Introduction
Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) comprises granulomatosis with polyangiitis (GPA, previously known as Wegener’s granulomatosis), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA, previously known as Churg–Strauss syndrome) [1]. The kidney is one of the most common organs involved in AAV [2], and the outcomes in patients with AAV have improved significantly over the past decades, although a significant proportion of them still develop end-stage renal disease (ESRD) [3]. Another important issue of outcomes is relapse, which is associated with subsequent progression to ESRD [4].
Throughout the pandemic of severe acute respiratory syndrome by coronavirus-2 (SARS-CoV-2) disease (COVID-19), many studies have reported a greater risk of poor outcomes among patients with various immune-mediated inflammatory diseases [5]. Patients with preexisting autoimmune diseases may undergo disease flare after COVID-19 infection [6, 7]. Meanwhile, COVID-19 infection has been proposed as a trigger of several autoimmune diseases as well [8, 9].
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There may be a reciprocal influence between AAV and COVID-19 infection. Patients with AAV have been reported to have a higher likelihood of developing severe COVID-19 [10]. Moreover, SARS-CoV-2 would even be an upstream trigger of AAV. For example, it was found by Vlachoyiannopoulos et al. that 13% of patients with critical COVID-19 pneumonia positivity of ANCA [11]; several studies reported cases developed after COVID-19 infection [12, 13]. However, the evidence about the impact of COVID-19 infection on the disease progression among patients with preexisting AAV is limited, in particular, disease flare and chronic kidney disease (CKD) progression. Thus, the purpose of this study was to identify risk factors for COVID-19 infection and to investigate the impact of COVID-19 infection on CKD progression and vasculitis flare in patients with AAV.
Methods
Study population
This study reviewed 276 Chinese patients with AAV, diagnosed at Peking University First Hospital from 1999 to 2022 and followed up regularly at the outpatient. All patients met the Chapel Hill Consensus Conference criteria for AAV [1]. Patients with secondary vasculitis or with other comorbid renal diseases were excluded. Treatment protocols were described previously [14]. This research was conducted in accordance with the Declaration of Helsinki and was approved by the Clinical Research Ethics Committee of the Peking University First Hospital. Written informed consent was obtained from each patient or the guardians.
Diagnosis of COVID-19
The diagnosis of COVID-19 is based on the detection of SARS-CoV-2 using polymerase-chain-reaction (PCR) assay [15], as well as antibody, metagenomic testing, CT scan, laboratory assay or a presumptive diagnosis based on symptoms and epidemiological history by physicians. Patients meeting the above criteria were then assessed for a COVID-19 diagnosis during the study period (November 1, 2022–May 1, 2023).
The evaluation and management of COVID-19 depended on the severity of the disease, as patients with mild-to-moderate signs and symptoms typically recovered at home, while patients with severe COVID-19 are usually hospitalized for observation and supportive care [15]. Severe clinical manifestations included a respiratory rate higher than 30 breaths per minute, an oxygen saturation of less than 93%, while the patient was breathing ambient air, a ratio of partial pressure to fraction of inspiration oxygen (PaO2/FiO2) ≤ 300 mmHg and the lesion progression more than 50% within 24–48 h in the chest imaging. Once either condition is met, the case would be diagnosed as severe COVID-19 infection [16].
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Clinical data and biochemical parameters
All the clinical and laboratory data were, respectively, collected from the medical records of the patients, including age, gender, diagnosis, date of diagnosis, ANCA serotype, disease phenotype, organ involvement, immunosuppressive therapies, concomitant treatment, laboratory values (serum creatinine [Scr], C-reactive protein [CRP], erythrocyte sedimentation rate [ESR], white blood cell count [WBC], neutrophils, lymphocytes, hemoglobin, CD4+ T cells, CD8+ T cells, natural killer [NK] cells and serum albumin). The estimated glomerular filtration rate (eGFR) was calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation [17]. The Birmingham vasculitis activity score system (BVAS) was used in evaluating the disease activity of AAV [18]. The clinical and biochemical parameters before infection were collected from these patients’ last visit before their first symptoms of COVID-19 infection, which ranged from one week to three months earlier.
Outcomes
Two critical outcomes are CKD progression and AAV flare. CKD progression was defined as incident ESRD and/or decline in eGFR by ≥ 50%, as described previously [19]. AAV flare was defined as the re-occurrence of disease attributable to active vasculitis, or worsened disease activity [20]. The outcome events were recorded during a 6-month observation period commencing from the day of diagnosis of COVID-19 infection.
Statistical analysis
Continuous variables with normal distribution were described by mean and standard deviation, while those with and non-normal distribution were described by median and interquartile range. Categorical variables were described by frequency and percentage. Univariate analysis was performed by the Kruskal–Wallis test, one-way analysis of variance (ANOVA), or the chi-square test, as appropriate. Correlation between quantitative variables was performed using Pearson’s (for data that were in normal distribution) or Spearman’s correlations (for data that were in skewed distribution). Logistic regression was performed to explore the associations between the assessed parameters. P < 0.05 was considered statistically significant. Statistical analysis was performed using SPSS 18.0 (Chicago, IL, USA).
Results
General data of the patients
A total of 276 patients with confirmed diagnosis of AAV were enrolled: 110 were male, and 166 were female, with a median age of 66.5 (range, 17–91) years at diagnosis. 213 (77.2%) of 276 patients had a diagnosis of COVID-19 infection. Of the 213 patients, 49 (23.0%) had severe COVID-19 infection, including 17 patients who died of COVID-19 infection. 133 (48.2%) of 276 patients received COVID-19 vaccinations, including 107 (38.8%) finished the initial vaccination by receiving two or more SARS-CoV-2 vaccines. The demographic and baseline data of the study population are summarized in Table 1.
Table 1
Demographic and baseline features of the study population
AAV patients without COVID-19 infection | AAV patients with mild-to-moderate COVID-19 infection | AAV patients with severe COVID-19 infection | AAV patients dying of COVID-19 infection | |
|---|---|---|---|---|
Number | 63 | 164 | 32 | 17 |
Age, y | 67.7 ± 11.0 | 61.9 ± 13.4 | 63.6 ± 13.2 | 69.7 ± 10.4 |
Male/Female | 21/42 | 64/100 | 11/21 | 14/3 |
Induction therapy/Maintenance therapy | 8/55 | 12/152 | 6/26 | 0/17 |
Vaccination/Not vaccination | 29/34 | 79/85 | 12/20 | 3/14 |
Dialysis/Not dialysis | 6/57 | 23/141 | 6/26 | 3/14 |
Serum creatinine, mg/dl | 1.78 ± 0.94 | 1.57 ± 0.74 | 2.14 ± 1.24 | 2.92 ± 1.67 |
eGFR, ml/min/1.73m2 | 43.0 ± 23.5 | 50.1 ± 26.5 | 37.0 ± 20.9 | 30.1 ± 21.3 |
MPO-ANCA/PR3-ANCA | 57/7 | 142/24 | 25/5 | 14/2 |
ANCA titers, RU/ml | 0 (0–104.8) | 0 (0–79.0) | 0 (0–103) | 0 (0–56.0) |
CRP, mg/l | 1.0 (0.0–5.0) | 2.0 (0.0–4.0) | 1.0 (0.0–7.8) | 4.5 (3.0–13.0) |
WBC, *109/l | 8.2 ± 5.7 | 7.4 ± 2.7 | 7.1 ± 2.9 | 7.4 ± 1.3 |
Neutrophils, *109/l | 5.3 ± 3.6 | 4.8 ± 2.3 | 4.9 ± 2.1 | 5.0 ± 1.2 |
Lymphocytes, *109/l | 2.0 ± 1.1 | 1.8 ± 0.8 | 1.6 ± 1.3 | 1.5 ± 0.5 |
Monocytes, *109/l | 0.50 ± 0.19 | 0.61 ± 0.75 | 0.51 ± 0.20 | 0.47 ± 0.10 |
CD4+ T cells, counts/ml | 793 ± 372 | 925 ± 530 | 658 ± 382 | 600 ± 256 |
Hemoglobin, g/dl | 12.1 ± 1.6 | 12.5 ± 1.7 | 12.0 ± 2.1 | 11.7 ± 2.4 |
Serum albumin, g/l | 39.7 ± 4.9 | 41.3 ± 3.2 | 39.3 ± 4.9 | 40.1 ± 4.2 |
Risk factors for severe COVID-19 infection in patients with AAV
For the risk factors of severe COVID-19 infection in patients with AAV, patients with severe COVID-19 infection were more likely to be male (OR 1.921 [95% CI 1.020–3.619], P = 0.043), suffer from worse kidney function (Scr, OR 1.901 [95% CI 1.345–2.687], P < 0.001; eGFR, OR 0.976 [95% CI 0.958–0.994], P = 0.009, respectively), and have higher CRP (OR 1.054 [95% CI 1.010–1.101], P = 0.017) and less likely to have initial vaccination (OR 0.469 [95% CI 0.231–0.951], P = 0.036), suggesting that vaccination had a significant protective effect among patients with AAV from severe COVID-19. Kidney function, and COVID-19 vaccination were significantly associated with severe COVID-19 infection in multivariable adjustment (Scr, adjusted OR 1.926 [95% CI 1.276–2.909], P = 0.002; initial COVID-19 vaccination, adjusted OR 0.212 [95% CI 0.046–0.969], P = 0.045, respectively).
For the risk factors of death from severe COVID-19 infection in patients with AAV, sex, Scr, CRP and COVID-19 vaccination were significant in unadjusted analysis, as patients with severe COVID-19 infection were more likely to be male (OR 11.958 [95% CI 2.661–53.746], P = 0.001) and have higher Scr (OR 2.311 [95% CI 1.313–4.065], P = 0.004) and CRP (OR 1.059 [95% CI 1.014–1.106], P = 0.009) and less likely to have vaccination (OR 4.773 [95% CI 1.063–21.437], P = 0.041). However, none of these factors was significantly associated with the mortality of severe COVID-19 infection in multivariable analysis.
Impact of COVID-19 infection on CKD progression or vasculitis flare among patients with AAV
Nine patients suffered from CKD progression, and three patients got AAV flare upon COVID-19 infection within three weeks. The clinical and biochemical parameters before and after COVID-19 infection are summarized in Table 2, including kidney function, disease activity of AAV, inflammatory indicators, various blood cells counts and nutrition condition.
Table 2
Clinical and biochemical parameters before and after COVID-19 infection
AAV patients without COVID-19 infection (n = 42) | AAV patients with mild-to-moderate COVID-19 infection (n = 111) | AAV patients with severe COVID-19 infection (n = 26) | |||||||
|---|---|---|---|---|---|---|---|---|---|
Baseline | Follow-up | P values | Baseline | Follow-up | P values | Baseline | Follow-up | P values | |
Serum creatinine, mg/dl | 1.62 ± 0.79 | 1.66 ± 1.04 | 0.545 | 1.56 ± 0.74 | 1.63 ± 0.82 | 0.038 | 1.92 ± 0.99 | 2.16 ± 1.36 | 0.020 |
eGFR, ml/min/1.73m2 | 46.1 ± 23.6 | 47.0 ± 24.6 | 0.454 | 50.9 ± 27.6 | 49.0 ± 26.2 | 0.094 | 39.1 ± 20.3 | 37.9 ± 14.6 | 0.050 |
Urine RBC, counts/HP | 1.4(0.4–5.1) | 1.0(0.0–1.0) | 0.195 | 1.0(0.0–2.0) | 0.9(0.4–2.9) | 0.256 | 1.1(0.4–8.3) | 0.8(0.3–3.3) | 0.528 |
ANCA titers, RU/ml | 20(0–102) | 32(0–143) | 0.209 | 0(0–80) | 21(0–88) | 0.574 | 30(0–100) | 0(0–105) | 0.123 |
CRP, mg/l | 1.0(0.0–5.0) | 2.0(0.0–6.3) | 0.847 | 2.0(0.0–4.0) | 2.0(0.0–4.6) | 0.285 | 1.0(0.0–7.8) | 5.0(0.0–14.5) | 0.021 |
ESR, mm/h | 27.0 ± 15.9 | 30.3 ± 22.5 | 0.193 | 26.7 ± 21.7 | 33.9 ± 26.9 | 0.001 | 22.4 ± 14.7 | 43.0 ± 29.0 | 0.005 |
WBC, *109/l | 8.1 ± 6.2 | 7.3 ± 2.3 | 0.396 | 7.3 ± 2.6 | 7.4 ± 2.7 | 0.305 | 6.6 ± 1.8 | 7.8 ± 3.0 | 0.017 |
Neutrophils, *109/l | 5.2 ± 3.7 | 4.8 ± 2.0 | 0.416 | 4.8 ± 2.2 | 5.0 ± 2.3 | 0.230 | 4.6 ± 1.8 | 5.5 ± 2.6 | 0.008 |
Lymphocytes, *109/l | 2.0 ± 1.2 | 1.9 ± 1.0 | 0.780 | 1.8 ± 0.7 | 1.8 ± 0.8 | 0.830 | 1.5 ± 0.9 | 15 ± 0.6 | 0.883 |
Monocytes, *109/l | 0.47 ± 0.17 | 0.52 ± 0.20 | 0.045 | 0.55 ± 0.40 | 0.55 ± 0.34 | 0.707 | 0.48 ± 0.16 | 0.62 ± 0.21 | 0.002 |
Platelets, *109/l | 213 ± 60 | 218 ± 54 | 0.320 | 215 ± 49 | 227 ± 67 | 0.012 | 192 ± 59 | 192 ± 64 | 0.993 |
CD4+ T cells, counts/ml | 470 ± 349 | 580 ± 187 | 0.352 | 851 ± 340 | 795 ± 324 | 0.130 | 553 ± 149 | 657 ± 211 | 0.259 |
CD8+ T cells, counts/ml | 690 ± 417 | 958 ± 569 | 0.093 | 898 ± 334 | 918 ± 439 | 0.699 | 623 ± 268 | 752 ± 358 | 0.091 |
NK cells, counts/ml | 141 ± 45 | 280 ± 156 | 0.182 | 513 ± 384 | 547 ± 351 | 0.527 | 211 ± 21 | 333 ± 212 | 0.124 |
Hemoglobin, g/l | 123.4 ± 13.8 | 122.7 ± 17.2 | 0.733 | 125.4 ± 16.0 | 124.8 ± 30.0 | 0.809 | 123.4 ± 13.8 | 122.7 ± 17.2 | 0.756 |
Serum albumin, g/l | 41.0 ± 3.6 | 40.1 ± 3.8 | 0.011 | 41.4 ± 3.3 | 40.8 ± 3.6 | 0.010 | 41.0 ± 3.6 | 40.1 ± 3.8 | 0.031 |
The impact of COVID-19 infection on the risk of CKD progression or vasculitis flare among patients with AAV was analyzed. Mild-to-moderate COVID-19 infection did not show significant impact on CKD progression or vasculitis flare among patients with AAV, while severe COVID-19 infection had a significant impact on the risk of CKD progression (OR 7.929 [95% CI 2.030–30.961], P = 0.003) and vasculitis flare (OR 11.842 [95% CI 1.048–133.835], P = 0.046) among patients with AAV. The clinical characteristics and outcomes of the three patients who suffered from AAV flare after COVID-19 infection are summarized in Table 3.
Table 3
Clinical characteristics and outcomes of patients suffering from AAV flare after COVID-19 infection
Age/Sex | Severe COVID-19 | Vaccination status | Time between COVID-19 infection and AAV flare | Symptoms | Serum creatinine, mg/dl | ANCA type/titers | BVAS | Therapy | Outcome | |
|---|---|---|---|---|---|---|---|---|---|---|
Patient 1 | 51/F | Yes | three shots | 14 days | Fever, fatigue, cough and hemoptysis | 1.21 | PR3-ANCA 105 RU/ml | 18 | Pulse methylprednisolone, prednisolone, CTX | AAV remission |
Patient 2 | 44/F | Yes | three shots | 15 days | Fever, cough and dyspnea | 4.55 | negative | 20 | plasmapheresis, pulse methylprednisolone, prednisolone, RTX | AAV remission, ESRD |
Patient 3 | 75/F | Yes | two shots | 20 days | Fever, cough and throat pain | 1.35 | MPO-ANCA > 200 RU/ml | 12 | Pulse methylprednisolone, prednisolone, CTX | AAV remission, CKD progression |
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Of the nine patients who suffered from CKD progression, six finished the initial vaccination by getting two or three shots of SARS-CoV-2 vaccines, while the other three were unvaccinated. Neither getting COVID-19 vaccination nor finishing the initial vaccination shows a significant effect on CKD progression (OR 2.906 [95% CI 0.735–11.493], P = 0.128; OR 3.640 [95% CI 0.920–14.405], P = 0.066, respectively). All three patients who got AAV flare upon COVID-19 infection finished the initial vaccination (Table 3), neither getting COVID-19 vaccination nor finishing the initial vaccination showed a significant effect on AAV flare.
Discussion
This current study is a large-scale real-world study to identify risk factors for severe COVID-19 infection and investigate the impact of COVID-19 infection on CKD progression and vasculitis flare among patients with AAV. Our results showed in AAV patients, those with severe COVID-19 infection required hospitalization, and those who died of COVID-19 infection were more likely to be male, with poor kidney function, and were less likely to have the vaccination. Meanwhile, severe COVID-19 infection significantly increased the risk of CKD progression and vasculitis flare in AAV patients.
The COVID-19 pandemic poses challenges in the management of diseases including both CKD and AAV. According to our results, there seemed to be a vicious circle between kidney dysfunction and severe COVID-19 infection. Consistently, Jdiaa et al. demonstrated an increased risk of mortality and hospitalization in patients with preexisting CKD when they had COVID-19 infection [21]. Therefore, prophylactic measures and critical care management would be of importance to patients with CKD who are susceptible to COVID-19 infection.
As above mentioned, flares of preexisting autoimmune diseases in patients with COVID-19 have been reported, including systemic lupus erythematosus (SLE) and IgA vasculitis [6, 7]. In the current study, severe COVID-19 infection increased the risk of vasculitis flare among patients with AAV. The underlying mechanism might involve autoimmune conditions activation triggered by a hyper-inflammatory state and viral persistence in SARS-CoV-2 infection [22]. First, elevated neutrophil extracellular nets (NETs) formation and excessive NETosis, referring to the process of neutrophil death and NETs releasing, have been observed and drawn great attention in COVID-19 infection [23‐25]. Second, complement activation in COVID-19 has been shown to interact with platelet activation and NETosis [26‐28]. Last but not least, the virus–host interactions may lead to both direct and indirect microvasculature damage through endothelial cell inflammation [29], thus playing as a ‘trigger factor’ for the onset or flare-up of AAV, all the above mechanisms also play essential roles in the pathogenesis of AAV [30], and more data are needed to establish solid evidence about this subject.
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Vaccines are considered the ‘game changer’ of the pandemic and are effective in the general population in preventing transmission, severe disease courses and mortality due to COVID-19 [31]. The current study indicated that vaccination had a significant protective effect on AAV patients from severe COVID-19 infection or dying of COVID-19 infection. What needs to be illustrated is that the protective effect would be significantly exerted only by receiving two or more shots of SARS-CoV-2 vaccines to finish the initial vaccination. As two sides of the same coin, it is worth noting that several newly onset or relapsing AAV cases following COVID-19 vaccination have also been reported [32‐35]. In our cohort, one patient with newly onset AAV after COVID-19 vaccination was included, presenting with severe disease including acute kidney injury. Thus, more data are needed to weigh the risk of a relapse against the benefits of COVID-19 vaccination.
The limitation of the current study was the need for more data about the general population and control group of non-AAV COVID-19 patients. According to published reports about the general population, there were several shared risk factors for severe COVID-19 infection, such as aging, male gender, renal failure, specific comorbidities, immunocompromised status, and being unvaccinated [36, 37]. According to another study on patients with SLE, the main risk factors for severe COVID-19 infection included receiving rituximab treatment, renal failure, complicated hypertension and being unvaccinated [38]. Thus, these shared risk factors among different populations underscore the importance of age, gender, renal function, and vaccination status in predicting the severity of COVID-19 infection.
Conclusions
AAV patients who were male with worse kidney function and without COVID-19 vaccination were more susceptible to severe COVID-19 infection, which in turn increased the risk of CKD progression and vasculitis flare among patients with AAV.
Acknowledgements
The authors acknowledge the valuable contribution of patients and their families.
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Declarations
Conflict of interest
The authors report no conflicts of interest.
Ethical approval
This study protocol adhered to the Declaration of Helsinki and was approved by the Ethics Committee of Peking University First Hospital. Written patient-informed consent was obtained from all participants.
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