|Year : 2022 | Volume
| Issue : 1 | Page : 4-9
Infections in systemic lupus erythematosus: A study of incidence and risk factors in 100 patients from western India
Ankan Jha1, Tridip Das2, Sunilkumar Rajmani Singh2, Jyotsna Oak2
1 Department of Endocrinology, Topiwala National Medical College and B. Y. L. Nair Charitable Hospital; Department of Medicine and Rheumatology, Kokilaben Dhirubhai Ambani Hospital, Mumbai, Maharashtra, India
2 Department of Medicine and Rheumatology, Kokilaben Dhirubhai Ambani Hospital, Mumbai, Maharashtra, India
|Date of Submission||31-Mar-2021|
|Date of Acceptance||13-Dec-2021|
|Date of Web Publication||27-Jan-2022|
Dr. Sunilkumar Rajmani Singh
Department of Rheumatology, Kokilaben Dhirubhai Ambani Hospital, Four Bungalows, Achutrao Patwardhan Marg, Andheri West, Mumbai - 400 053, Maharashtra
Source of Support: None, Conflict of Interest: None
Aim: The present study was conducted to evaluate the incidence and characteristics of infections in patients of systemic lupus erythematosus (SLE) and determine the risk factors for infection.
Materials and Methods: This is a prospective, observational study carried out at a single-center, tertiary care hospital. The study included all adult SLE patients diagnosed as per the revised American College of Rheumatology (ACR) criteria from January 2015 to October 2019. Episodes of infection and pathogens isolated were recorded.
Results: A total of 100 patients with SLE were evaluated (94 females and 6 males). Forty-seven (47%) patients suffered from 54 episodes of infection. Urinary tract infections were most common (31.48%), followed by skin and mucous membrane (27.78%). Escherichia coli (E. coli) was the most common organism isolated in 9 (16.8%) cases. Tuberculosis was seen in 6 (11.1%) patients. Forty-three (79.6%) patients had a SLE disease activity index score of more than 5 at the time of infection. Significant risk factors for infection included use of prednisolone, prednisolone dose higher than 10 mg, use of cyclophosphamide within the preceding 3 months of infections, use of other immunosuppressive agents, and leukopenia. Renal lupus and presence of comorbidities did not have a significant association with occurrence of infections. The relative risk of infections in SLE patients was 4.7 compared to non SLE controls.
Conclusion: Patients of SLE are at increased risk for various infections. Management of SLE needs vigilance for infection and judicious use of immunosuppressive drugs.
Keywords: Cyclophosphamide, infections, prednisolone, systemic lupus erythematosus, tuberculosis
|How to cite this article:|
Jha A, Das T, Singh SR, Oak J. Infections in systemic lupus erythematosus: A study of incidence and risk factors in 100 patients from western India. Indian J Rheumatol 2022;17:4-9
|How to cite this URL:|
Jha A, Das T, Singh SR, Oak J. Infections in systemic lupus erythematosus: A study of incidence and risk factors in 100 patients from western India. Indian J Rheumatol [serial online] 2022 [cited 2022 Aug 16];17:4-9. Available from: https://www.indianjrheumatol.com/text.asp?2022/17/1/4/336664
| Introduction|| |
Systemic lupus erythematosus (SLE) is an autoimmune disorder that is characterized by multi-system involvement and production of antibodies. Auto antibodies and immune complexes bind to tissues, resulting in widespread systemic manifestations.
There has been a considerable improvement in survival of patients with SLE due to early diagnosis and availability of more effective treatment.,, Immunosuppressive drugs have become the gold standard for the treatment of major organ involvement in SLE. However, patients on immunosuppressive therapy are predisposed to several infections that range from commoner ones to uncommon and opportunistic infections. Bacterial infections are most frequent followed by viral and fungal infections. The intrinsic immune dysfunction in patients with SLE, disease activity and the use of immunosuppressants to control the disease, increase their susceptibility to infections. Other risk factors include high anti-DNA titers, low complement levels, nephritis, and leukopenia. Infections also remain one of the commonest causes of mortality and morbidity in patients with SLE. Serious infections requiring hospitalization or intravenous antibiotics injection are associated with mortality and known to occur in 11%–45% of patients with SLE.
The incidence and type of infections vary in the developing countries. The endemicity of certain infections like tuberculosis, particularly increases the risk for such infections. There is a paucity of data regarding the overall risk of infections in SLE in India. There are also a limited number of studies that have evaluated controlled and prospective data to analyze the type of infection and related risk factors. The present study aims to analyze the incidence and characteristics of infections in SLE and also to determine the various related risk factors.
| Materials and Methods|| |
This is a prospective observational study carried out at a single-center, tertiary care hospital during January 2015 to October 2019. The study was approved by Institutional Scientific and ethics board, Kokilaben Dhirubhai Ambani Hospital, ISEB Code: C-3/63/2014 via letter dated 15th September 2014. The study included adult SLE patients, who fulfilled at least four criteria, as defined by the 1997 revised criteria of the American College of Rheumatology (ACR) and non SLE controls. Non SLE controls were patients of Rheumatoid arthritis (RA) who attended our outpatient department during the study period and fulfilled ACR criteria of RA. It included all patients with SLE who were on regular follow up visits at the outpatient department and also who were hospitalized as a consequence of complications of SLE or infections. The study was carried out after the approval of the ethics committee. Informed consents were taken from all patients who were willing to participate in this study. All patients were followed up in our department of Rheumatology every 3 months and earlier in case of an emergency.
Definition of infection
Infections were diagnosed by means of supportive clinical features and positive cultures and/or response to antibiotic therapy. When cultures of bacterial isolates were not available or negative, diagnosis of infections was made on the basis of clinical findings in combination with the antibiotic therapy response. The site of infection and the type of microorganism were recorded. In the absence of supportive data or whenever there was a doubt about the cause of symptoms, no infection was recorded.
Risk factors for infection
Risk factors such as disease activity at the time of infection (using mean SLE disease activity index [SLEDAI] score), presence of active lupus nephritis, presence or absence of leukopenia, average daily dose of prednisolone, use of cyclophosphamide in the preceding 3 months, and use of other immunosuppressive drugs like mycophenolate mofetil and azathioprine were noted for all the patients.
Disease activity at the time of infection was evaluated using SLEDAI.
A patient was considered to have a renal activity if they had a new onset and/or recent increase in proteinuria >0.5 g/24 h, hematuria-more than 5–10 red blood cells (RBCs) in high power field excluding stone infection or other causes, pyuria-more than 5 white blood cell in high power field after excluding infection, heme, granular or RBC casts. Renal biopsy was not done for all patients; hence, these data were not included.
Total leukocyte count during infections was recorded. Leukopenia was defined as a total White blood count <4000/cu mm. For comparison, those patients who did not develop infections during the course of study, their least leukocyte count during the study period was recorded.
Prednisolone use at the time of infection was noted. For comparison, the maximum dose of prednisolone during the study period in patients who did not develop infection was recorded. Based on the dose of prednisolone per day, patients were categorized into no prednisolone, <10 mg, between 10 and 20 mg and more than 20 mg.
Immunosuppressive agents at the time of infection were recorded. For comparison purposes, those who did not develop infections during the study period but were on immunosuppressants during the study period were considered. An association between cyclophosphamide use in the preceding 3 months and occurrence of infections was evaluated.
Infections in patients with SLE were compared with the control group of patients with RA to estimate the risk of infection in SLE patients. We included consecutive RA patients fulfilling ACR criteria during the same period of the study and collected the data of their demographic character and recorded the number of infections and hospitalizations due to infection. The risk factors for infection were determined by comparing the SLE patients who developed infection with those who did not develop any infection.
Data were collected using a case record form. Continuous variables are expressed as means with standard deviation and categorical variables as proportions or percentages. Data were analyzed using t-test, Fisher's exact test, and Chi square test. P < 0.05 was considered statistically significant.
Based on the literature, it was found that 40% of subjects having SLE had at least one infection. Expecting the 10% variation of this result, at 95% confidence interval, the sample size was 92. Rounding off this figure we took 100 patients as a sample size. Matched controls of 100 RA patients were compared with the SLE patients from January 2015 to October 2019.
| Results|| |
A total of 100 patients with SLE were evaluated which included 94 females and 6 males. The mean age was 37.04 years (standard deviation [SD] 14) in SLE patients and 42 years in controls. The median duration of SLE in these patients was 28 months (interquartile range [IQR] 36.25). During the period under study, 47 (47%) patients suffered from at least one infection. Out of these 47 patients, 5 patients suffered from 2 episodes of infection and 1 patient suffered from 3 episodes of infection. Hence, the total number of infections was 54. The median disease duration at time of infection was 41.5 (IQR 33). The median duration of follow up at the time of infection was 17 months (IQR 11).
Anatomical site involved
[Table 1] summarizes the anatomical sites of distribution among the total number of infections (n = 54). Urinary tract infection accounted for the majority of these infections, followed by skin and mucous membrane. [Table 2] describes the causative organisms in patients with infection. Escherichia More Details coli was the most common organism isolated. Candidiasis and Herpes zoster infection were based on clinical features. No cultures were available in 7 (12.96%) cases. There were no polymicrobial or multiple site infections.
|Table 1: Anatomical site involved in infections in patients with systemic lupus erythematosu (n=54)|
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|Table 2: Types of causative organisms in infections in patients with systemic lupus erythematosus (n=54)|
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Infection and immunosuppressive therapy
At the time of infection, 18 patients (33.33%) were on mycophenolate mofetil, while ten patients were on azathioprine. Two patients were receiving both methotrexate and azathioprine, while four were receiving methotrexate alone. Six patients had received cyclophosphamide infusion (500 mg) in the preceding 1 month. Fourteen cases (25.93%) of infection were not receiving any immunosuppressive therapy.
Among the SLE patients who did not develop any infection, eight were on immunosuppressants while 45 of them were not on any immunosuppressants. There was significant association (P < 0.001) between use of immunosuppressant and infections.
Infections and prednisolone
Out of 47 patients of SLE who developed infections, only one of them was not receiving prednisolone. Among 53 patients of SLE who did not develop infection, 24 of them were on prednisolone, while 29 of them were not on prednisolone at the time of infection. Three was a significant association (P < 0.0001) between prednisolone use and occurrence of infections.
The study also evaluated the relationship between dose of prednisolone and occurrence of infections in SLE patients. Out of the 47 SLE patients who developed infection, 16 were receiving doses of prednisolone more than 10 mg, was significant while only 5 of the total non-infected SLE patients were receiving prednisolone more than 10 mg. There was a significant association (P = 0.0025) between prednisolone dose of more than 10 mg/day and occurrence of infections in patients of SLE.
SLEDAI scores during infections
As evident from [Table 3], 43% of the patients had a SLEDAI score between 5 and 10, while 20 (37.04%) had a SLEDAI score more than 10.
|Table 3: Systemic lupus erythematosus disease activity index score during infection in patients with systemic lupus erythematosus|
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Renal lupus and risk of infection
Thirty-seven (78.7%) patients had evidence of active renal lupus during the onset of infections. Out of the 53 SLE patients who did not have infection, 37 (69.81%) had active renal lupus at some point during the study period. There was no significant association of infection with active renal lupus.
Presence of comorbidities
Diabetes Mellitus, hypertension and hypothyroidism and their association with infection was evaluated. There was no significant association with the presence of comorbidities (P = 0.943).
Comparison of systemic lupus erythematosus with rheumatoid arthritis
Hundred matched RA controls were studied during the study duration. The median duration of disease for RA was 18 months (IQR 12). Majority of them were on combination of disease modifying anti rheumatic drugs like methotrexate, hydroxychloroquine, and sulfasalazine while 12% had been on glucocorticoids. Relative risk for infection as compared to patients with RA was 4.7 [Table 4]. Out of the 10 infections in RA patients, 5 were urinary tract infections, 3 had upper respiratory tract infection while 1 had tuberculosis and 1 had viral gastroenteritis.
|Table 4: Comparison of infections in systemic lupus erythematosus and rheumatoid arthritis patients in our study|
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Mortality: Three SLE patients died during the study period due to systemic complications of SLE. No infection related death was seen.
| Discussion|| |
Infection is a frequent problem in patients with SLE and contributes significantly to morbidity and mortality. In this study of 100 patients with SLE, it was observed that patients with SLE have an increased risk of infection. The details of infection and associated risk factors were studied in a prospective manner.
Early diagnosis and advancement in therapeutic interventions has improved the survival in patients with SLE; however, infections still contribute significantly to the morbidity and mortality in these patients. This is particularly relevant to developing countries with high prevalence of infections. The female (F) to male (M) ratio in this study was 16:1. This is in contrast to the F:M ratio of 8:1 in the study from North India and similar to the ratio of 18:1 in the study from South India., The global female to male ratio of SLE ranges from 4.3-13.6, according to different studies. The mean age of patients suffering from infections was 37.04 years (SD = 14.0). Previous Indian studies have reported infections in relatively younger SLE patients. However, our findings were similar to that reported in the study from Brazil where the mean age of SLE patients with infection was 39 years. The demographic factors could also explain the higher incidence of urinary tract infections reported in several studies.
In this study, infections were seen in 47% of patients. In a retrospective study conducted by Shyam et al. from India, 26.5% of the patients were found to be suffering from at least one infection. However, a recent study from Mumbai reported a significantly higher incidence (80.7%) of infection. Bosch et al. reported 36% prevalence of infections in patients with SLE. In a prospective study by A Zonana-Nacach et al., out of 200 SLE outpatients, 65 (32%) had infections. The incidence of infection reported may vary depending on the geographic location, the endemicity of certain infections, the design of the study and the setting in which the study was performed. We found the relative risk of infection in our SLE patients to be 4.7 as compared to patients with RA. Bosch et al. in 2006 reported a relative risk of 1.63 (P < 0.05) in comparison to non-SLE controls who were outpatients with no risk factors of infection and attended at different departments in their hospital.
We had 54 episodes of infections with urinary tract infection being the most common (31.4%) followed by skin and mucous membrane (27.78%). Pulmonary infections were seen in 8 (14.81%) patients. In this study, the most frequent infections were bacterial (46%). Gram negative enteric bacilli affecting the urinary tract was most common. Escherichia coli was the most common organism isolated, seen in 9 (16.8%) cases. These results are similar to that reported by Zonana-Nacach et al. in which the most common sites of infections were urinary (26%), skin (23%) followed by systemic and vaginal. None of our patients had vaginal infections. The study by Bosch and et al. also revealed similar figures with skin and mucous membrane as the most common anatomical site involved (16%) followed by urinary tract (12.7%).
In a recent study from Mumbai, tuberculosis was the most common manifestation reported in 40 cases (29%) out of 139 patients with SLE. C. Shyam et al. also reported prevalence of tuberculosis to be 32% among the patients who had suffered from infections. We had six (11.1%) cases of tuberculosis of which two patients had extra pulmonary tuberculosis. In a study of 146 SLE patients from India, a prevalence of 11.6% was reported. In another study from India, tuberculosis was reported in 8.8% of SLE patients. Tuberculosis was seen in 5% of SLE patients in a study from Korea, while Bosch et al. from Spain reported tuberculosis in only 2% of their SLE patients. Higher prevalence of tuberculosis in Indian studies highlights the existing burden of tuberculosis in our country.
The following risk factors for infections were identified that were significant as a causation factor-use of prednisolone, prednisolone dose higher than 10 mg, use of cyclophosphamide within the preceding 3 months of infections, use of immunosuppressive agents such as mycophenolate, azathioprine and methotrexate and leukopenia. Other factors that were evaluated but did not have a significant association with occurrence of infections were presence of renal lupus and presence of comorbidities. The above results were consistent with results by Bosch et al. in which leukopenia, usage of prednisolone and prednisolone dose more than 20 mg was found to be a significant risk factor for infections. The study by Zonana-Nacach et al. found significant association between renal activity, prednisolone dose and intravenous cyclophosphamide. We also found a significant association between usage of cyclophosphamide in the preceding 3 months and occurrence of infections. However, in contrast to these studies, we did not find a significant association between renal lupus and occurrence of infections. This is similar to that reported by other studies from India., The association of azathioprine with an increased incidence of infections was noted by Lee et al. However, in a subsequent study by Ginzler et al., azathioprine was only associated with an increased incidence of herpes zoster in patients with SLE.
In the present study, 79.6% of the episodes of infection had a SLEDAI score of >5 at the time of infection, signifying moderate to very high disease activity. This is similar to the findings of Rajadhyaksha et al. from Mumbai. However, we have not performed a multivariate analysis to ascertain the contribution of various risk factors in development of infection. It is possible that SLE patients with higher disease activity may be on more immunosuppression which can itself lead to more infections. Zonana et al. found that the SLEDAI score of >4 was the only variable associated with infection in the multivariate analysis. However, a nested case control study by Irastroza et al. showed that SLEDAI score did not modify the risk of major infections in SLE patients. Borba et al. also reported that most episodes of Herpes zoster occurred during periods of remission.
Three SLE patients died during the period under study. However, deaths in these patients were due to systemic complications of SLE rather than infections. In a retrospective study, Kim and colleagues found that the most common cause of death in 544 Korean lupus patients was infection, mainly manifesting as Gram-negative bacterial sepsis. We had no infection related death. This could be due to the fact that we have included both hospitalized and outpatients and hence both minor and major infections have been included.
There are certain limitations in this study. The true incidence of infection may be affected due to the fact that certain infections may have been treated elsewhere and hence not documented. We have not compared the data on complement levels and SLEDAI score between SLE patients who developed infection and those who did not. Data on chemoprophylaxis and vaccination have not been included in our study and further prospective controlled studies are needed to look at the effectiveness of these strategies in Indian patients with SLE.
| Conclusion|| |
The present study suggests that patients of SLE appear to have an increased risk for various infections when compared to patients with RA. Urinary tract is the most common anatomical site involved followed by skin and mucous membrane. Escherichia coli is the most common organism isolated followed by Candida and Streptococcus pneumoniae. Risk factors significantly associated with infections include use of prednisolone more than 10 mg/day, use of immunosuppressive agents, leukopenia, and use of cyclophosphamide in the preceding 3 months.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4]