF, plasma exchange, rituximab
5	Gracia-Ramos et al., 2021 25	M	45	Fever, arthralgia, anemia, thrombocytopenia, impaired renal function, pleural effusion, ascites, pulmonary infiltrates	ANA, dsDNA, Ro, LA, low complements	PCR confirmed	NIL	3 weeks	Pulse methylprednisolone, GC, chloroquine, IVIG, rituximab with improvement
6	Hali et al., 2021 26	F	25	Fever, generalized skin rash, myalgia, oral ulcers, pulmonary infiltrates, anemia, leukopenia, lymphopenia, proteinuria, pericardial effusion	ANA, dsDNA, antiphospholipid antibodies	PCR confirmed	NIL	2 weeks	Pulse methylprednisolone, GC with improvement
7	Zamani et al., 2021 27	M	39	Fever, skin rash, LL edema, leukopenia, thrombocytopenia, pulmonary infiltrates, sensory neuropathy, proteinuria, renal biopsy: Class I LN	ANA, dsDNA, Ro, LA, low CH50	SARS-CoV2 IgG positive	NIL	COVID-19 symptoms 2 months before the current presentation	Pulse methylprednisolone, GC, HCQ, IV pulse CYC; improved after 6 months
8	Ali et al., 2022 28	F	22	Anemia, anasarca, cervical lymphadenopathy, alopecia, oral ulcers, proteinuria and active urinary sediments	Sm, U1RNP	PCR confirmed	NIL	Concurrent	Controlled with GC, HCQ and IV pulse CYC
9	Kazzi et al., 2022 29	M	37	Fever, muscle weakness, generalized skin rash, proteinuria, leukopenia; renal biopsy – class II LN	ANA, dsDNA, low complements	PCR confirmed	NIL	6 weeks	GC, MMF, HCQ, resolution of symptoms after 3 months
10	Ramachandran et al., 2022 30	M	53	Polyarthritis, generalized edema, nephrotic range proteinuria; renal biopsy – class IV LN	ANA, dsDNA, low complements	NS	NIL	1 month	Pulse methylprednisolone, GC, MMF, HCQ; improvement after 2 months
11	Present report	F	38	LL edema, acute kidney injury, nephrotic syndrome, renal biopsy: Class IV LN, fever, pulmonary infiltrates, hemolytic anemia, lymphopenia, thrombocytopenia, serositis	ANA, dsDNA, Ro, low complements	RAT + ve	NIL	10 days	High dose GC, HCQ, MMF; improved after 8 weeks
12	Present report	F	66	Fever, hemolytic anemia, lymphopenia, lymphadenopathy, pleural effusion, pulmonary infiltrates, proteinuria	ANA, dsDNA, anti-La, low complements	PCR confirmed	Yes	7 days	GC, MMF; improved after 8 weeks

F = female; M = male; PCR = polymerase chain reaction; GC = glucocorticoid; HCQ = hydroxychloroquine; LAC = lupus anticoagulant; aCL = anticardiolipin; TCZ = tocilizumab; MMF = mycophenolate mofetil; IV = intravenous; IVIG = intravenous immunoglobulin; CYC = cyclophosphamide; RAT = rapid antigen test; LL = lower limb; LN = lupus nephritis.

The prevalence of SLE manifestations in these SARS-CoV2-infected patients, in decreasing order of frequency, was renal (92%), hematological (75%), serositis (58%), dermatological (50%), and pneumonitis (50%). There was also a high prevalence of the anti-dsDNA in these patients (83%), whereas the antiphospholipid antibodies were present in 25% of all cases. All the patients were treated with usual immunosuppressive regimens for SLE. Improvement was reported in 10 patients but two patients (17%) deteriorated and finally succumbed.

Discussion

We reported two patients without known autoimmune diseases who developed lupus nephritis for the first time shortly after SARS-CoV-2 infection. The temporal relationship between the onset of lupus nephritis and the SARS-CoV-2 infection suggests a causal relationship. Together with other 10 patients with de novo SLE or lupus nephritis reported in the literature, it appears that renal, serosal, hematological and pulmonary parenchymal manifestations are over-represented when compared with typical SLE cohorts of different ethnic groups.^32,33 Although fever, cytopenias, and pulmonary infiltrates are common features of SARS-CoV-2 infection, serositis and renal involvement is rather uncommon for a viral infection. Post-SARS-CoV2 pulmonary abnormalities that include organizing pneumonia has been reported in up to one-third of patients, ³⁴ which is difficult to differentiate from pneumonitis caused by SLE. The high prevalence of the anti-dsDNA antibodies is also characteristic of these de novo SLE cases. The high mortality of COVID-19–related SLE is a concern, which is probably related to massive cytokine release triggered by the viral infection.

The SARS-CoV2 contains a large single-stranded RNA and its genome consists of around 30,000 nucleotides. ³⁵ This provides an enhanced ability of the virus to interact with the human immune system. In fact, 28 proteins with homologous regions to SARS-CoV-2 peptides have been identified that could potentially function as autoantigens in infected patients who manifested with autoimmune phenomena. ³⁶ Although molecular mimicry has been postulated as a major mechanism of COVID-induced autoimmunity, ³⁷ bystander activation induced by a hyper-inflammatory state (cytokine release), epitope spreading and viral persistence driving immune-mediated injury and the formation of neutrophil extracellular traps have also been hypothesized.^10,38 Autoantibodies commonly described in SLE, including the antiphospholipid antibodies,^6,7 have been detected in patients with SARS-CoV-2 infection. Moreover, clinical flares of various rheumatic diseases and de novo onset of well-defined autoimmune diseases, including SLE, have well been reported after infection with SARS-CoV2.^9–18

Vaccination against SARS-CoV2 has been shown to reduce the risk of severe disease, hospitalization and mortality. ³⁹ However, the worry of vaccine-induced autoimmunity and flares of the underlying disease is a major deterrent for patients with SLE to receive the COVID-19 vaccines. Serious vaccine-induced complications are uncommon^40,41 and the benefits of vaccination outweigh its risk. Moreover, case–control studies failed to show increase in SLE flares after COVID-19 vaccination. ⁴² The knowledge that SARS-CoV-2 infection itself could also trigger disease flares and development of new autoimmune phenomena could provide an argument for the higher benefit-to-risk ratio of the COVID-19 vaccines during epidemics. More studies are needed to confirm the observation for increased flares of SLE post-COVID-19, as well as to compare the incidence of viral related disease flares with that attributed by the COVID-19 vaccines.

ORCID iD

Chi Chiu Mok https://orcid.org/0000-0003-3696-1228