Clinical course and prognostic factors of COVID-19 infection in patients with chronic inflammatory-rheumatic disease: A retrospective, case-control study

Abstract

Objectives: This study aims to investigate the prognosis of novel coronavirus disease-2019 (COVID-19) infection in patients with the chronic inflammatory-rheumatic disease and evaluate the effects of immunosuppressive drugs on the prognosis, clinical characteristics, laboratory findings and hospitalization periods of the rheumatic patients with COVID-19 infection.

Patients and methods: Between April 2020 and March 2021, a total of 101 patients (30 males, 71 females; mean age: 48±14.4 years; range, 46 to 48 years) with the rheumatic diseases diagnosed with COVID-19 infection were included. A total of 102 age- and sex-matched patients (35 males, 67 females; mean age: 44±14.4 years; range, 28 to 44 years) who were diagnosed with COVID-19 infection and had no history of rheumatic disease in the same period were included as the control group. Data including demographic characteristics of the patients, presence of any symptoms of COVID-19 disease, laboratory data at the time of diagnosis, and treatments administered were collected.

Results: The rate of hospitalization was higher in 38 (37%) patients without rheumatic diseases than in 31 (31%) patients with rheumatic diseases (p=0.324). The rate of lung infiltration on radiographic examination was higher in patients without rheumatic diseases (40% vs. 49%) (p=0.177). COVID-19 infection symptoms such as anosmia 45 (45%), ageusia 51 (50%), shortness of breath 45(45%), nausea 29 (29%), vomiting 16 (16%), diarrhea 25 (25%) and myalgia-arthralgia 81 (80%) were higher in patients with rheumatic diseases. In terms of laboratory values, lymphocyte count (p=0.031) was statistically higher in patients without rheumatic diseases. Hydroxychloroquine (35%), oseltamivir 10 (10%), antibiotics 27 (26%), acetylsalicylic acid 52 (51%), and supplementary oxygen 25 (25%) treatments which used to cure COVID 19 infection were administered more in patients without rheumatic diseases. The number of treatments administered was higher in patients without rheumatic diseases (p<0.001).

Conclusion: Patients with the chronic inflammatory-rheumatic disease have more symptoms due to COVID-19 infection, but the disease course is not poor and hospitalization rates are lower.

Introduction

The clinical spectrum of novel coronavirus disease-2019 (COVID-19) is quite wide and ranges from asymptomatic to life-threatening or fatal disease. Several risk factors have been associated with a poor prognosis including advanced age, sex, and comorbidities such as diabetes, hypertension, lung, and cardiovascular diseases.[1-3]

The COVID-19 pandemic caused by severe acute respiratory syndromecoronavirus 2 (SARS-CoV-2) is particularly worrying for patients with rheumatic diseases or those who are immunocompromised. In general, immunosuppression and presence of comorbidities are associated with an increased risk of significant infections in patients with rheumatic diseases.[4] Therefore, these individuals may be at a higher risk for a severe clinical course that can lead to hospitalization, complications, and death during COVID-19 disease.[4]

Immuno-mediated diseases and immunosuppressive treatments increase susceptibility to viral and bacterial infections and, therefore, it is predicted that understanding the effects of COVID-19 infection on the patients is an urgent need.[5-7]

Vabret et al.[8] reported that it would be particularly interesting to examine how severe COVID-19 disease-associated with a hyperinflammatory process affects COVID-19 expression in patients with a pre-existing inflammatory disease or using immunosuppressive agents. Some medicines such as hydroxychloroquine and interleukin-6 (IL-6) inhibitors, which are used in the treatment of rheumatic diseases, are being investigated for the prevention and treatment of COVID-19 disease and/or management of complications including cytokine storm that may develop due to the disease.[9-11]

In a series of patients with rheumatic diseases and COVID-19 infection, it was reported that the use of disease-modifying antirheumatic drugs (DMARDs) did not increase the possibility of hospitalization. As in the general population, the study showed higher COVID-19-related hospitalization rates in patients with an older age and/or patients that have rheumatic diseases with comorbidities.[4] In another study, patients with rheumatic diseases and COVID-19 infection had a higher rate of mechanical ventilation, but had similar clinical characteristics and hospitalization rates to COVID-19 patients without the rheumatic disease. They reported that important inferences could be obtained from the findings of patients with rheumatic diseases, but they needed to be confirmed with further studies.[12]

In a recent study, the immunosuppressive treatments used by patients with rheumatic or musculoskeletal diseases who had COVID-19 infection did not seem to protect against the severe course of COVID-19 infection.[13] It was further stated that patients with rheumatic or musculoskeletal diseases using DMARDs did not indicate that stopping immunosuppressive medications could prevent COVID-19 or other infections, as it did not have a worse outcome than non-rheumatic controls. They also concluded that patients with an advanced age that had rheumatic or musculoskeletal diseases and comorbidities were at risk for a more severe course of COVID-19 infection.

There is little evidence surrounding factors associated with COVID-19 in patients with underlying inflammatory-rheumatic diseases. In this respect, studies that examine the clinical course of patients with rheumatic diseases after COVID-19 infection are needed. In this study, we aimed to investigate the differences between patients with rheumatic diseases who had COVID-19 infection during the pandemic period and those without rheumatic diseases in terms of basic clinical characteristics, laboratory findings, prognosis, length of stay in hospital, and treatment.

Patients and Methods

This retrospective, observational, paired case-control study was conducted at Sakarya University School of Medicine, Department of Rheumatology and Department of Infectious Diseases and Clinical Microbiology between April 16^th, 2020 and March 16^th, 2021. A total of 101 patients (30 males, 71 females; mean age: 48±14.4 years; range, 42 to 48 years) with the rheumatic diseases diagnosed with COVID-19 infection were included. A total of 102 age- and sex-matched patients (35 males, 67 females; mean age: 44±14.4 years; range, 28 to 44 years) who were diagnosed with COVID-19 infection and had no history of rheumatic disease in the same period were included as the control group. Patient data were obtained from patient's medical records and electronic patient data monitoring systems.

Patients in the group with rheumatic diseases who we detected as positive for SARS-CoV-2 by means of polymerase chain reaction (PCR) performed in our center included all of the adult patients diagnosed with spondyloarthritis (SpA), rheumatoid arthritis (RA), psoriatic arthritis (PsA), familial Mediterranean fever (FMF) and connective tissue diseases (systemic lupus erythematosus, Sjögren syndrome and systemic sclerosis, etc.) and others (polymyalgia rheumatic, gout, Behçet's disease, and reactive arthritis). The control group data were taken from the databases of the center where participants that were matched on a 1 to 1 basis with the patients with rheumatic diseases at the time of diagnosis of COVID-19 infection in terms of sex, age, and comorbidity were treated.

The diagnosis of COVID-19 was made by PCR tests. For this purpose, SARS-CoV-2 was investigated by PCR tests by way of taking oropharyngeal and nasopharyngeal swab samples simultaneously from patients who presented with COVID-19 infection compatible complaints such as fever, cough, headache, muscle joint pain. Complaints and symptoms of the patients such as fever (temperature >38°C), cough, shortness of breath, myalgia, arthralgia, fatigue, flu, nausea, vomiting, headache, diarrhea, dysgeusia, and anosmia were recorded. The laboratory data of the patients at the time of diagnosis were also taken from the patient files. The time from the onset of symptoms to the PCR test and the presence and degree of lung involvement on radiological imaging were also recorded.

The diagnosis group, duration of the disease, and treatments administered before COVID-19 disease were recorded among the specific factors for rheumatic diseases. Treatments administered before COVID-19 disease were grouped as follows: conventional synthetic disease-modifying antirheumatic drugs (csDMARD), (i.e., hydroxychloroquine, chloroquine, methotrexate, leflunomide, sulfasalazine cyclophosphamide, cyclosporine, and azathioprine) or targeted synthetic or biologic disease-modifying antirheumatic drugs (ts/bDMARD) (tumor necrosis factor-alpha [TNF-α], IL-1, IL-6 or IL-23/IL-17 inhibitors, abatacept, rituximab, Janus kinase inhibitors [JAK]) and others (glucocorticoids, non-steroidal anti-inflammatory drugs and those not administering treatment).

The treatment administered to patients with COVID-19 was also recorded. The most commonly used treatments in COVID-19 infection offered in our center were hydroxychloroquine, antivirals (favipiravir and oseltamivir), glucocorticoids, plasma, non-steroidal anti-inflammatory drugs, acetylsalicylic acid, supplementary oxygen, and low-molecular-weight heparin anti-cytokines (anti-IL-1 and anti-IL-6).

Patients with any malignancy and recent infection were excluded from all of the study. Patients with chronic inflammatory-rheumatic diseases were excluded from the control group.

Statistical analysis

Statistical analysis was performed using the IBM SPSS version 22.0 software (IBM Corp., Armonk, NY, USA). The Shapiro-Wilk test was used to examine whether continuous numerical variables showed a normal distribution. Descriptive data were expressed in mean ± standard deviation (SD) or median (interquartile range [IQR]) or number and frequency. The significance was compared using the chi-square (χ²) test for categorical variables and the Mann-Whitney U test for continuous variables for differences in disease-specific characteristics between cases and controls. A p value of <0.05 was considered statistically significant.

Results

There were 101 (49.7%) patients in the group with rheumatic diseases and 102 (51.3%) in the group without rheumatic diseases. The mean ages and sex of the groups were not significantly different (p=0.951 and p=0.582). The smoking rate of patients without rheumatic diseases was two (4%), while the smoking rate of patients with rheumatic diseases was seven (13%). Comorbidities were hypertension in 16 patients (30%), diabetes in seven (13%), cardiovascular disease in two (4%), and lung disease in two patients (4%) in the group with rheumatic diseases. Comorbidities took the form of hypertension in 16 patients (31%), diabetes in 12 (23%), cardiovascular disease in 12 (23%), and lung disease in five patients (10%) in the group without rheumatic diseases. In the group with rheumatic diseases, hypertension in 16 (30%) patients, diabetes in seven (13%), cardiovascular disease in two (4%), and lung disease in two (4%) patients were recorded as comorbid disorders, while in the other group they were in 16 (31%), 12 (23%), in 12 (23%), and five (10%), respectively. Patients with COVID-19 infection but without rheumatic disease were under the medical treatment with anti-rheumatic drugs such as csDMARD in 41 (76%), bDMARD, 15 (%28) and lowdose glucocorticoid (10 mg/day) 13 (%23). Overall characteristics and laboratory data of the groups participating in the study are shown in Tables 1 and 2. The patients included in the study were well balanced by age, sex, comorbidity, and smoking.

Table 1. Baseline demographic and clinical characteristics of COVID-19 patients with and without rheumatic disease

Table 2. Symptoms, clinical course and treatments of COVID-19 patients with and without rheumatic disease

The diagnoses of patients with rheumatic diseases were SpA (n=15, 27%), connective tissue diseases (CTD) (n=11, 21%), PsA (n=9, 17%) and RA (n=7, 13%). The mean duration of the rheumatic disease was 7.6±5.96 years (Table 3). Most of the patients with previous rheumatic diseases were using biological agents (n=26, 48%) and csDMARD (n=22, 40%) (Table 3). None of the patients in the group without rheumatic diseases were taking any of these drugs.

Table 3. Baseline characteristics of patients with rheumatic diseases

In terms of laboratory values, lymphocyte count (median (IQR)=2 (1-2), p=0.025) and white blood cell count (median (IQR)=7 (6-9), p=0.025) were statistically higher in patients with rheumatic diseases. Only neutrophil-to-lymphocyte ratio (NLR) (median (IQR)=2 (2-4), p=0.048) was higher in the group without rheumatic diseases. There was no significant difference between the groups in terms of other laboratory values.

The mean time between the onset of symptoms and the time of referral to the physician was 3.8±3.2 days in patients with rheumatic diseases and 4.6±3.3 days in patients without rheumatic diseases. Besides, 38 (73%) patients without rheumatic diseases were hospitalized due to COVID-19 infection compared to 17 (31%) patients with rheumatic diseases (p<0.001). Similarly, the incidence of radiographic pneumonia was significantly (p=0.012) higher in the group without rheumatic diseases (n=31, 60%). The need for intensive care occurred only in one patient in the group without rheumatic diseases.

In terms of COVID-19 symptoms, myalgiaarthralgia 45 (83%), ageusia 28 (52%), anosmia 23 (43%), shortness of breath 18 (33%), nausea 17 (31%), diarrhea 16 (30%), and vomiting 10 (19%) were seen in the group with rheumatic diseases, and these rates were significantly higher in this group. Only asthenia-fatigue rate was higher in the group without rheumatic diseases, as it was seen in 38 (73%) patients.

Hydroxychloroquine (35%), oseltamivir 10 (10%), antibiotics 27 (26%), acetylsalicylic acid 52 (51%), and supplementary oxygen 25 (25%) treatments which used to cure COVID-19 infection were administered more in the group without rheumatic diseases. Moreover, the number of treatments administered was higher in the group without rheumatic diseases (median (IQR)= 3 (2-3), p<0,001). Only favipiravir 46 (85%) treatment seemed to be administered more in the group with rheumatic diseases. In the study, 14 participants were not receiving medical treatment, 50 participants were using csDMARD, 37 participants were using b/ts DMARD in the rheumatic patients group. Hematocrit and platelet values were significantly higher in the group using b/tsDMARDs. No correlation was found between the clinical parameters of COVID-19 in the rheumatic group according to the medical treatment used (Tables 4 and 5). In the study, the duration of the disease in rheumatic patients was determined as 30 patients between one and four years, 33 patients between five and nine years, and 38 people who were 10 years and older. Ferritin levels were higher in those with a disease duration of 10 years or more. There was no significant difference between other laboratory parameters. No significant correlation was found between disease duration and clinical parameters in the rheumatic group (Tables 6 and 7).

Table 4. The relationship between rheumatic drugs and COVID-19 laboratory parameters

Table 5. COVID-19 clinical and treatment parameters according to rheumatic drugs

Table 6. COVID-19 laboratory parameters by duration of rheumatic disease

Table 7. Distribution of rheumatic disease by years and COVID-19 clinical and treatment parameters

Discussion

In the present study, we reported from our center how patients with and without rheumatic diseases were affected by COVID-19 infection in a matched case-control study. In this study, the symptom rates (anosmia, ageusia, shortness of breath, nausea, vomiting, diarrhea, and myalgia-arthralgia) and white blood cell count, from among the laboratory findings, were higher in patients with rheumatic diseases. Asthenia-fatigue and lymphocyte count, ferritin, dimer, CRP count were higher in the group without rheumatic diseases. Patients with the rheumatic disease had less few treatments administered due to COVID-19 infection.

The COVID-19 is a viral infection that manifests itself with systemic involvement and mainly affects the upper respiratory tract and lungs. It is important to clarify the clinical data and factors affecting the prognosis in individuals with autoimmune and autoinflammatory diseases during COVID-19 disease in terms of the course of the disease.[7,12]

In a multi-center study comparing the clinical data in patients with rheumatic diseases and those without rheumatic diseases during COVID-19 disease, there was no significant difference between the groups with and without rheumatic diseases in the rate of hospitalization.[14] Kastritis et al.[15] reported that the risk of COVID-19 infection in patients with systemic autoimmune diseases did not appear to be much higher than in the general population with similar comorbidities and that these two populations did not appear to be different compared to the general population in terms of hospitalization requirements, intensive care unit admission, or death. Similarly, there was no significant difference in the rate of hospitalization between patients rheumatic diseases and the group without rheumatic diseases in our study. In contrast, Arleo et al.[16] reported that rheumatologic patients with COVID-19 had higher rates of hospitalization and intensive care admission than those without rheumatic disease. However, the rate of hospitalization in patients with rheumatic diseases was stated as 46% in a multi-center study that compiled the hospitalization parameters of patients with rheumatic diseases and with COVID-19 infection in the literature. It was found that there was no relationship between non-steroidal anti-inflammatory drugs (NSAIDs) or antimalarials used by patients with rheumatic diseases and hospitalization due to COVID-19 infection in the same study. Moreover, it was considered that b/tsDMARD monotherapy was associated with a lower probability of hospitalization and a largely anti-TNF-driven effect.[4] In our study, a total of 87 participants from patients with inflammatory disease were using cs or bDMARDs. There was no significant difference between the medical treatments used by rheumatic patients and the clinical symptoms of COVID-19, the treatment of COVID-19 infection, and the incidence of hospitalization. Hasseli et al.[22] showed that some anti-rheumatic drugs such as hydroxychloroquine, anakinra, and IL-6 inhibitors had an interesting role in the course of COVID-19 infection. It was also reported that high-dose corticosteroid use (10 mg and above), advanced age, and comorbidities were factors associated with a higher rate of hospitalization. In the rheumatic disease group, all of the patients with COVID-19 infection were under the medication of low dose corticosteroids (≤10 mg/day).

It is estimated in the literature that lymphocyte counts in COVID-19 disease may give clues about the severity and clinical consequences of the disease.[17] The lymphocyte ratios in patients without rheumatic diseases were found to be higher than in patients with rheumatic diseases in this study. In the literature, lymphocyte rates are low during the COVID-19 disease, particularly in the first two weeks of the disease. There are also studies indicating that a low lymphocyte ratio during COVID-19 disease is associated with a severe form of the disease, namely acute respiratory distress syndrome. It is also stated that if low lymphocyte levels persist for a long time in patients with COVID-19, the disease may become more severe.[18] The lymphocyte ratio in patients without rheumatic diseases was higher than in patients with rheumatic diseases in our study. Unlike the previous study, the rate of hospitalization and oxygen requirement were not in patients without rheumatic diseases than in patients with rheumatic diseases in our study.

The NLR gives information about inflammatory status in patients, and it has prognostic value in diseases such as malignancies, cardiovascular diseases, connective tissue diseases, as well as infections. A high NLR in COVID-19 disease is associated with a high risk of severe disease and mortality.[19] However, in this study, platelet and hematocrit values of participants with rheumatic disease under bDMARD treatment were found to be higher than those who received csDMARDs. However, there was no significant difference in the COVID-19 clinic. Although the rate of NLR in patients with rheumatic diseases was lower, the difference between the groups was not significant; besides, the rate of hospitalization did not significantly differ between the two groups in our study.

Pablos et al.[14] reported that cardiovascular diseases and obesity were detected more in patients with rheumatic diseases. The rate of comorbidity in our patients with rheumatic diseases was 44%, and there was no significant difference between the two groups in the rate of comorbidity in our study. Besides, most of the patients in both groups had no comorbidity. According to the literature data, age and comorbidity correlated positively with hospitalization during COVID-19 infection.[20] The mean age of the patients in our study was lower than in the above-mentioned study, this may explain the lower rate of comorbidity in our patients with rheumatic diseases, and the duration of the rheumatic disease may also increase the incidence of comorbidity. A clear relationship between the duration of rheumatic disease and the clinical progression of COVID-19 has not been reported in the literature. in our study, there was no significant difference between disease duration and clinical progression of COVID-19 in participants with inflammatory disease.

In our study, interstitial lung involvement in the course of COVID-19 infection (n: 40% vs. 50%, p=0.177) was lower in patients with rheumatic diseases compared to patients without rheumatic diseases. In line with our findings, Pablos et al.[14] reported that radiological lung involvement was higher in patients without rheumatic diseases and with COVID-19 infection compared to patients with rheumatic diseases. D’Silva et al.[12] reported that the need for mechanical ventilation during COVID-19 disease was higher in patients with rheumatic diseases than in patients without rheumatic diseases; however, there was no information provided about interstitial lung involvement in that study.

The macrophage-derived cytokine storm seen in the course of COVID-19 disease can damage tissues by causing inflammation. It is also known that cytokine storm causes tissue damage secondary to inflammation with a similar mechanism in rheumatic diseases. Tissue damage that occurs as a result of this pathological inflammatory process may overlap with the radiological findings seen in COVID-19 infection and with the radiological findings related to the current rheumatic disease.[21] Anti-cytokine treatments used by patients with the rheumatic diseases may prevent the release of cytokines that cause lung damage; however, there is no literature data to prove this suggestion.

It was found that COVID-19 infection symptoms such as loss of smell and taste, vomiting, diarrhea, myalgia, and arthralgia were higher in patients with rheumatic diseases than in patients without rheumatic diseases in our study. Fatigue was more prominent in patients without rheumatic diseases. In previous studies, complaints such as cough, fever, fatigue, headache, dyspnea, loss of taste and smell, diarrhea were reported as the main symptoms seen in patients with rheumatic diseases that have COVID-19 infection.[22] However, in the literature, that there was no significant difference between patients with rheumatic diseases and those without rheumatic diseases in clinical symptoms due to COVID-19 infection.[12,14]

Alzahrani et al.[23] reported that fever, myalgia, and cough were the most frequently reported symptoms (78.7%, 78.7%, and 74.5%, respectively) among the symptoms of COVID-19 infection. During the COVID-19 pandemic, hydroxychloroquine, methotrexate, and colchicine were attempted at various stages for the treatment and prophylaxis.[24] There are randomized, observational studies in the literature investigating the potential therapeutic effects of JAK inhibitors and anti-cytokine biological agents in COVID-19 disease.[25] However, there is clinically and prognostically no significant effect of these cs and bDMARDs in patients with rheumatic diseases during COVID-19 infection.[7,15] Jung et al.[26] evaluated with a cohort study patient with rheumatic diseases using hydroxychloroquine and having COVID-19 infection. They reported that hydroxychloroquine use did not reduce the occurrence of COVID-19 in patients with rheumatic diseases before exposure to COVID-19 infection. Hydroxychloroquine was used more in patients in the group without rheumatic diseases as the treatment of COVID-19 infection, and the need for oxygen and antibiotic treatment was higher in this group in our study. In agreement with the literature, there was no significant effect of hydroxychloroquine on prognosis in our study.

Ferri et al.[27] investigated COVID-19 infection in an Italian case series by comparing patients with chronic arthritis and the general population. They found an increased rate of COVID-19 infection in connective tissue diseases in patients with systemic lupus or large vessel vasculitis. Ongoing DMARDs and particularly bDMARDs did not affect the results of symptomatic and generally mild COVID-19 disease in these cases. Montero et al.[28] concluded that more research was needed to evaluate specific immunosuppressive drugs and other comorbidity interactions, but according to the findings and in agreement with the other studies, patients with the rheumatic diseases did not need to discontinue immunosuppressive drugs. They also reported that minimizing glucocorticoid exposure would be important due to its association with poorer outcomes.[2]

Nonetheless, this study has some limitations. Firstly, radiological examinations were not evaluated in some of the patients with mildly symptomatic COVID-19 infection. The other limitation was the heterogeneous structure of our study resulting from its design. The strength of our study was that it was performed in real-life conditions that allowed us to comprehensively evaluate the baseline clinical characteristics of patients with COVID-19 infection, as well as their laboratory findings and COVID-19 treatment.

In conclusion, it is known that the risk of comorbidity and infection in patients with rheumatic diseases is higher than in the normal population. During the COVID-19 pandemic, it has been a matter of curiosity to what extent patients with rheumatic diseases are at risk, the prognosis of the disease, and how much the treatments would affect the disease. The literature shows that the clinical data of patients with rheumatic diseases that have COVID-19 infection are not significantly different than those of the normal population, but a definitive algorithm for treatment and prognosis is still not created. Evaluation of clinical data and prognostic characteristics of COVID-19 disease in patients with rheumatic diseases should be done carefully. We believe that this study would contribute to the treatment and clinical management of patients with rheumatic diseases during the COVID-19 pandemic.

During the COVID-19 pandemic, high-dose glucocorticoids has been a matter of intention with age and comorbidity in patients with rheumatic diseases. Ongoing csDMARD and bDMARD has no effect on COVID-19 outcomes, anti-rheumatic treatment schedule should be continued without any interruption.

Citation: Nas K, Güçlü E, Keskin Y, Dilek G, Kalçık Unan M, et al. Clinical course and prognostic factors of COVID-19 infection in patients with chronic inflammatoryrheumatic disease: A retrospective, case-control study. Arch Rheumatol 2023;38(1):44-55.

The study protocol was approved by the Sakarya University School of Medicine Ethics Committee (E-71522473-050.01.04- 25237-246). The study was conducted in accordance with the principles of the Declaration of Helsinki.

A written informed consent was obtained from each patient.

Data Sharing Statement:
The data that support the findings of this study are available from the corresponding author upon reasonable request.

Idea/concept: K.N., M.K.U.; Design; E.G., Y.K.; Control/supervision: I.T., K.N.; Data collection and/or processing: A.K., G.D.; Analysis and/or interpretation: N.C., G.D.; Literature review: E.G., K.N., M.K.U., Writing the article: G.D., Y.K.; Critical review: A.K., E.G.; References and fundings: I.T., K.N.; Materials: Y.K., K.N.

The authors declared no conflicts of interest with respect to the authorship and/or publication of this article.

The authors received no financial support for the research and/or authorship of this article.

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