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ORIGINAL ARTICLE
Ahead of print publication  

Impact of COVID-19 on rheumatic diseases in india: Determinants of mortality and adverse outcome: A retrospective, cross-sectional cohort study


1 Department of Clinical Immunology & Rheumatology, SMS Medical College & Hospital, Jaipur, India
2 Department of Clinical Immunology & Rheumatology, St John's Medical College Hospital, Bangalore, India
3 ChanRe Rheumatology and Immunology Center and Research, Bangalore, India
4 Center for Arthritis and Rheumatism excellence, Kochi, Kerala, India
5 Division of Clinical Immunology & Rheumatology, Smt. NHL Municipal Med college and SVP hospital, Ahmedabad, India
6 Optima Arthritis & Rheumatology Clinic, Bangalore, India
7 Department of Clinical Immunology & Rheumatology, Medanta Super Speciality Hospital, Indore, India
8 Department of Clinical Immunology & Rheumatology, Manipal Hospital, Bangalore, India
9 Department of Clinical Immunology & Rheumatology, Dayanand Medical College & Hospital, Ludhiana, India
10 STAR Rheumatology Clinics and SVP Hospital, Ahmedabad, Gujarat, India
11 Citi Neuro Centre, Hyderabad, Telangana, India
12 Department of Medicine, SMS Medical College & Hospital, Jaipur, India
13 Omkar Rheumatology Clinic, Ahmedabad, India
14 Department of Clinical Immunology & Rheumatology, Subodaya Rheumatology Hospital, Ahmedabad, India
15 Apollo Hospital, Ahmedabad, India
16 Rheumatology Clinic, Ahmedabad, India
17 Department of Clinical Immunology & Rheumatology, Yashoda hospitals, Malakpet, Hyderabad, Telangana, India
18 Department of Clinical Immunology & Rheumatology, Amala institute of medical Sciences, Thrissur, India
19 Arthritis and Rheumatology Centre, Indore, India
20 Fortis Escorts Hospital, Jaipur, India

Date of Submission14-Dec-2021
Date of Acceptance01-Apr-2022
Date of Web Publication26-Jul-2022

Correspondence Address:
Vineeta Shobha,
Department of Clinical Immunology and Rheumatology, St John's Medical College Hospital, Sarjapur Road, Bengaluru - 560 034, Karnataka
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/injr.injr_278_21

  Abstract 


Introduction: There is varying impact of COVID19 on world population depending on ethnicity, age and underlying co-morbidities. However, the lack of data regarding the effect of COVID on patients with rheumatological disorders (RDs) from different nations adds to uncertainty on disease outcome. Across the world, many rheumatology associations have joined hands to collate-related information. A national database under Indian Rheumatology Associations (IRAs) was developed to understand the impact of underlying RD and immunosuppressants during the COVID pandemic on its severity and outcome in our country.
Methods: All registered members of IRA were invited to participate in this registry and provide information of reverse transcription–polymerase chain reaction confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV2)-infected RD patients using an online platform https://iradatabaseard.in/iracovid/index.php. The results of the data were analyzed using the appropriate statistics. Multivariate logistic regression was used to analyze the impact of different variables on mortality. Odds ratio and 95% confidence interval were used to define risk of death.
Results: In this retrospective cross-sectional study, data for 447 RD patients who were infected with SARS-CoV2 data were available as of December 1, 2020. The mean age was 47.9 ± 14.4 years, including two children and 93 (20.8%) geriatric age group patients, male: female ratio was 0.4:1 and mean disease duration was 79.3 ± 77.1 months. Rheumatoid arthritis was the most common RD. Underlying disease was quiescent in 54.7% and active in 18.4% patients. Most common medications at the time of COVID diagnosis were steroids (57.76%) and hydroxychloroquine (67.34%). Fever and cough were the most common symptoms. More than half of the patients (54.4%) needed hospitalization. Oxygen requirement was noted in 18.8%, intensive care unit admission, and invasive ventilation was needed in 6.0%, and 2.9% patients, respectively. Complete recovery was seen in 95.5% of patients and 4.47% (n = 20) expired due to COVID. The presence of comorbidity, dyspnea, and a higher neutrophil count was statistically significantly associated with death (P < 0.05). None of the other factors affected COVID-19 outcome.
Conclusion: This is the largest cohort from a single nation looking at the interface between RD and COVID. The results indicate that patients with RD do not show increased mortality despite current use of disease-modifying anti-rheumatic drugs/immunosuppressants.

Keywords: Adverse outcome, autoimmune rheumatic disease, COVID-19, mortality, severe acute respiratory syndrome coronavirus 2 infection



How to cite this URL:
Jain A, Shobha V, Chandrashekara S, Shenoy P, Pandya SC, Chotalia P, Kumar S, Malviya S, Singh YP, Patil A, Gupta V, Srivastava P, Parimi VP, Kodishala C, Janardana R, Pinto B, Bhandari S, Rankawat G, Jadhav PP, Potugari D, Sharma V, Parmar A, Kayidhi S, Antony PT, Badika A, Sharma A. Impact of COVID-19 on rheumatic diseases in india: Determinants of mortality and adverse outcome: A retrospective, cross-sectional cohort study. Indian J Rheumatol [Epub ahead of print] [cited 2022 Dec 5]. Available from: https://www.indianjrheumatol.com/preprintarticle.asp?id=352104




  Introduction Top


COVID has affected the world population and economics at an unprecedented level. The impact has just not been limited to human life directly as evident by case-fatality rate but has disrupted health and chronic medical care of non-COVID patients indirectly. COVID has affected 79 million reported cases and over 1.7 million as on December 27, 2020.[1] Repercussions on chronic diseases are yet to be completely recognized. The immunomodulated patients of chronic rheumatic diseases are believed to be affected at least as much as the general population.[2] However, there is an uncertainty regarding the effect of the virus infection whether these patients will have a suppressed immune response, thereby keeping them safe from the cytokine storm or the immunesuppression will cause higher morbidity and mortality. Some researchers believe that the use of immunomodulatory therapies in various autoimmune rheumatic diseases can suppress the immune response and result in an enhanced viral replication, leading to an adverse clinical outcome. On the contrary, some researchers suggest that the immunomodulatory therapies may subjugate the cytokine storm due to COVID as has been evidenced with glucocorticoids and tocilizumab in some reports.[3],[4],[5] However, whether this will stand the test of time needs to be seen.

There is a large contrast in COVID disease outcomes due to multiple factors such as the population measured, especially age, comorbidities, and sampling strategy.[6] There is numerous data emerging from centers all across the world focusing on rheumatological disorders (RDs) and COVID including a number of surveys trying to understand the incidence, severity and outcome of COVID in this vulnerable population. Most of the studies have so far suggested similar risk factors of poor outcome as the general population including age and presence of comorbidities. However, these studies had their limitations including smaller sample size, and hence a need to do large scale, population or nationwide registry based studies to study risk and outcomes across various RD. The South Asian population including Pakistani and Bangladesh have been shown to have increased mortality due to COVID-19.[7] Black and Minority Ethnic Populations across the world seem to be more severely affected posing a challenge to the rheumatology community.[8] The disease characteristic of RD is also different from the rest of the world. Indian ethnic develop diseases such as rheumatoid arthritis (RA) at a much younger age, with higher associated co-morbidities such as impaired glucose tolerance and diabetes.[9],[10]

Across the world, many rheumatology associations have joined hands to collate COVID-related information on a similar platform. Indian Rheumatology Association (IRA) proposed to develop an anonymized database for RD patients who develop COVID infection (both symptomatic and asymptomatic). A National Database under IRA was developed to comprehend the impact of COVID and formulate national guidelines for our patients. The main objectives were to understand the impact of underlying RD and immunosuppressants during the COVID pandemic on its severity and outcome in our country.


  Methods Top


This retrospective, cross-sectional study is an IRA initiative. All registered members of IRA were invited to participate in this registry and provide information of reverse transcription–polymerase chain reaction (RT-PCR) confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV2)-infected RD patients using an online platform https://iradatabaseard.in/iracovid/index.php and record information regarding demographics, number of affected household contacts, symptomatology, underlying RD, disease activity status, current and past immunosuppressive treatment, comorbidities including diabetes, hypertension, Coronary artery disease, chronic kidney disease, hypothyroidism and outcome of COVID infection. Organ involvement was defined as involvment of kideny, lung, central or peripheral nervous system as part of rheumatic disease. Information was also captured to assess the status of immunosuppressive agents during the COVID infection. The registry format was consensus driven and was approved by ChanreRICR Ethical Committee (EC-CRICR/SN-143/121A/2020 dated 9-12-2020). Waiver of consent was obtained. As the rheumatologists were not the primary treating physicians during COVID infection, data was extracted from outpatient or inpatient records and confirmed telephonically with treating physicians or patients. The data were extracted on December 1, 2020 from this ongoing registry as the first COVID peak showed signs of subsidence in India. Data quality assessment including a check on duplicates was performed. The audited data where there was mismatch in the probability were reconfirmed with the data provider. All data were anonymized and stored without revealing the patient's identity. Pediatric and geriatric populations were defined as those below 17 years and above 59 years, respectively, based on practice in India and cutoff by the United Nations.[11] The underlying RD diagnosis and disease flare were based on rheumatologist's opinion. Symptom review of COVID was retrieved retrospectively by recall. Details of outcome including death, and need for ventilatory support have been extracted from discharge summaries, interviews of treating physicians, and patients where feasible.

Inclusion criteria

All RD patients who report to the rheumatologists with confirmed COVID illness were enrolled (RT-PCR positive).

Exclusion criteria

COVID-like illness but COVID test results were negative.

Data analyses

The results of the data were analyzed using appropriate statistics. Normalcy of data was assessed and age was not normally distributed and hence was categorized. Continuous variables were expressed as mean with standard deviation (SD) and categorical variables expressed as number and percentage. The categorical variables were compared for significance (P < 0.05) using the Chi-square test using Social Science Statistics (https://www.socscistatistics.com/tests/Chi-square2/default2.aspx visited on 17/03/2021). Multivariate logistic regression was used to analyze the impact of different variables on mortality. Odds ratio and 95% confidence interval (CI) were used to define risk of need for ventilation and death. Odds ratio and 95% CI were calculated using MS Excel (Version: 2102 (16.0.13801.20266).


  Results Top


As of December 1, 2020, 447 RD and SARS-CoV2-infected patients' data were available. The mean age was 47.9 ± 14.4 years, including two children and 93 (20.8%) geriatric age group patients. Male: Female ratio was 0.4:1 and mean disease duration was 79.3 ± 77.1 months. Similar to COVID peak in India, the majority of patients were reported in September–November 2020 with maximum contribution from Karnataka and Kerala (n = 272 cases). Majority were homemakers (49.9%); other professions included public servants (7.2%) and health care professionals (4.7%). In a large majority, the underlying RD diagnosis was RA (38.1%), followed by systemic lupus erythematosus (SLE) (12.3%) and axial spondyloarthritis (AS) (7.9%) [Figure 1]. Seven patients were pregnant. The average of 1.46 close contacts was affected per patient.
Figure 1: Underlying rheumatological disorders in COVID-19 patients. Others included undifferentiated arthritis, fibromyalgia, primary antiphospholipid syndrome, degenerative joint disease, scleritis, and hidradenitis suppurativa

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Clinical profile of COVID patients and rheumatological disorders including disease flare

Fever and cough were the most common symptoms seen in our cohort [Figure 2]. One-fourth patients had loss of taste or smell. Mean (SD) hemoglobin, total leukocyte counts, absolute neutrophil, absolute lymphocyte count, and ferritin at the time of admission were 11.60 (2.07), 5405.87 (4658.3), 3564.91 (3919.58), 1427.58 (2116.15), and 333.44 (306.57), respectively. Underlying disease was quiescent in 54.7% and active in 18.4% patients at the time of COVID infection. However, accurate assessment of disease activity was not available in 25.1% patients. Most common medications at the time of COVID diagnosis were steroids (57.76%) and hydroxychloroquine (HCQ) (67.34%). Biological disease-modifying anti-rheumatic drugs (bDMARDs) and tofacitinib were used in 9.01% and 0.61% patients only [Table 1].
Figure 2: Symptomatology in patients with autoimmune rheumatic diseases expressed as percentage

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Table 1: Immunosuppressive agents at the time of COVID diagnosis

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Treating health-care professionals had stopped immunosuppressive agents in 42.5% patients during COVID infection and restarted them after a mean of 17.04 ± 9.56 days. A large majority had no other comorbid illness (58.7%). Hypertension (18.3%) and hypothyroidism (9.6%) were other frequent comorbidities in our cohort. Diabetes and other comorbidities including ischemic heart disease, carcinoma, and chronic kidney disease were seen in 6.5% and 5.3% population, respectively. In our cohort, 7.08% patients were obese (body mass index >29.99). A minority of the patients were on angiotensin-converting enzyme inhibitors (ACEi) (13.75%) and anti-platelet (8.33%).

Outcome

More than half of the patients (54.4%) needed hospitalization. Oxygen requirement was seen in 18.8%. Intensive care unit admission and invasive ventilation were needed in 6.0% and 2.9% patients, respectively. Complete recovery was seen in 94.9% of patients and 4.47% (n = 20) expired due to COVID (8 RA, 4 SLE, 2 AS, one each of Psoriatic Arthritis, Mixed connective tissue diseases and 4 others). Of the twenty who expired, three patients had active underlying RD at the time of death, 12 had inactive disease. Disease activity information was not available for five patients who expired. Two patients were still admitted at the time of data analyses. Three out of seventeen patients who needed ventilation showed complete recovery. All seven pregnant women showed complete recovery. The cause of death was not available in six patients (two died at home), 11 died due to respiratory failure and sepsis, and three due to multiorgan dysfunction syndrome. There was a suspicion of pulmonary embolism and myocarditis in one patient with respiratory failure.

None of the factors related to underlying RD including type and DMARDs, comorbidity affected COVID19 outcome [Table 2]. Dyspnea and a higher neutrophil count were significantly associated with death (P< 0.05, [Table 2]). Ferritin levels were higher in patients who expired (589.58 ± 113.99 ng/ml) when compared to survivors (321.64 ± 309.56 ng/ml) but did not reach statistical significance (P = 0.09).
Table 2: Impact of Rheumatic disease related and unrelated variables on death

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There was no significant difference when gender, disease duration, disease activity, use of steroids, bDMARDs, targeted synthetic DMARDs (tsDMARDs), ACEi/angiotensin receptor blockers (ARBs) were compared between patients needing ventilator versus those who did not need ventilator (data not shown).


  Discussion Top


Outbreak of SARS-CoV2 has affected populations all over the world with major concern for patients who have been immunocompromised. Collaboration across various rheumatic organizations has helped in allaying some of the concern but data from India were lacking. This work was an initiative of the IRA with a large cohort of 447 patients covering 14 states and 1 union territory. More than half of the patients were hospitalized and 4.47% died. The presence of comorbidities, dyspnea, and a higher neutrophil count was significantly associated with poor outcome. There were no increased risks associated with age, gender, smoking, pregnancy, and use of ACEi, conventional synthetic DMARDs, bDMARDs, tsDMARDs, type of RD, and disease activity status of underlying RD.

Most common rheumatic disease in the registry was akin to the prevalence of rheumatic disease. This was similar to the cohort reported by Global Rheumatology Alliance (GRA).[12] There was no impact of any specific underlying RD on COVID outcome. Mortality rate was higher than the general population in India (1.4%) but was less than the GRA cohort (9%) despite a higher rate of hospitalization in India. Higher rates of hospitalization may not be a true reflection of disease severity as admission policies have changed over time as we learnt more about the disease. Lower rate of mortality could be because of the higher proportion of patients in the younger age group, less intensive immunosuppression, lesser use of bDMARDS and tsDMARDs and lesser comorbidities in our cohort when compared to other reported cohort. However, none of these factors had any significant negative or positive association with mortality in our analyses. We will need more data to refute or establish this hypothesis. Death rate (3.3%) was similar to a survey conducted in 3136 patients across six tertiary referral centers by Saadoun et al.[13] In comparison, Fredi et al. in their observational study done at a single center, found 4.2% swab confirmed cases of COVID in 1525 patients with rheumatic and musculoskeletal diseases,[14] reported higher but similar mortality rate as general population (15% vs. 13.75%).[14],[15] This underlines the differences in mortality in different ethnic groups across the world. Differences in prevalence, age, management and type of RD, and sampling methods could be some of the factors, resulting in varied incidence and outcome of COVID. However, overall, there was no increased risk when compared to the general population.

A study by Zhong et al. however concluded that patients with RD might be more susceptible, with lower risk in HCQ users.[16] We did not find any difference in risk with use of HCQ. There have been conflicting results on the use of HCQ with Chen et al.[17] reporting faster time to clinical recovery but Jun.[18] and GRA[12] found no advantage in using HCQ similar to our results. Similarly, Monti et al. concluded there were no increased risks in patients with chronic arthritis on disease-modifying therapy.[19] Contrary to previous studies, we did not find any significant risk with the use of steroids or cDMARDS or bDMARDs.[12],[20] Contrary to our results, GRA in their recent data on 600 patients from 40 countries found glucocorticoid exposure of ≥10 mg/day to be associated with a higher odds of hospitalization and anti-tumor necrosis factor with a decreased odds of hospitalization. None of our patients were on IL6 inhibitors for underlying RD. We did not find any association of disease outcome with nonsteroidal anti-inflammatory drugs or ACEi or ARBs. ACE2 receptors on epithelial cells are a portal of entry for SARS-COV-2. Similar to our report, a meta-analysis of 10 studies found neither the risk of COVID nor severity of infection to be increased with the use of ACEi/ARBs.[21]

In the first few reports of COVID and RD, Favalli et al. reported three patients to have mild COVID in their survey of 530 patients in Italy with no mortality.[22] Subsequently, their updated survey did not find incidence or the complications to be different from the general population (0.62%, rheumatic diseases vs. 0.66%).[3] Williamson et al. observed that people with a diagnosis of RA, SLE or psoriasis, analysed as a combined group (5.1% of the study population), were (slightly) more likely to die in relation to COVID compared to people without one of these diagnoses.[23] Ye et al. found higher risk of respiratory failure in their cohort of rheumatic diseases when compared with the nonrheumatic population.[24] Respiratory failure was the most common cause of death in our series.

GRA had reported a median time to recovery or death of 13 days but we could not capture these details for most of our patients as the discharge policy has changed as the pandemic progressed. In the large majority of our patients, the immunosuppressive agents were withheld and were reinstituted in 1.5–4 weeks. Overall there is a variation in factors affecting disease outcome as more reports of COVID and RD emerge.

We believe that further results from the ongoing IRA registry will help to understand the differential risk of SARS-CoV2 infection and adverse outcome between various rheumatic diseases, the individual risk associated with use of various classes of immunosuppressants, as well as the long-term effects of COVID in this population.

This is the largest cohort from a single nation looking at the interface between RD and COVID. Homogeneity of the data, to a large extent, was ensured as data were entered into an online database using a predesigned capture form. All COVID cases were RT-PCR confirmed. Except for three cases, we had details on the status of disease outcome at the time of writing this paper.

Retrospective design of the study has its own limitations. Data capturing is voluntary, and not all IRA members were able to contribute due to institute restrictions and conversion of some hospitals to COVID hospitals; therefore, cases enrolled do not represent all possible cases. The distribution of age was not normal, and hence, we used different categories was another shortcoming. Another limitation was the lack of a control group containing patients with RD but without SARS-CoV2 infection. However, such analyses are really difficult as there are lack of details on preventive measures and elaborate primary care data.

However, this cohort can be considered a good representative sample. We might have captured more patients who had easy access to health care and were hospitalized but results indirectly add confidence that there was no increased case fatality rate for patients with RD when compared to other cohorts reported across the world and patients fared better when compared to other comorbidities such as diabetes, hypertension, and renal disease which resulted in higher deaths.

IRA Database is still capturing the data and is an ongoing effort. Results of these efforts indicate that patients with RD do not show increased mortality despite the current use of DMARDs/immunosuppressants.

[TAG:2]Conclusion [/TAG:2]

This is the largest cohort from a single nation looking at the interface between rheumatic diseases and COVID-19. The results indicate that patients with rheumatic diseases do not show increased mortality despite current use of disease-modifying anti-rheumatic drugs/immunosuppressants. None of the factors apart from presence of comorbidity and higher neutrophil count influenced the outcome.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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