key: cord-0287073-lyuop5jv
authors: Brodin, Rakel; Desirée van der Werff, Suzanne; Hedberg, Pontus; Färnert, Anna; Nauclér, Pontus; Bergman, Peter; Requena-Méndez, Ana
title: The association between pre-exposure to glucocorticoids and other immunosuppressant drugs with severe COVID-19 outcomes
date: 2022-05-27
journal: nan
DOI: 10.1016/j.cmi.2022.05.014
sha: a979d2ab0b8f64fcca6af24f3675dd4768cf98e8
doc_id: 287073
cord_uid: lyuop5jv

Objectives Whether pre-infection use of immunosuppressant drugs is associated with COVID-19 severity remains unclear. The study was aimed to determine the association between pre-infection use of immunosuppressant drugs with COVID-19 outcomes within one month after COVID-19 diagnosis. Methods This cohort study included ≥18 years-old individuals with underlying conditions associated with an immunocompromised state and diagnosed with COVID-19 between February-2020 and January-2021 at Karolinska University Hospital, Stockholm. Exposure to immunosuppressant drugs was defined based on dose and duration of drugs (glucocorticoids, and drugs included in L01 or L04 chapter of ATC-classification) before COVID-19 diagnosis. Outcomes included hospital admission, ICU admission, mechanical ventilation, mortality, renal failure, stroke, pulmonary embolism, and cardiac event. Odds ratios(OR) were calculated using logistic regression and baseline covariate adjustment for confounding with inverse probability of treatment weights. Results Of 1067 included individuals, 444 were pre-exposed to immunosuppressive treatments before COVID-19 diagnosis (72 high-dose glucocorticoids, 255 L01 drugs(antineoplastics), 198 L04(other immunosuppressants) and 78 to multiple drugs). There was no association between pre-exposure and hospital admission (OR 0.83,[95%CI 0.64-1.09]) due to COVID-19. Pre-exposure to L01 or L04 drugs were not associated with hospital admission (aORs: 1.23[0.86-1.76] and 1.31[0.77-2.21) or other outcomes. High-dose glucocorticoids (≥20mg/day prednisolone equivalent) were associated with hospital admission (aOR 2.50[1.26-4.96]), cardiac events (aOR 1.93,[1.08-3.46]),pulmonary embolism (aOR 2.78[1.08-7.15]) and mortality (aOR 3.48,[1.77-6.86]) due to COVID-19. Conclusions Antineoplastic and other immunosuppressants drugs were not associated with COVID-19 severity whereas high-dose glucocorticoids were associated. Further studies should evaluate the effect of pre-exposure of different dose of glucocorticoids on COVID-19 prognosis.

COVID-19 severity (chronic kidney disease, lung disease, diabetes mellitus(DM), liver disease, cardiac 116 disease, and hypertension), using ICD-10 codes(Appendix 3). 117

Dichotomous variables were described as frequencies and percentages. Age was included as a 119 continuous variable, but a restriction to <70 years-old was pre-determined. Clinical characteristics of 120 the cohort were assessed, with standardized mean difference <0.1 considered as well balanced. 121

Logistic regression models were used to estimate unadjusted and adjusted(weighted) odds 122 ratios(95%CI) of the outcomes for exposed compared to unexposed patients. We analysed 123 subgroups of immunosuppressant drugs fitting separate models, including the exposure to different 124 doses of glucocorticoids. 125

Inverse probability of treatment weighting(IPTW) model was used to adjust for observed differences 126 between the exposed and unexposed cohorts. Each individual's propensity score(PS) was estimated 127 based on known confounders (age, sex, underlying conditions, and other comorbidities such as 128 hypertension cardiac disease, or DM),(Appendix 3). 129

Missing data were considered for the outcomes evaluated with laboratory parameters(AKI and ACE) 130 and a complete case analysis approach was planned. 131

In the sensitivity analysis, we restricted the cohort to individuals with underlying conditions 132 diagnosed <2.5 years before COVID-19; a stricter definition of cardiac events was used(TnT>50ng/l) 133 considering potential elevation of TnT for other reasons, and differences between first and second 134 phase of the pandemic (cut-off 15-August 2020)were investigated [13] . 135

Data management and analysis were performed using . 136

Ethical approval was obtained by the Stockholm Ethical Review Board (Dnr-2018 (Dnr- /1030 with 137 amendment for COVID-19(Dnr-2020-01385) . The study adheres to the Strengthening the Reporting 138 of Observational Studies in Epidemiology(STROBE),(Appendix 4). 139

Between 27-February-2020 and 15-January-2021, 7929 patients were diagnosed with COVID-19. Of 141 them, 1735 patients had underlying diseases associated with an immunocompromised state. After 142 screening for eligibility, 668 patients were excluded due to not fulfilling inclusion criteria, leaving 143 1067 individuals for the final study population (Figure 1) . 144

The median age was 64 years(IQR 51-75) and 45.2%(482/1067) were female. A cancer diagnosis was 145 identified among 46.1%(492/1067), autoimmune diseases in 28.6%(305/1067), haematological 146 conditions in 15.0%(160/1067) and solid organ transplants in 10.3%(110/1067). Among 147 41.5%(444/1067) patients fulfilling the criteria for exposure to immunosuppressive treatment 148 (immunosuppressant drugs detailed in Appendix 5), 45.7%(203/444) were female, the median age 149 was 61(IQR 50-71 years) and 78(17.6%) were exposed to multiple immunosuppressant drugs. 150

Patients without any immunosuppressive treatment were slightly older (median age 66, IQR 53-78 151 years) and had a non-significant lower proportion of female patients (44.8%(279/623,p-152 value=0.762), (Table 1) . 153

There were 772 hospitalized patients, with a median temperature of 37.4C°(36.8-38.1), median 154 respiratory rate of 20 breaths/minute (17-24) and median oxygen saturation of 96%(94-98). 155

Pre-exposure to any immunosuppressant drug and COVID-19 outcomes 156

No significant association was found between exposure to immunosuppressive treatments and 157 hospital admission, ICU admission, mechanical ventilation, acute renal failure, cardiac events, 158 pulmonary embolism, or mortality, in both unadjusted and adjusted analyses (Table 2) . Similarly, 159 after IPTW, there were no statistically significant differences in the odds of any of the outcomes 160 among individuals with chronic immunosuppression and their counterparts, compared to unexposed 161 individuals (Appendix 6). When limiting the cohort to individuals <70 years, acute cardiac events 162 were significantly associated with exposure to immunosuppressive treatments (adjusted OR(aOR) 163 Exposure to low dose or to high dose but recurrent and short treatment with glucocorticoids (i.e., 179 cancer patients administered glucocorticoids before chemotherapy) was not significantly associated 180 with any of the outcomes in the adjusted analysis. However, the test for trend showed an increasing 181 odd of hospital admission, ICU admission, cardiac event and mortality when increasing the dose of 182 glucocorticoids (Table 3) . 183

In the analysis by categories of underlying categories, high dose of glucocorticoids was associated 184 with higher mortality in cancer and autoimmune diseases patients; hospital and intensive care 185 admission were also associated with autoimmune diseases(Appendix 8). 186

No association was found between treatment with antineoplastic drugs(L01) and COVID-19 188 outcomes, neither in unadjusted nor adjusted logistic regression( Figure 2 and Table 4 ). 189

Exposure to immunosuppressants(L04) was associated with a higher ICU admission in the entire 190 cohort (OR 1.69,[95%CI 1.02-2.81]), and with a lower percentage of pulmonary embolism (OR 191 0.17, ). However, these findings were not observed in the adjusted analysis. No 192 associations were found in the adjusted analysis in <70 years-old individuals (Table 4) . 193

Using a stricter definition of a cardiac event(TnT>50), no association was found between exposure to 195 immunosuppressive treatments and cardiac events in unadjusted analysis (OR 0.73, being consistent with the adjusted analysis. Conversely, the aOR of acute kidney injury was 210 J o u r n a l P r e -p r o o f 0.35(95%CI 0.14-0.89) and the aOR of cardiac events 0.51(95%CI 0.29-0.91) among cancer patients 211 compared to transplant patients,(Appendix 13). 212

In this cohort-study, antineoplastic agents (L01 chapter of ATC classification) and other type of 214 immunosuppressant drugs (L04 chapter) were not associated with worse COVID-19 outcomes. 215

However, we observed that high-dose glucocorticoids were associated with an increased odds of 216 hospital admission, cardiac events, pulmonary embolism, and mortality independently of the 217 treatment with other immunosuppressant drugs. These results were also consistent in individuals 218 <70 years-old, although an association between low-dose glucocorticoids and COVID-19 outcomes 219 did not reach statistical significance. 220

Overall, we did not find any association between immunosuppressed individuals with severe COVID-221 19 outcomes. However, in individuals <70 years-old, the expose to immunosuppressant drugs was 222 significantly associated with the odds of having a cardiac event. This association was not observed in 223 the sensitivity analysis restricted to higher cut-off(TnT>50ng/l). Other factors may also contribute to 224 mild increase of TnT, such as the viral disease per se that may exerts temporary cardiac disfunction 225 as described in other viral infections such as H7N9 [14] The lack of association between immunosuppressant drugs and severe COVID-19 outcomes has been 231 also reported in another study [7] . However, grouping the drugs into only two classes may have 232 precluded detection of associations with individual drugs. Also, although the concomitant use of 233 immunosuppressant drugs and the elderly age further increases the risk of infections[25], we did not 234 find this association in the adjusted regression analysis.

One study on individuals with inflammatory bowel disease, found an association between 236 glucocorticoids exposure and a poor outcome, although the cut-off dose of glucocorticoids was not 237 indicated [20] . Another cohort study also found a worsened prognosis of SARS-CoV-2 infection in 238 those exposed to >7.5mg/day equivalent of prednisolone [21] . In our study, we defined the exposure 239 to high-dose glucocorticoids based on CDC recommendations, which state that below 20mg/day, 240 there is no major increased risk of developing severe complications from a viral infection and 241 therefore allowing the use of attenuated live vaccines [12] . 242

The harmful effect of chronic exposure to glucocorticoids could be particularly related to the 243 suppression of immune T-cells response; consequently, patients may not manifest common signs 244 and symptoms of infection as clearly [23] leading to a failure in early recognition of infection [24] . 245

However, the association with glucocorticoids but not with other immunosuppressants and COVID-246 19, may be driven by the severity of the underlying disease stage. This may differ depending on the 247 type of disease, since multiple studies reported a higher mortality in transplant patients [26] and 248 haematological cancer [27] . In our study, transplant patients were less likely to be hospitalized 249 whereas were associated with an increased odds of ICU admission. This discrepancy could be 250 justified because we included outpatient visits and phone call from long-term and well controlled 251 transplant patients who did not require hospitalization and also because advanced cancer patients 252 are not usually candidates for intensive care. 253

First, although the study included over 1000 individuals, the sample size precluded a proper analysis 255 among different categories of underlying conditions which may increase the hospitalization risk 256 itself. We tried to overcome this bias by including only individuals with underlying conditions and we 257 also considered IPTW adjustment, finding consistent results regardless of analytic strategy. 258

While we adjusted for a range of covariates, other unmeasured factors may drive the association 259 between steroid use and the COVID-19 outcome(residual cofounding). We did not study other 260 outcomes associated with the use of glucocorticoids such as sepsis [28, 29] . 261 Data were not collected for the purpose of this study. Hence, the reasons of the outcomes were not 262 ascertained and could be others than COVID-19. We added other indirect indicators of COVID-19 263 such as blood temperature, respiratory rate, or oxygen in hospitalized patients, what did not show 264 any difference among exposed and non-exposed patients. Furthermore, by limiting the follow-up 265 period to one month from COVID-19 diagnosis, overestimation of COVID-19 outcomes is assumed to 266 be minimal. Finally, a potential misclassification of exposed individuals for which the 267 immunosuppressant therapy was not properly registered cannot be ruled out. 268

Our cohort contains local data from a Swedish tertiary centre but it includes outpatients and 269 telephonically followed-up patients. Hoek Non pre-exposure 1 n=623 p-value Absolute standardized mean difference between exposed and non-exposed 

Leucocyte count (n=771) 7.4 (5.2-11.1) 6.8 (4.9-9) 5.6 (3.8-7.8) 6.8 (5.4-8.9) 6.2 (4.4-8.5) 6.7 (5.5-9) 0.016 0.23 6.4 (5-8. Categorical variables described as frequency (%); Continuous variables are described as median (IQR); Abbreviation: L01= Antineoplastic agents included in the L01 chapter of the Anatomical Therapeutic Chemical (ATC ) classification; L04= Other immunosuppressants drugs included in the chapter L04 of the ATC classification; BMI=Body Mass Index; AST=aspartate aminotransferase; ALT=alanine aminotransferase; ALP=alkaline phosphatase. Lab parameters refers to pre COVID-19 value. Leucocytes x109/L; Severe neutropenia considered with those under 0.5 x109/L neutrophils; Lymphopenia <0.1 x109/L lymphocytes; Haemoglobin g/L; Creatinine µmol/L; AST µkat/L; ALT µkat/L; ALP µkat/L; Vitals signs refers to first value at hospital admission; Body temperature: degree Celsius; Respiratory rate: breaths/minute; Saturation; % oxygen; Number of visits refers to total amount of hospitalization or visits to outpatient clinic within past year before COVID-19; 1 Pre-exposure definition: prednisolone ≥20mg/day or equivalent (ATC class H02) for at least 15 days during past month, rituximab and alemtuzumab during the past six months, all others(ATC classes L01 and L04, excluding rituximab and alemtuzumab) during the past 3 months; 2 Three individuals with a history of organ transplant, organ rejection and now on the waiting list for a new transplant, therefore unexposed. For the other individual, the reason for unexposed treatment could not be further evaluated. 3. n= 157; 4. n=307; 5. n=435; 6. n=130; 7. n=309; 8. n=441 

low and high dose; a: p-value calculated using chi-square test; b: Adjusted for age, sex, cardiac disease, hypertension, number of outpatient visits within past year, underlying condition and if treated with other immunosuppressant drugs (L01 or L04); c: Including age as quadratic variable in adjusted model; d: Test for trend showed significant increasing trend of the association between dose of glucocorticoids with hospital admission (p-value= 0.008), cardiac event (p-value=0.029) and mortality (p-value=0.01) in the entire cohort and with hospital admission (p-value=0.020), ICU admission (p-value=0.041), cardiac event (p-value=0.10) and mortality (p-value=0.001) in the <70 years-old cohort; e: Analysis on acute renal failure was restricted to hospitalized patients was performed using the KDIGO algorithm; Doses of glucocorticoids defined as: No treatment: Treatment with L01, L04 or no treatment, Low dose: <20mg/ day equivalent to prednisone or recurrent high dose