|Ahead of print publication
Do all patients with rheumatic Diseases have a higher risk of COVID 19? Initial results from the Karnataka Rheumatology Association COVID 19 Cohort Study (KRACC)
Vineeta Shobha, K Chanakya, Vikram Haridas, Sharath Kumar, Pramod Chebbi, Benzeeta Pinto, Vikramraj Jain, Subramaniam Ramaswamy, Shiv Prasad, Abhishek Patil, Vijay K Rao, GC Yathish, BG Dharmanand, Ramesh Jois, Ashwini Kamath, Chethana Dharmapalaiah, KN Sangeeta, Ramya Janardana, C Srinivasa, AS Harshini, Nagaraj Srinivasulu, Yogesh Preet Singh, Shweta Singhai, KM Mahendranath, S Chandrashekara
Karnataka Rheumatology Association, Bengaluru, Karnataka, India
|Date of Submission||15-Sep-2020|
|Date of Acceptance||04-Nov-2020|
Department of Clinical Immunology and Rheumatology, St John's Medical College Hospital, Sarjapur Road, Bengaluru - 560 034, Karnataka
Source of Support: None, Conflict of Interest: None
Background: Patients with autoimmune rheumatic diseases (AIRD) may be at an increased risk for COVID-19 infection and poorer outcomes when compared with the general population. We undertook this study to estimate the risk of COVID-19 infection in our AIRD population and determine parameters which contribute to its occurrence.
Methods: We prospectively recruited all consecutive AIRD patients on immunosuppressive therapy from 14 specialist rheumatology centers across south Indian state of Karnataka during current COVID-19 pandemic and followed them longitudinally.
Results: Among 3807 participants, the majority were women (2.9:1), mean age was 43.8 (+14.3) years, rheumatoid arthritis (52.1%), and systemic lupus erythematosus (14.8%) were the most frequent diagnosis. Twenty-three (0.6%) patients contracted SARS-CoV-2 infection. Age >60 years (P = 0.01), diabetes (P = 0.009), hypertension (P = 0.001), preexisting lung disease (P = 0.0002), current prescription of either angiotensin-converting enzyme inhibitor or angiotensin receptor blockers (P = 0.01), and higher glucocorticoids dosage (P = 0.002) were identified as potential risk factors in our cohort. The past use of cyclophosphamide (P = 0.0001) or mycophenolate mofeti (P = 0.003) or biologics (P = 0.001) also had a significant association with COVID-19 infection. Hydroxychloroquine use did not influence occurrence or outcome. The presence of underlying lung disease (relative risk - 3.08, 95% confidence interval - 1.21, 8.44, P = 0.029) was the only independent risk factor associated with the risk of COVID positivity in the multivariate analysis. Incidence rate of COVID-19 infection was similar to that of the general population (P = 0.22).
Conclusions: The incidence of SARS CoV-2 infection in AIRD population is comparable to the general population. Underlying lung disease was the most important risk factor apart from older age, diabetes, hypertension, and a higher glucocorticoid dosage.
Keywords: Autoimmune rheumatic diseases, COVID-19, SARS-CoV-2 infection
|How to cite this URL:|
Shobha V, Chanakya K, Haridas V, Kumar S, Chebbi P, Pinto B, Jain V, Ramaswamy S, Prasad S, Patil A, Rao VK, Yathish G C, Dharmanand B G, Jois R, Kamath A, Dharmapalaiah C, Sangeeta K N, Janardana R, Srinivasa C, Harshini A S, Srinivasulu N, Singh YP, Singhai S, Mahendranath K M, Chandrashekara S. Do all patients with rheumatic Diseases have a higher risk of COVID 19? Initial results from the Karnataka Rheumatology Association COVID 19 Cohort Study (KRACC). Indian J Rheumatol [Epub ahead of print] [cited 2021 Dec 9]. Available from: https://www.indianjrheumatol.com/preprintarticle.asp?id=313577
| Introduction|| |
In the ongoing COVID-19 pandemic, its relentless spread across countries has led to significant morbidity and mortality, especially in the elderly and those with comorbidities. Generally, patients with autoimmune rheumatic diseases (AIRD) are considered at a higher risk of infections, largely determined by the underlying disease subgroup, organ systems involved, and the degree or severity of immunosuppression. Specifically, the risk of infection is higher in those with systemic disease, the use of higher dose of glucocorticoids, and intense immunosuppression such as cyclophosphamide and biologics.,,,,, The safety of immunosuppressants (IS), biologics, and small molecules in the treatment of immune-mediated rheumatic diseases (AIRD) during COVID-19 pandemic has been addressed through registry data from across the world. In addition, there are some reports to suggest that certain drugs such as hydroxychloroquine (HCQ), biologics such as tumor necrotic factor inhibitors (TNFi) and tocilizumab, and Janus kinase inhibitors may have protective and therapeutic role in COVID-19.,
The risk factors associated with the occurrence and adverse outcome of COVID-19 infection in patients with AIRD requires further research. India has experienced a relatively late peak for SARS-CoV-2 infection in the last few weeks. We undertook this study to analyze the safety of IS, incidence rate, and risk factors for COVID-19 infection and identify parameters associated with unfavorable outcome in our patients with AIRD.
| Methods|| |
This is a prospective, multicenter, noninterventional, longitudinal, ongoing study involving 14 specialist rheumatology centers across Karnataka, India. Consecutive patients with AIRD on follow-up with collaborating centers were recruited into this study. Clinical information was recorded using a structured case record form developed for this study, and a harmonization meeting was conducted across all recruiting centers. Nonimmune-mediated rheumatologic disorders and those not on treatment with IS were excluded from the study. Specific information pertaining to the current and or past use of all IS and glucocorticoids, their duration, and dosing was extracted. All comorbidities, including preexisting lung diseases, were recorded. Medication history including the use of antihypertensives such as angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blockers (ARBs), antiplatelet agents, and anticoagulants were recorded. Monthly follow-up telephone calls were made to all recruited patients seeking information regarding COVID-19 such as symptoms, exposure risk, and results of any COVID-19 test, if conducted. COVID-19 testing protocols for symptomatic infection or exposed contacts as per existing guidelines were adhered to. The incidence rate of COVID-19 in the AIRD cohort was calculated and compared with the general population from the corresponding regions and districts of Karnataka. Respective institute ethics committees approved the study.
Descriptive statistics were reported as mean and standard deviation for continuous variables, number, and percentages for categorical variables. The unit for person time for incidence computation (number of COVID-19 cases/total person time at risk) in this study is reported as person days which was computed as 143 days for the study duration. Association of COVID-19 positive with clinical characteristics of the study population was assessed using Chi-square/Fisher's exact test as appropriate. Student's t-test was used to compare the means between COVID-19 and non-COVID-19 groups. Bivariate and multivariate log binomial regression analysis was performed, and unadjusted and adjusted relative risk (RR) along with 95% confidence interval (CI) was reported. Variables that showed P < 0.20 in the bivariate analysis was considered for multivariate analysis. P < 5% was considered statistically significant. Statistical analyses were carried out using SPSS version 25.0 (IBM headquartered in Armonk, New York).
| Results|| |
We recruited 3807 patients into this study from March 2020 to August 10, 2020. Mean age of the cohort was 43.8 ± 14.3 years and included 100 children (<18 years), three-fourth were women. The baseline demographics of the studied population, duration of illness, disease specifics, and current and past IS used are detailed in [Table 1] and [Supplementary Table 1]. Sixty-one patients (1.6%) were current smokers. The most common disease diagnosis was rheumatoid arthritis (RA) (52.2%), followed by systemic lupus erythematosus (SLE) (14.8%) and spondyloarthropathy (8.2%). Almost two-fifth of our patients were currently using glucocorticoids, more than three-fourth being low dose (7.5 mg/day) prednisolone equivalent. Overall, 41 patients (1.07%) were tested for COVID-19 infection using reverse transcription polymerase chain reaction, and 23 patients (0.6%) were detected positive. Parameters associated with COVID-19 positivity were age >60 years (P = 0.01), comorbidities such as diabetes (P = 0.009), hypertension (P = 0.001), presence of underlying lung disease (P < 0.0001), and use of either ACEi or ARBs (P = 0.01). Past use of IS, namely, glucocorticoids (P = 0.01), cyclophosphamide (P = 0.0001), mycophenolate mofetil (MMF) (P = 0.003), and biologics (P = 0.001)) also had significant association with COVID-19 positivity. Overall, the COVID-19-infected group was older and using higher mean steroid doses (P = 0.002) presently. HCQ use was noted in 2102 (55.2%) patients; there were no significant differences between COVID-19 infected and the overall cohort with respect to HCQ use. Only 130 (3.4%) of our cohort had received flu vaccination in the past 1 year; however, in the COVID-19-infected cohort, 4 (19%) had been vaccinated. The relative risk of occurrence of COVID-19 with 95% CI is detailed in [Table 1], and results of bivariate and multivariate analysis are appended in [Supplementary Table 2]. In the bivariate analysis, age, the presence of diabetes mellitus (DM), hypertension, preexisting lung disease, and the past use of immunosuppressant, ACEi/ARBs, and flu vaccine use were significantly associated with the risk. However, multivariate results indicated that the presence of underlying lung disease (RR - 3.08; 95% CI [1.21, 8.44] P = 0.029) was the only independent risk factor after adjustment for other variables. Although nonsignificant, the presence of DM was associated with a 2.32 times the risk of COVID-19 positivity (95% CI 0.87, 6.12) (P = 0.09); compared to non-DM cohort.
|Table 1: Comparative analysis of COVID and non-COVID Karnataka Rheumatology Association cohort|
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Of the COVID-19-infected subgroup (n = 23), the majority had minimal symptoms, 15 (65.2%) were hospitalized, and intensive care was required in 3 (13%). Overall, three patients succumbed to COVID-19 infection, all of whom had significant comorbidities. First was an 88-year-old smoker who had RA with interstitial lung disease, was also a diabetic with a prior history of treated malignancy, and currently treated with prednisolone and HCQ. The second was a 77-year-old male with undifferentiated connective tissue disease who had previously received high doses of prednisolone, azathioprine, and past cyclophosphamide. The third was a 61-year-old female with inflammatory myositis, chronic obstructive lung disease on prednisolone, MMF, and past cyclophosphamide use.
The incidence of COVID-19 infection in our cohort was not significantly different from the incidence in the general population (P = 0.22) as depicted in [Table 2]. None of the children were diagnosed with COVID-19 infection.
|Table 2: Comparative analysis with Karnataka* population COVID-19 incidence|
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| Discussion|| |
COVID-19 infection occurrence is multifactorial, however, increasing age and underlying medical conditions influence severity and outcome. In this study, we present prospective multicentric data of AIRD patients during COVID-19 pandemic from Karnataka, India. We found an almost similar incidence of COVID-19 AIRD cohort as that of the general population. A study from Lombardy in 955 patients with rheumatic diseases also revealed a similar incidence rate of 0.62%. A smaller study from Tuscany reported an incidence of 0.2%. Pablos et al. reported a higher prevalence of COVID-19 in Spain with a relative risk of 1.32 compared to the general population. Zhong et al. from Hubei province, China, reported higher odds ratio (2.68) for COVID-19 infection among patients with rheumatic diseases as compared to their family members.
The risk factors for COVID-19 identified in our cohort were age and comorbidities such as diabetes, hypertension, and prior lung disease, which is similar to that reported in other cohorts. Specific risk factors identified were a higher current dose of steroids and the past use of certain IS. However, preexisting lung disease had the strongest independent association. Interestingly, we did not find an increased risk with any particular diagnosis. There are no data regarding COVID-19 infection in juvenile onset AIRD; none of the children in our cohort had symptoms requiring COVID-19 testing as the per current Indian guidelines. The study from Spain that included 26,131 patients found an increased risk in patients with systemic autoimmune diseases other than SLE, and those on bDMARDs and tsDMARDs. Even though our numbers are small, none of our patients on TNFi or tsDMARDs developed COVID-19 infection. Global rheumatology alliance reported reduced odds for hospitalization in patients on TNF inhibitors. Since severe COVID-19 is associated with cytokine release, it is possible that TNF inhibitors modify the severity of COVID-19. We did not find any association with the use of HCQ in our study. Despite in vitro studies and small clinical studies showing promise, the trials of HCQ in postexposure prophylaxis and treatment have not shown benefit., However, a study from Hubei province noted that users of HCQ had a lower risk of COVID-19 infection than patients taking other disease-modifying antirheumatic drugs (odds ratio 0·09). We noted a higher relative risk of COVID-19 in patients on ACEi/ARBs, this may most likely be due to the presence of other concomitant risk factors. Similarly, flu vaccine had been administered more frequently in those who developed COVID-19 infection. In our resource-constrained setting, the flu vaccine is frequently offered only to those with lung disease and comorbidities which may explain this association.
Most of the patients in our cohort who developed COVID-19 had mild symptoms. The mortality due to COVID-19 was higher than that of the general population. This may be due to the presence of comorbidities as discussed earlier. A case–control study from China including 21 patients with rheumatic diseases found a mortality rate of 9%, which was similar to controls. However, respiratory failure was more common in patients with rheumatic diseases. In a report from the US hotspot, a higher need for admission to intensive care units and mechanical ventilation was noted in AIRD patients as compared to the general population. The Global rheumatology alliance reported a mortality of 9% among COVID-19-infected rheumatic disease. Even though the mortality was higher in our cohort, the overall risk for COVID-19 is comparable.
Our study has several limitations. Chronic rheumatic disease subset of patients is likely to be more cautious and get tested even with mild symptoms compared to the general population. This may have influenced infection rates in our cohort. Due to the advent of virtual consultations, we could not accurately assess the influence of current disease activity and severity although it is indirectly reflected in the current steroid dose and immunosuppression. Finally, many regulatory guidelines for testing and treatment protocols are in force, which influence hospitalization rates and outcome.
The strengths of our study include its multicenter prospective design with longitudinal physician-driven telephonic follow-ups. Recruitment of this cohort from practicing rheumatology centers permits accuracy of diagnosis and analysis of past and current IS.
| Conclusion|| |
Patients with rheumatic diseases are not at significantly increased risk of COVID-19 compared to the general population. Older age, diabetes, hypertension, and chronic lung disease are risk factors for infection. A higher dose of glucocorticoids was associated with an increased risk; however, no other current IS drugs including HCQ use were associated with the occurrence of infection. The final outcome was favorable in most patients.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
This is an ongoing study across multiple rheumatology centers across India. With COVID-19 infection, incidence rates rapidly escalating across several parts of our country, a more detailed report during plateau, or declining phase of infection may provide further information on risk factors and their outcome.
We thank Ms Sumithra Selvam, Department of Biostatistics, St John's Research Institute, SJNAMS, Bengaluru, for her support.
Financial support and sponsorship
Karnataka Rheumatology Association.
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2]